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File Attachment

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Discovering Odors

Series Editor Marie-Christine Maurel

Discovering Odors

Geacuterard Brand

First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley amp Sons Inc

Apart from any fair dealing for the purposes of research or private study or criticism or review as permitted under the Copyright Designs and Patents Act 1988 this publication may only be reproduced stored or transmitted in any form or by any means with the prior permission in writing of the publishers or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address

ISTE Ltd John Wiley amp Sons Inc 27-37 St Georgersquos Road 111 River Street London SW19 4EU Hoboken NJ 07030 UK USA

wwwistecouk wwwwileycom

copy ISTE Ltd 2019 The rights of Geacuterard Brand to be identified as the author of this work have been asserted by him in accordance with the Copyright Designs and Patents Act 1988

Library of Congress Control Number 2019947394 British Library Cataloguing-in-Publication Data A CIP record for this book is available from the British Library ISBN 978-1-78630-521-3

Contents

Preface ix

Chapter 1 Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell 1

Chapter 2 A Nobel Prize for the Nose and Retraction in Science 5

Chapter 3 Sperm and Lily of the Valley 9

Chapter 4 Vibrational Theory and the Astonishing Story of Researcher Luca Turin 13

Chapter 5 The Famous Madeleines The Proust Phenomenon a Scientific Spoliation 17

Chapter 6 The Smell of Rain 21

Chapter 7 The Neanderthal Nose 25

Chapter 8 Mr and Mrs Kallmann Have a Son When Losing Your Nose and Losing Your Gonads Go Hand in Hand 29

Chapter 9 Whiplash or Losing Your Sense of Smell Following a Head Injury 33

vi Discovering Odors

Chapter 10 Phantom Odors 37

Chapter 11 These Odors That Make Your Head Hurt 41

Chapter 12 The Sleeperrsquos Nose 45

Chapter 13 Surstroumlmming The Worst Odor in the World 49

Chapter 14 It Smells Like Cheese 53

Chapter 15 What Fennel Reveals to Us 57

Chapter 16 Mustard Goes Up My Nose and Onions Make Me Cry Discovering a Third Unknown Chemical Sense 61

Chapter 17 Lavender at the Dentist Aromatherapy a Myth or a Reality 65

Chapter 18 Catnip and Pregnant Women Some Variations in Sensitivity to Odors 69

Chapter 19 If You Eat Too Much Fat You Will Lose Your Sense of Smell 73

Chapter 20 Expertsrsquo Noses 77

Chapter 21 Filled with Smells 81

Chapter 22 Obesity and Chocolate 85

Chapter 23 The Nose on the Plate A Difficult Scientific Consensus 89

Chapter 24 The Smell of a Hot Croissant When Our Sense of Smell Nibbles Away at Our Free Will 93

Chapter 25 The Dog That Sniffs Out Cancer 97

Contents vii

Chapter 26 Smells to Cure Cancer 101

Chapter 27 A Depressed Patientrsquos Nose 105

Chapter 28 Gogolrsquos Nose or ldquoEmpty Noserdquo Syndrome 109

Chapter 29 She Smells Parkinsonrsquos 113

Chapter 30 And What Does Parkinsonrsquos Smell Like 117

Chapter 31 Alzheimerrsquos Nose Losing Sense of Smell and Losing Memory the Same Story 121

Chapter 32 The Smell of Old People 125

Chapter 33 The Smell of Death 129

Chapter 34 Red Meat Garlic and Sex Appeal 133

Chapter 35 Tears and Desire Stop Crying it Doesnrsquot Turn Me On Anymore 137

Chapter 36 With a Bad Nose Comes a Poor Flirt 141

Chapter 37 Itrsquos All in the Sweat 143

Chapter 38 The Smell of Fear 147

Chapter 39 What Epigenetics Owes to the Nose How Fear Learned From an Odor can be Transmitted to Offspring 151

Chapter 40 Odor and Pain 155

Chapter 41 Odorology 159

Chapter 42 On the Trail of Odors 163

Chapter 43 The Electronic Nose 167

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Discovering Odors

Series Editor Marie-Christine Maurel

Discovering Odors

Geacuterard Brand

First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley amp Sons Inc

Apart from any fair dealing for the purposes of research or private study or criticism or review as permitted under the Copyright Designs and Patents Act 1988 this publication may only be reproduced stored or transmitted in any form or by any means with the prior permission in writing of the publishers or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address

ISTE Ltd John Wiley amp Sons Inc 27-37 St Georgersquos Road 111 River Street London SW19 4EU Hoboken NJ 07030 UK USA

wwwistecouk wwwwileycom

copy ISTE Ltd 2019 The rights of Geacuterard Brand to be identified as the author of this work have been asserted by him in accordance with the Copyright Designs and Patents Act 1988

Library of Congress Control Number 2019947394 British Library Cataloguing-in-Publication Data A CIP record for this book is available from the British Library ISBN 978-1-78630-521-3

Contents

Preface ix

Chapter 1 Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell 1

Chapter 2 A Nobel Prize for the Nose and Retraction in Science 5

Chapter 3 Sperm and Lily of the Valley 9

Chapter 4 Vibrational Theory and the Astonishing Story of Researcher Luca Turin 13

Chapter 5 The Famous Madeleines The Proust Phenomenon a Scientific Spoliation 17

Chapter 6 The Smell of Rain 21

Chapter 7 The Neanderthal Nose 25

Chapter 8 Mr and Mrs Kallmann Have a Son When Losing Your Nose and Losing Your Gonads Go Hand in Hand 29

Chapter 9 Whiplash or Losing Your Sense of Smell Following a Head Injury 33

vi Discovering Odors

Chapter 10 Phantom Odors 37

Chapter 11 These Odors That Make Your Head Hurt 41

Chapter 12 The Sleeperrsquos Nose 45

Chapter 13 Surstroumlmming The Worst Odor in the World 49

Chapter 14 It Smells Like Cheese 53

Chapter 15 What Fennel Reveals to Us 57

Chapter 16 Mustard Goes Up My Nose and Onions Make Me Cry Discovering a Third Unknown Chemical Sense 61

Chapter 17 Lavender at the Dentist Aromatherapy a Myth or a Reality 65

Chapter 18 Catnip and Pregnant Women Some Variations in Sensitivity to Odors 69

Chapter 19 If You Eat Too Much Fat You Will Lose Your Sense of Smell 73

Chapter 20 Expertsrsquo Noses 77

Chapter 21 Filled with Smells 81

Chapter 22 Obesity and Chocolate 85

Chapter 23 The Nose on the Plate A Difficult Scientific Consensus 89

Chapter 24 The Smell of a Hot Croissant When Our Sense of Smell Nibbles Away at Our Free Will 93

Chapter 25 The Dog That Sniffs Out Cancer 97

Contents vii

Chapter 26 Smells to Cure Cancer 101

Chapter 27 A Depressed Patientrsquos Nose 105

Chapter 28 Gogolrsquos Nose or ldquoEmpty Noserdquo Syndrome 109

Chapter 29 She Smells Parkinsonrsquos 113

Chapter 30 And What Does Parkinsonrsquos Smell Like 117

Chapter 31 Alzheimerrsquos Nose Losing Sense of Smell and Losing Memory the Same Story 121

Chapter 32 The Smell of Old People 125

Chapter 33 The Smell of Death 129

Chapter 34 Red Meat Garlic and Sex Appeal 133

Chapter 35 Tears and Desire Stop Crying it Doesnrsquot Turn Me On Anymore 137

Chapter 36 With a Bad Nose Comes a Poor Flirt 141

Chapter 37 Itrsquos All in the Sweat 143

Chapter 38 The Smell of Fear 147

Chapter 39 What Epigenetics Owes to the Nose How Fear Learned From an Odor can be Transmitted to Offspring 151

Chapter 40 Odor and Pain 155

Chapter 41 Odorology 159

Chapter 42 On the Trail of Odors 163

Chapter 43 The Electronic Nose 167

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Series Editor Marie-Christine Maurel

Discovering Odors

Geacuterard Brand

First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley amp Sons Inc

Apart from any fair dealing for the purposes of research or private study or criticism or review as permitted under the Copyright Designs and Patents Act 1988 this publication may only be reproduced stored or transmitted in any form or by any means with the prior permission in writing of the publishers or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address

ISTE Ltd John Wiley amp Sons Inc 27-37 St Georgersquos Road 111 River Street London SW19 4EU Hoboken NJ 07030 UK USA

wwwistecouk wwwwileycom

copy ISTE Ltd 2019 The rights of Geacuterard Brand to be identified as the author of this work have been asserted by him in accordance with the Copyright Designs and Patents Act 1988

Library of Congress Control Number 2019947394 British Library Cataloguing-in-Publication Data A CIP record for this book is available from the British Library ISBN 978-1-78630-521-3

Contents

Preface ix

Chapter 1 Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell 1

Chapter 2 A Nobel Prize for the Nose and Retraction in Science 5

Chapter 3 Sperm and Lily of the Valley 9

Chapter 4 Vibrational Theory and the Astonishing Story of Researcher Luca Turin 13

Chapter 5 The Famous Madeleines The Proust Phenomenon a Scientific Spoliation 17

Chapter 6 The Smell of Rain 21

Chapter 7 The Neanderthal Nose 25

Chapter 8 Mr and Mrs Kallmann Have a Son When Losing Your Nose and Losing Your Gonads Go Hand in Hand 29

Chapter 9 Whiplash or Losing Your Sense of Smell Following a Head Injury 33

vi Discovering Odors

Chapter 10 Phantom Odors 37

Chapter 11 These Odors That Make Your Head Hurt 41

Chapter 12 The Sleeperrsquos Nose 45

Chapter 13 Surstroumlmming The Worst Odor in the World 49

Chapter 14 It Smells Like Cheese 53

Chapter 15 What Fennel Reveals to Us 57

Chapter 16 Mustard Goes Up My Nose and Onions Make Me Cry Discovering a Third Unknown Chemical Sense 61

Chapter 17 Lavender at the Dentist Aromatherapy a Myth or a Reality 65

Chapter 18 Catnip and Pregnant Women Some Variations in Sensitivity to Odors 69

Chapter 19 If You Eat Too Much Fat You Will Lose Your Sense of Smell 73

Chapter 20 Expertsrsquo Noses 77

Chapter 21 Filled with Smells 81

Chapter 22 Obesity and Chocolate 85

Chapter 23 The Nose on the Plate A Difficult Scientific Consensus 89

Chapter 24 The Smell of a Hot Croissant When Our Sense of Smell Nibbles Away at Our Free Will 93

Chapter 25 The Dog That Sniffs Out Cancer 97

Contents vii

Chapter 26 Smells to Cure Cancer 101

Chapter 27 A Depressed Patientrsquos Nose 105

Chapter 28 Gogolrsquos Nose or ldquoEmpty Noserdquo Syndrome 109

Chapter 29 She Smells Parkinsonrsquos 113

Chapter 30 And What Does Parkinsonrsquos Smell Like 117

Chapter 31 Alzheimerrsquos Nose Losing Sense of Smell and Losing Memory the Same Story 121

Chapter 32 The Smell of Old People 125

Chapter 33 The Smell of Death 129

Chapter 34 Red Meat Garlic and Sex Appeal 133

Chapter 35 Tears and Desire Stop Crying it Doesnrsquot Turn Me On Anymore 137

Chapter 36 With a Bad Nose Comes a Poor Flirt 141

Chapter 37 Itrsquos All in the Sweat 143

Chapter 38 The Smell of Fear 147

Chapter 39 What Epigenetics Owes to the Nose How Fear Learned From an Odor can be Transmitted to Offspring 151

Chapter 40 Odor and Pain 155

Chapter 41 Odorology 159

Chapter 42 On the Trail of Odors 163

Chapter 43 The Electronic Nose 167

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

First published 2019 in Great Britain and the United States by ISTE Ltd and John Wiley amp Sons Inc

Apart from any fair dealing for the purposes of research or private study or criticism or review as permitted under the Copyright Designs and Patents Act 1988 this publication may only be reproduced stored or transmitted in any form or by any means with the prior permission in writing of the publishers or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address

ISTE Ltd John Wiley amp Sons Inc 27-37 St Georgersquos Road 111 River Street London SW19 4EU Hoboken NJ 07030 UK USA

wwwistecouk wwwwileycom

copy ISTE Ltd 2019 The rights of Geacuterard Brand to be identified as the author of this work have been asserted by him in accordance with the Copyright Designs and Patents Act 1988

Library of Congress Control Number 2019947394 British Library Cataloguing-in-Publication Data A CIP record for this book is available from the British Library ISBN 978-1-78630-521-3

Contents

Preface ix

Chapter 1 Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell 1

Chapter 2 A Nobel Prize for the Nose and Retraction in Science 5

Chapter 3 Sperm and Lily of the Valley 9

Chapter 4 Vibrational Theory and the Astonishing Story of Researcher Luca Turin 13

Chapter 5 The Famous Madeleines The Proust Phenomenon a Scientific Spoliation 17

Chapter 6 The Smell of Rain 21

Chapter 7 The Neanderthal Nose 25

Chapter 8 Mr and Mrs Kallmann Have a Son When Losing Your Nose and Losing Your Gonads Go Hand in Hand 29

Chapter 9 Whiplash or Losing Your Sense of Smell Following a Head Injury 33

vi Discovering Odors

Chapter 10 Phantom Odors 37

Chapter 11 These Odors That Make Your Head Hurt 41

Chapter 12 The Sleeperrsquos Nose 45

Chapter 13 Surstroumlmming The Worst Odor in the World 49

Chapter 14 It Smells Like Cheese 53

Chapter 15 What Fennel Reveals to Us 57

Chapter 16 Mustard Goes Up My Nose and Onions Make Me Cry Discovering a Third Unknown Chemical Sense 61

Chapter 17 Lavender at the Dentist Aromatherapy a Myth or a Reality 65

Chapter 18 Catnip and Pregnant Women Some Variations in Sensitivity to Odors 69

Chapter 19 If You Eat Too Much Fat You Will Lose Your Sense of Smell 73

Chapter 20 Expertsrsquo Noses 77

Chapter 21 Filled with Smells 81

Chapter 22 Obesity and Chocolate 85

Chapter 23 The Nose on the Plate A Difficult Scientific Consensus 89

Chapter 24 The Smell of a Hot Croissant When Our Sense of Smell Nibbles Away at Our Free Will 93

Chapter 25 The Dog That Sniffs Out Cancer 97

Contents vii

Chapter 26 Smells to Cure Cancer 101

Chapter 27 A Depressed Patientrsquos Nose 105

Chapter 28 Gogolrsquos Nose or ldquoEmpty Noserdquo Syndrome 109

Chapter 29 She Smells Parkinsonrsquos 113

Chapter 30 And What Does Parkinsonrsquos Smell Like 117

Chapter 31 Alzheimerrsquos Nose Losing Sense of Smell and Losing Memory the Same Story 121

Chapter 32 The Smell of Old People 125

Chapter 33 The Smell of Death 129

Chapter 34 Red Meat Garlic and Sex Appeal 133

Chapter 35 Tears and Desire Stop Crying it Doesnrsquot Turn Me On Anymore 137

Chapter 36 With a Bad Nose Comes a Poor Flirt 141

Chapter 37 Itrsquos All in the Sweat 143

Chapter 38 The Smell of Fear 147

Chapter 39 What Epigenetics Owes to the Nose How Fear Learned From an Odor can be Transmitted to Offspring 151

Chapter 40 Odor and Pain 155

Chapter 41 Odorology 159

Chapter 42 On the Trail of Odors 163

Chapter 43 The Electronic Nose 167

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Contents

Preface ix

Chapter 1 Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell 1

Chapter 2 A Nobel Prize for the Nose and Retraction in Science 5

Chapter 3 Sperm and Lily of the Valley 9

Chapter 4 Vibrational Theory and the Astonishing Story of Researcher Luca Turin 13

Chapter 5 The Famous Madeleines The Proust Phenomenon a Scientific Spoliation 17

Chapter 6 The Smell of Rain 21

Chapter 7 The Neanderthal Nose 25

Chapter 8 Mr and Mrs Kallmann Have a Son When Losing Your Nose and Losing Your Gonads Go Hand in Hand 29

Chapter 9 Whiplash or Losing Your Sense of Smell Following a Head Injury 33

vi Discovering Odors

Chapter 10 Phantom Odors 37

Chapter 11 These Odors That Make Your Head Hurt 41

Chapter 12 The Sleeperrsquos Nose 45

Chapter 13 Surstroumlmming The Worst Odor in the World 49

Chapter 14 It Smells Like Cheese 53

Chapter 15 What Fennel Reveals to Us 57

Chapter 16 Mustard Goes Up My Nose and Onions Make Me Cry Discovering a Third Unknown Chemical Sense 61

Chapter 17 Lavender at the Dentist Aromatherapy a Myth or a Reality 65

Chapter 18 Catnip and Pregnant Women Some Variations in Sensitivity to Odors 69

Chapter 19 If You Eat Too Much Fat You Will Lose Your Sense of Smell 73

Chapter 20 Expertsrsquo Noses 77

Chapter 21 Filled with Smells 81

Chapter 22 Obesity and Chocolate 85

Chapter 23 The Nose on the Plate A Difficult Scientific Consensus 89

Chapter 24 The Smell of a Hot Croissant When Our Sense of Smell Nibbles Away at Our Free Will 93

Chapter 25 The Dog That Sniffs Out Cancer 97

Contents vii

Chapter 26 Smells to Cure Cancer 101

Chapter 27 A Depressed Patientrsquos Nose 105

Chapter 28 Gogolrsquos Nose or ldquoEmpty Noserdquo Syndrome 109

Chapter 29 She Smells Parkinsonrsquos 113

Chapter 30 And What Does Parkinsonrsquos Smell Like 117

Chapter 31 Alzheimerrsquos Nose Losing Sense of Smell and Losing Memory the Same Story 121

Chapter 32 The Smell of Old People 125

Chapter 33 The Smell of Death 129

Chapter 34 Red Meat Garlic and Sex Appeal 133

Chapter 35 Tears and Desire Stop Crying it Doesnrsquot Turn Me On Anymore 137

Chapter 36 With a Bad Nose Comes a Poor Flirt 141

Chapter 37 Itrsquos All in the Sweat 143

Chapter 38 The Smell of Fear 147

Chapter 39 What Epigenetics Owes to the Nose How Fear Learned From an Odor can be Transmitted to Offspring 151

Chapter 40 Odor and Pain 155

Chapter 41 Odorology 159

Chapter 42 On the Trail of Odors 163

Chapter 43 The Electronic Nose 167

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

vi Discovering Odors

Chapter 10 Phantom Odors 37

Chapter 11 These Odors That Make Your Head Hurt 41

Chapter 12 The Sleeperrsquos Nose 45

Chapter 13 Surstroumlmming The Worst Odor in the World 49

Chapter 14 It Smells Like Cheese 53

Chapter 15 What Fennel Reveals to Us 57

Chapter 16 Mustard Goes Up My Nose and Onions Make Me Cry Discovering a Third Unknown Chemical Sense 61

Chapter 17 Lavender at the Dentist Aromatherapy a Myth or a Reality 65

Chapter 18 Catnip and Pregnant Women Some Variations in Sensitivity to Odors 69

Chapter 19 If You Eat Too Much Fat You Will Lose Your Sense of Smell 73

Chapter 20 Expertsrsquo Noses 77

Chapter 21 Filled with Smells 81

Chapter 22 Obesity and Chocolate 85

Chapter 23 The Nose on the Plate A Difficult Scientific Consensus 89

Chapter 24 The Smell of a Hot Croissant When Our Sense of Smell Nibbles Away at Our Free Will 93

Chapter 25 The Dog That Sniffs Out Cancer 97

Contents vii

Chapter 26 Smells to Cure Cancer 101

Chapter 27 A Depressed Patientrsquos Nose 105

Chapter 28 Gogolrsquos Nose or ldquoEmpty Noserdquo Syndrome 109

Chapter 29 She Smells Parkinsonrsquos 113

Chapter 30 And What Does Parkinsonrsquos Smell Like 117

Chapter 31 Alzheimerrsquos Nose Losing Sense of Smell and Losing Memory the Same Story 121

Chapter 32 The Smell of Old People 125

Chapter 33 The Smell of Death 129

Chapter 34 Red Meat Garlic and Sex Appeal 133

Chapter 35 Tears and Desire Stop Crying it Doesnrsquot Turn Me On Anymore 137

Chapter 36 With a Bad Nose Comes a Poor Flirt 141

Chapter 37 Itrsquos All in the Sweat 143

Chapter 38 The Smell of Fear 147

Chapter 39 What Epigenetics Owes to the Nose How Fear Learned From an Odor can be Transmitted to Offspring 151

Chapter 40 Odor and Pain 155

Chapter 41 Odorology 159

Chapter 42 On the Trail of Odors 163

Chapter 43 The Electronic Nose 167

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Contents vii

Chapter 26 Smells to Cure Cancer 101

Chapter 27 A Depressed Patientrsquos Nose 105

Chapter 28 Gogolrsquos Nose or ldquoEmpty Noserdquo Syndrome 109

Chapter 29 She Smells Parkinsonrsquos 113

Chapter 30 And What Does Parkinsonrsquos Smell Like 117

Chapter 31 Alzheimerrsquos Nose Losing Sense of Smell and Losing Memory the Same Story 121

Chapter 32 The Smell of Old People 125

Chapter 33 The Smell of Death 129

Chapter 34 Red Meat Garlic and Sex Appeal 133

Chapter 35 Tears and Desire Stop Crying it Doesnrsquot Turn Me On Anymore 137

Chapter 36 With a Bad Nose Comes a Poor Flirt 141

Chapter 37 Itrsquos All in the Sweat 143

Chapter 38 The Smell of Fear 147

Chapter 39 What Epigenetics Owes to the Nose How Fear Learned From an Odor can be Transmitted to Offspring 151

Chapter 40 Odor and Pain 155

Chapter 41 Odorology 159

Chapter 42 On the Trail of Odors 163

Chapter 43 The Electronic Nose 167

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

viii Discovering Odors

Chapter 44 The Plane Nose The Methods of the Fraunhofer-Institut fuumlr Bauphysik to Get Up in the Air 171

Chapter 45 The Gender of the Nose 175

Chapter 46 The Newbornrsquos Nose 179

Chapter 47 The Smell of a Handshake 183

Chapter 48 The Nose and Perfumes 187

Chapter 49 Odorshellip A Hobby 191

Chapter 50 Tell Me What You Smell Irsquoll Tell You Who You Are But Not Where You Come From On Genetic Variations in Odor Perception 195

Conclusion 199

References 201

Index 223

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Preface

It is common to read that smell is an unknown sense that it is a primitive or archaic sensorial modality and that the human species is not very efficient with the use of the nose If we consider that it is one of the first senses to appear during evolution then yes it is primitive but considering the human nose as mediocre is a false belief based on 19th-Century scientific considerations

In biology there are three states of knowledge obviously closely interconnected relating to questions of structure functioning and functional potential Today although there are still some problematic areas the structure of the olfactory system(s) is known The same applies to functioning although there are more questions than there are about structure (eg peri-receptor space influence of the metabolism and cortical information processing) However there are still many questions about the functional aspects of the human species in other words ldquowhat is the pointrdquo

This book while it naturally sometimes refers to aspects of structure and functioning is mainly concerned with functional aspects Obviously and to a large extent there are hypotheses in the process of being verified but from all the research conducted in recent years it seems that the sense of smell will never cease to surprise us What it is used for is not always directly apprehended by consciousness but olfaction undeniably maintains a considerable place in our relationship with the world with others and in the regulation of our physiological and psychological states Above all it greatly influences our most fundamental behaviors (nutrition sexuality emotional responses etc)

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

x Discovering Odors

Paul Broca (1824ndash1880) remains forever recognized in the history of medical science for putting his name to the area of language production in the brain What is less well known is that his curiosity about neuroanatomy also led him to become interested in the olfactory system (Broca 1879) He was the first to publish the idea that smell is an inferior sense in humans due to the ratio of the volume of olfactory bulbs to the volume of the brain1 This ratio is indeed very disadvantageous for the human species compared to other species such as dogs or rodents Then Freud came onto the scene interested in and influenced by Brocarsquos work and postulated that smell was mainly linked to sexuality and that because of its regression in humans it was at the origin of psychosexual developmental disorders psychological conflicts and all mental illnesses The scientific fame of Broca and Freud led to a scientific disaffection with the sense of smell for most of the 20th Century and many biologists and psychologists today persist in their belief that humanity has an impaired sense of smell (McGann 2017) Smell is therefore minor from a functional point of view

However from the end of the 20th Century scientific work in many fields ndash physiology genetics molecular biology neuroanatomy psychophysics etc ndash gradually explained the complexity of the structure and functioning of the olfactory system its uniqueness and its interactions with other systems (including and beyond sensory systems)

However it is only in recent years that scientists from all four corners of the globe have embarked on the investigation of functional issues The growing literature on the subject makes it clear that we often move from genial experiences to general works we witness debates which are as constructive as they are heated and pointless and we are as excited about this as much we find the situation ironic Being interested in the functional aspects of olfaction ndash mainly in humans ndash is inevitably combined with some scientific stories that challenge us The purpose of this book is to try to combine these two considerations in order to better understand the current state of knowledge about all these ldquostrange odorsrdquo that surround us

In the coming years research work will undoubtedly close in on a few major axes and many will probably not appear in the future Before that day comes this book provides a non-exhaustive overview of how we perceive these strange odors and how they influence our relationship to the world

1 Today this report is no longer considered relevant Other more appropriate data are retained such as the number of cells the number of projections to other areas and so on

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Preface xi

ldquoOf the five senses that man possess the most precious is common senserdquo (Alphonse Karr)

Geacuterard BRAND

University of Burgundy

September 2019

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

1

Dr Foslashllingrsquos Flair Discovery of Phenylketonuria by Smell

Asbjoslashrn Foslashlling (1888ndash1973) a Norwegian doctor and specialist in metabolism is famous for his flair ndash in the literal sense ndash for discovering a previously unknown disease phenylketonuria (PKU) still called Foslashllingrsquos disease in Scandinavia

Phenylketonuria is a genetic disease that inhibits the bodyrsquos ability to naturally metabolize phenylalanine a substance that is widely present in our diets since it is found in virtually all animal and plant proteins Our body needs phenylalanine even though it cannot produce it It is therefore an essential part of our diet People with phenylketonuria do not have the enzyme that transforms phenylalanine which then accumulates before being transformed into toxic substances by the liver (phenylketones) The prevalence of this metabolic disease varies from one country to another Estimated numbers are 110000 in Europe including high numbers in Turkey for example with 14000 but the disease is almost absent in Finland (1100000) without any real explanation for these differences

Until Foslashllingrsquos discovery (Foslashlling 1934) no one knew anything about this serious condition which results in developmental problems in childhood characterized by motor and intellectual difficulties that can lead to severe intellectual disabilities One day Dr Foslashlling welcomed a mother and her 6-year-old daughter into his office The child was born without any particular problems but over time the mother realized that her daughter was not developing normally and that she was showing increasing signs of motor and intellectual disabilities At 6 years of age she walked with a lot of pain and could say only a few words In addition this woman had given birth to a

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

2 Discovering Odors

son two years after her daughter Problems linked to his development were even more noticeable at 4 years of age he could not speak could not walk and could not eat alone The mother of these children had seen many specialists but at that time medicine did not have many answers to questions about developmental disability or intellectual disability

Foslashlling like his colleagues used the usual tests and diagnostic tools without detecting anything that could explain a deterioration in the health of the two children However one particular element ndash at first sight insignificant ndash caught his attention The children emitted a strong odor similar to the smell of mold It emanated from both their skin and urine Urine tests carried out before and then by the other doctors had not revealed anything in particular and Foslashlling decided to carry out another test the Gerhard test The aim was to look for the presence of a compound called acetylacetic acid a potential marker of diabetes No link between diabetes and developmental and intellectual disability could be found so Foslashlling decided to follow a simple observation (ldquosomething common is present in the urine of both childrenrdquo) and carry out an experimental trial (ldquoI use all the tools at my disposal and we will see what comes out of itrdquo) In the Gerhard test ferric chloride is mixed with urine and if acetylacetic acid is present then the urine turns purple In this case and to the doctorrsquos great surprise the urine of the two children turned green The conclusion that an unknown molecule was present in the urine of the two children was certain so all that remained was to identify it (although at this stage it was not certain that there was a link between the molecule and the childrenrsquos deficient state) After many months of analysis he finally discovered that the substance in question was phenylpyruvic acid normally absent in the urine He wondered whether this substance had a role in the childrenrsquos motor and intellectual disabilities

To answer this new question and in a sensible approach Dr Foslashlling applied Gerhardrsquos test to 400 children in specialized institutions in Norway In about 10 of them the urine turned green and it was concluded that it was probably a metabolic dysfunction of genetic origin Since phenylpyruvic acid is normally absent in the urine it had to come from the transformation of another molecule Starting from the proximity of the molecular structure he suspected phenylalanine an amino acid that is common in our diets This was a bold statement at the time as it amounted to considering that the intellectual and motor disabilities observed in the children could be due to a substance naturally present in certain foods Consistent in his approach he decided to take a certain number of children with green urine and subject

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Dr Foslashllingrsquos Flair 3

them to a strict diet without phenylalanine The problem was significant since this molecule is present in most food products particularly in milk eggs meat and so on However with this strict diet the urine quickly lost its characteristic musty odor no longer turned green following the Gerhard test and therefore no longer contained phenylpyruvic acid

Following Dr Foslashllingrsquos exemplary exploratory work it took several years to develop processes to eliminate phenylalanine from foods and to provide alternative foods for patients with phenylketonuria It was only in 1953 (Bickel et al 1953) that the first complete diet treatment was offered and in 1963 (Guthrie and Susi 1963) that a routine screening test was developed for newborns

Currently the mechanisms involved in this disease are well understood (Ghozlan and Munnich 2004) from the genetic dysfunction that underlies the process to the metabolic dysfunctions that result from it and to the neurological disorders that cause motor and cognitive disorders Thanks to screening and a suitable diet low in phenylalanine children can develop normally and no longer show any kind of disability

There is no doubt that the citizen of Oslo Asbjoslashrn Foslashlling would have deserved a Nobel Prize in Medicine and Physiology for this major discovery due to his observational skills and sense of smell that helped to improve the lives of thousands of children around the world

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

2

A Nobel Prize for the Nose and Retraction in Science

On December 10 2004 American researchers Linda Buck and Richard Axel received the Nobel Prize in Physiology and Medicine from the Karolinska Institute in Stockholm This prize was awarded in recognition of their work on the discovery of olfactory receptors first published on April 5 1991 in the journal Cell a prestigious journal in cell biology At that time the interest of the scientific community was immediately aroused by the discovery of a new gene family coding olfactory receptors This discovery finally confirmed the molecular basis for odor recognition Until then no one had been able to explain how the olfactory system detected the thousands of odors we are likely to perceive (see Chapter 4) In the study of sensory mechanisms that of the sense of smell therefore proved to be very delayed compared to other modalities such as hearing (the Nobel Prize was awarded to Von Bekesy in 1961 for his work on the cochlea) or vision (the Nobel Prize was awarded to Wald in 1967 for his work on the retina) Four decades thus separate discoveries relating to transduction in the eye and inner ear from discoveries based on the sense of smell However while the publication of Buck and Axelrsquos paper improved the understanding of odor decoding mechanisms many subsequent questions remain open on integrative and treatment processes in the central nervous system on the impact of odors on behavior and on psychological processes ndash questions that are addressed in this book

These are receptors coupled with a specific type of protein (G proteins already known to be involved in the recognition of certain neurotransmitters and hormones) which when activated cause a series of chain reactions inside the cell leading to the activation of nerve impulses Perhaps the most

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

6 Discovering Odors

surprising result following the American researchersrsquo discovery was the considerable number of genes coding olfactory receptors in humans In the initial article published in the Cell journal in 1991 only 18 genes were mentioned It should be noted that in an animal with a high-performing sense of smell like mice about a thousand genes have been inventoried In humans 862 olfactory genes have been identified with the knowledge that many of them (56) are actually pseudogenes which means that they are not (or no longer) functional1 A decline in smell is often noted when discussing evolution in the human species (although this issue is controversial ndash see Chapter 7) while there are almost no pseudogenes in some mammals such as mice

But Linda Buckrsquos story does not end with her Nobel Prize In fact it constitutes an illustrated case of retractions in science In 2001 she published an article in the renowned journal Nature with Zhihua Zou one of her post-doctoral students in her Harvard laboratory (Zou et al 2001) for which she had to sign a retraction in 2008 The results initially published could not be replicated with replication being ndash as everyone can agree ndash the best guarantee of validity The first author of the publication Zou refused to sign the retraction in a deleterious atmosphere where Linda Buck apparently blamed him In any case this raised questions about Ms Buckrsquos role holding her responsible suggests that she did not ldquocontrolrdquo (or only from a very far distance) her studentrsquos work Worse still two and a half years later she had to make two further retractions for articles published in 2005 in the journal PNAS (Proceedings of the National Academy of Sciences) and in 2006 in the journal Science Before their retraction these two articles had been widely cited in the scientific literature

Linda Buck was in no way disconcerted by these retraction cases She continues to travel to international conferences and receive applause A little like the current policy caught with their hand in the cookie jar the guilty party apologizes flatly2 (or not) and continues on their way as if nothing or almost nothing had happened

These excesses in research have become a real scourge a depressing gangrene Every week the Retraction Watch website created in 2010

1 Recent studies (notably Prieto-Godino et al 2016) suggest that some pseudogenes in the olfactory modality may actually be functional

2 ldquoIt is disappointing of courserdquo said Buck ldquoThe important thing is to correct the literature I sincerely apologize for any confusion that its publication may have causedrdquo

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

A Nobel Prize for the Nose and Retraction in Science 7

announces the retraction of scientific literature from several publications with a total of between 500 and 600 per year The changes in researchersrsquo activities in recent years are undoubtedly not unconnected to this phenomenon the hunt for fame the race for contracts and funding etc are in the image of the conflicts of interest that are today flourishing everywhere

Withdrawal or retraction means that the publisher considers that the data are no longer considered reliable and the article should no longer be cited There are many reasons for the loss of reliability Historically the most well-known fraud is outright plagiarism which persists despite the verification tools put in place by the major scientific publishing houses Another barely believable but very real case of fraud is for an author to be their own reviewer Indeed scientific journals are said to be peer-reviewed and each paper submission is generally critically analyzed by two or three experts in the field not having any relationship of interest with the team that wishes to publish Many publications have therefore been retracted in recent years simply because the reviewers were the authors themselves Of course there is still the widespread possibility of tampering with or even simply inventing experimental data The biggest counterfeiters are undoubtedly the Japanese anesthetist Yoshitaka Fujii and the German Joachim Boldt whose dozens of articles have been removed Other incredible stories are told in labs such as that of the Czech biochemist who had to retract an article after he was surprised by video surveillance in the process of manipulating samples to verify his controversial initial results

Obviously the list of scientific misdeeds on the Retraction Watch website is growing faster than Pinocchiorsquos nose

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

3

Sperm and Lily of the Valley

Sperm has to make a long and perilous journey to reach the egg Until the early 2000s the process by which they progress and orient themselves to reach and fertilize the egg was not known and many teams of researchers were working on this issue However it was recognized that sperm orientation was most likely dependent on the chemical environment (a phenomenon called chemotaxis) as demonstrated in the aquatic environment in some invertebrates In this context Marc Spehrrsquos German team working on reproductive biology focused on a new hypothesis the potential presence of olfactory receptors (ORs) in sperm In the journal Science (Spehr et al 2003) the team published its work which sent shockwaves through the scientific community Marc Spehr and his collaborators first isolated an olfactory receptor that is actually present in the sperm code name OR1D2 (alias hOR17-4) Not knowing the nature of the odorant that could bind to this receptor the researchers proceeded by experimental trial and error using several molecules They discovered that by using the fluorimetric method that bourgeonal (lily of the valley scent) not only activated this receptor but was also a chemical attractant for sperm in vitro This molecule was indeed present in the fluid surrounding the egg but no one knew where it came from from the egg itself or from other elements of the female reproductive system

Once this discovery was published a large number of popular articles appeared with catchy titles such as ldquosperm have a noserdquo ldquothe egg smells like lily of the valleyrdquo ldquothe spermrsquos favorite fragrancerdquo and so on It has been popularized that sperm travel using their sense of smell to reach the egg which in turn emits an attractive smell This misunderstanding continued until the 1990s reaching its peak with the publication (Sinding et

Discovering Odors First Edition Geacuterard Brand

copy ISTE Ltd 2019 Published by ISTE Ltd and John Wiley amp Sons Inc

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

10 Discovering Odors

al 2013) of another German team from the University of Dresden aimed at linking male infertility with anosmia (olfactory loss) specific to lily of the valley scent The idea was relevant but the results were unconvincing despite the researchersrsquo peremptory conclusions

Infertility affects a significant proportion of the population A study conducted in France in 2007ndash2008 showed that the proportion of couples wishing to have a child and whose pregnancy was not announced after 12 months was 24 and 11 after 24 months The logic of shared responsibility is respected since in about 50 of cases it is the man who is infertile A number of causes are well-identified such as a lack of sperm mobility as in the case of varicocele1 for example or a deficiency in sperm composition However for 25 of infertile men there are no symptoms that can be diagnosed as to the reason for infertility (this is called idiopathic infertility)

It has therefore been known since 2003 with the discovery of the OR1D2 receptor mentioned above that olfactory receptors are present in regards to sperm particularly in the middle part of the flagella and that they play a role in mobility The OR1D2 receptor is activated by bourgeonal (lily of the valley scent) and inhibited by undecanal (green leaf scent) Assuming that bourgeonal is an attractive chemical agent for human sperm the German researchers hypothesized that men who were insensitive to the scent of lily of the valley could have sperm that was not receptive to bourgeonal Without this activation mechanism the lack of response to bourgeonal could be responsible for fertility problems2

Two groups of men were compared a fertile group composed of 22 young fathers (average age of 31 years) who served as a control group and a group of 15 men (average age of 345 years) with idiopathic infertility Men in the latter group were recruited from infertility consultants whose sperm tests showed no evidence of infertility and whose partner was not infertile did not take any contraceptive methods and had not reported pregnancy in the past 2 years Sensitivity was self-assessed for three odorants bourgeonal helional (green smell wet grass type and close to the smell of melon)

1 Varicocele is a varicose vein of the testicles corresponding to a dilation of the veins of the spermatic cord

2 Interestingly it has been shown (Olsson and Laska 2010) that women are less sensitive to bourgeonal than men This result is all the more interesting because in general women are more sensitive to odors than men

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire

Sperm and Lily of the Valley 11

retained for its structural proximity to the bourgeonal and phenyl ethyl alcohol (close to a rose scent) without a structural relationship with bourgeonal Measuring the intensity of odors revealed that the group of infertile men considered bourgeonal to be less intense than the group of fertile men while no difference was found for the other two odors The authors attributed this decrease in sensitivity to a reduced functioning of the OR1D2 receptor They even concluded that it was possible to diagnose certain types of infertility with olfactory threshold tests and also proposed an ecological contraceptive method based on undecanal which is known to inhibit the OR1D2 receptor However these conclusions had to be qualified because in the same study the authors had carried out standardized measurements of detection thresholds for the three odorants (measures more suitable for evaluating a dysfunction of olfactory receptors) that did not show any difference between the two groups of men and this for the three odors including bourgeonal3

The physiological reality is probably more complex Indeed progesterone a female sex hormone is attractive to sperm by acting on specific ionic channels called CatSper (cation channels of sperm in context not to be mistakenly spelled CatSpehr) Progesterone opens these channels and modifies the calcium level in the sperm and consequently the mobility of the flagellum The men whose gene regulating the function of CatSper is defective are therefore infertile We now know that bourgeonal acts in the same way as progesterone by opening the CatSper channels directly without passing through the olfactory receptors present in the sperm and following the complex sequence of events activating nasal olfactory cells Moreover bourgeonal can only be active at concentrations a thousand times higher than that of progesterone The initial study of Spehr in vitro approached this criterion which is therefore very far from the physiological reality The poetic Lily of the Valley phenomenon would therefore ultimately only be a laboratory artifact and it cannot be said that sperm smells like lily of the valley

In addition there are olfactory receptors elsewhere than in the nose and on sperm cells In 2014 a biomedical team in Washington discovered

3 Recently an Italian team (Ottavio et al 2015) determined bourgeonal detection thresholds in 37 men (aged 20ndash36 years) and jointly measured the intensity of sexual desire (using the International Index of Erectile Function ndash IIEF ndash scale) The results showed that the lower the detection threshold for bourgeonal (better sensitivity) the higher the intensity of sexual desire