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HUNGRY FOR THE CURE

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The future of edible vaccines

THE TRIPLE HELIX EXECUTIVE MANAGEMENT TEAM

Chief Execullve Olflcer Mizel Djukic

Execullve Edllor-ln-Chlef Monisho Bhollochoryo

Chief Operollng Officer. N. America Akosh Shah

Chief Operallng Olflcer, Europe Philippe Bradley

Chief Operollng Olflcer. Australia Kym Huynh

Chief Operollng Officer. Asia Kerk Sze Yen

Executive Producllon Editor Matt Bolestrino

Editor-In-Chief. £-publishing Kale Neofsey

Chief Internal Affairs Officer Horilho Dosori

Chief Technical Officer Nick Tolonelli

Chief Human Resource Office Ant Romesh

NORTH AMERICA PIVISION Execullve Director,

Chapter Operations Ernest (Ted) Gomez Execullve Director,

Business Development Arjun Noskor

Execullve Director, Morkellng Colhoryn Howord-Teplonsky

Executive Director. High School Operallons

Sonia Sorkor Business and Morkellng Division

Alex lp. Margot Kobolkin. Anjoli Verghis. Viroj Mehta. Vijeth

Iyengar, Star li. Mahesh Madhavan. Nicole Hui. Sean Yue, Christopher Louie. Gabriel Kim.

Carolyn Davies. Allie Schnidmon. Alessandro Szulc. Jenny Lee

EUROPE DIVISION Execullve Director,

Business Development Michelle Lam

Execullve Director, Internal Affairs

Christopher Stoinlon

ASIA DIVISION Chief Operating Officer

(In Training) Xavier Vanessa Anne Jio Min

Execullve Director, Internal Affairs Chon Hei Ching

AUSTRALIA DIVISION Executive Director, Internal Affairs

Viktorijo Pe trevsl:o

GLOBAL LITERARY & PROPUCT!ON Senior Lllerory Editors Kristina liu. Eric Fritz.

Winnie Tsong.Kojo Minto. Gorrell R. Leonard. Stephen Ro

Managing Production Editors Joson Belsky. Christine Chu.

Stephanie Chiao

A global forum for science in society

Senior Production Editors Angelo Lieu. Benjamin Tzou.

Christine Russell. David Liang, James Yeh, Kelly Kooy, Micl1oel Leung

Production Editors Kim-Yen Nguyen, Bradley French. Alvin Chen. Anno Owczorczyk.

Bradley Imp. Marl: Fontana. Michael Turchin, Yang Gu. Koillyn

Mitchell. Austin lhm. Brion Yeo. Claire J. Lee. Dustin Hong.

James Uoo. Jennifer Kao. Joanne Cheung. Lindsay Parrish. Victoria

Chu. Sleven Schlonsker. Zoe Doyle

E·PUBL!SHING PIVISION Associate Editors

Jennie Wong, Budri Abubol:erShorif. Steven Kong

Assistant Editors Aris Boros. Anthony Golinolo

Graphics Editors Anthony Golinoto. Gorre ll

Leonard, Simon Crone Coordinators

Thomas Ling. Elisabeth Rounis. Lisa Lin. Steve Truboc, Sosho Gordner

GLOBAL TECHNOLOGY DIVISION Technology Directors

Basil Carr

CHAPTER LEAPERSHIP Cornell University

Yeleno Kuznelsovo. President Eugenio Shmidt. Editor-in-Chief

University of California, Berkeley Amil Saxena, President

Surbhi Sarno. Editor-in-Chief

University of Pennsylvania Gordon Su. President

Joshua Molz. Editor-in-Chief

MIT Alex Hsu. President Koleryno Kukuruzo.

Editor-in-Chief

Johns Hopkins University Shereef Elnohol. President

Vishol Chongroni. Editor-In-Chief

Yale University Tomosz Siergiejul:, President

Eric Cioromello. Co-Editor-in-Chief Ivan C . Lett. Co-Editor-in-Chief

Brown University Anita Mozloom. President Joanna Liu. Editor-in-Chief

Dartmouth College Felicia Reid, President

Columbia University Kenneth Choi. President

Chrisllne Chong, Editor-in-Chief

Carnegie Mellon University SeungJin Pork, President

Erin Goldberger. Editor- in-Chief

Harvard University Allen Chen. President

Shirleen Soh. Editor-in-Chief

Arizona State University Derrick Anderson. President

Kimberly Buettner. Editor- in-Chief

University of Chicago Deepo Sen, President

Sam Govzy. Editor-in-Chief

University of California, Los Angeles

William luang. President Sean Aroyosiril:ul . Editor-in-Chief

Princeton University Patrick Ho. Co-President Soish Setty. Co-President

Cambridge University James Shepherd. President

Michaela Freeland. Editor-in-Chief

Oxford University Georgia Gale-Grant. President &

Editor-in-Chief

Melbourne University Soak Jin Ong, President

ton Findlay, Editor-in-Chief

Notional University of Singapore Kerk Sze Yen. President

Lim Shimin, Gwynne. Editor-in-Chief

UNC Chapel Hill Julio Conway. President

Colby Day. Editor-in-Chief

University of Co!Jiornlo. Son Diego James Lin. President

Britto Mason. Editor-in-Chief

Northwestern University Rohan Dixit. President

Hong Kong University Chon Hei Ching. President

University of Co!Jiornlo, Davis Fronk Sousa. President

Unlverslly of Sydney Herry Bosul:i, President

Emory University Samantha Ehrlic. President

Unlverslty College London Hino Shohid. President

Eddie Guzdor. Editor -in-Chief

London School of Economics Elizabeth Peon. President Alice Ryan, Editor-in·Chief

King's College London Chris Mullan, President

Cbgpter gt Cgmbrldge UnlveD!ty

EXECUTIVE BOARP President

James Shepherd (Coius) Edllor·ln-Chlel

Michaela Freeland (Newnhom) Assistant Edllor·ln-Chlel

Amy Songom (Emmanuel) Director ol Marketing

Anisho Sharma (Girton) Events Olllcer

Audry Lee (SI John's) Secretary

Victor Chong Technical Director

Alex Reo (Churchill) Assistant Technical Director

Kendra Leigh (King's) Director of E-Pubtlshlng

Thomas Ling ex-officio Senior Treosuer

Dr. David Summer> (Coius)

LITERARY TEAM Senior Editor

Shen-Hon Lee (Christ's) Associate Editors

Tanyello Allison (Girton) Dorshon Bhrambholl (Coius)

Michaela Freeland (Newnhom) Da niel Jact:son (Downing) James Shepherd (Caius)

Contributing Writers Michaela Freeland (Newnhom) Thomas Kluyver (Pelerhouse)

Audry Lee (Queens') Simon Melderis (Churchill) Shreyos Mukund (Christ ' s)

Protul Rovi (Christ ' s) James Shepherd (Coius)

MARKETING JEAM Junior Treasurer

Geraldine Huang (Newnhom) Former Director of Marketing

Deepok Chandrosekhoron (Coius) Form~ Assistant Di'ector of Marketing

Benedict Crompton (Caius) Former Senior Marketing Olllcer

Charlotte Heotes (Coius) Marketing Officers

Fo11ono Mioh (Girton) College Secretaries

Jem Logonolhan (Magdalene) Siyomlnl Sivononlhon

(SI Cothorines) Thonusho Anothokumor (Robinson)

Kendra Leigh (King's) Moll Kuet (SI John's)

Alice Turnbull (Downing)

FACULTY REVIEW BOARD Academic Advisory Board

Prolessor Peter Ulllewood (Trinity) Dr. David Summers (Coius)

Dr. Ed Tonner (CoiusJ Dr. Peter Wethers (SI Colhorines)

Senior Reviewers Dr. Bob Butcher (Coius)

Or. Jim Hoseloll Academic Reviewers

Dr. Kathy Liddell (Downing)

Ms. Anl)e du Bois-Pedoln (Magdalene)

Dr. David Riches (Coius) Professor Malcom Ferguson-Smith

(Pelerhouse) Prolessor Joe Herbert (Coius)

Graduate Reviewers Sophie Lourenson (Mogdelene)

Mlco Tololovlc (Christ 's)

INSIDE

Table of Contents

International Articles

3-5

.. __ ..... 6-8

9-1 1

-·. 12-16

Global Polio Eraait:oti0n: Imminent or Impossible? Alyssa Sclafani @ P-enn

I '':; f-Affective Forecasting and th~ Pursuit of Hop8iness Katherine lone @ Dartmo\ll~ ...

"' Nonotoxicology:• ·V[hot You Can't See May Harm You Lisa Lin ~Jo~ns ~gpkins ........ .. __ I

. ~ .

·---Edible Vaccines: fronsge~ic P.lont Research Introduces New Vaccine Technology ..

• ~ r Samantha A. Conroy @ CMU • ~

toil

Cambridge Articles

17-21

22-25

26-28

29-31

32-33

34-36

37-40

Out of Sight. Out of Mind: Medical Breakthroughs that Never Reach the Third World Shreyas Mukund

The Future of Biofuels Thomas Kluyver

The British BSE Crisis - A Case Study of the Role of Science in Mass Hysteria Simon Melderis

The Importance of Memory Audry Lee

The Ethics of Placebo Trials in Different Economic Contexts Proful Rovi

Taking Off - The Implications of Moss Space Tourism Michaela Freeland

Responsibility to the Truth: The MMR Scandal and Scientific Froud James Shepherd

- .

• .. :.,.,

Top image courtesy of http://www.d ed .mo.gov/

THE TRIPLE HELIX Spring 2007

· NEWS

Message from the CEO Dear members. friends, and advisors ofThe Triple Helix:

As 2007 begins with a great start for The Triple Helix, we reflect on its brief but exciting history. In less than eighteen months, The Triple Helix has gone from a very localized organization at just a few universities around the United States to an emerging leader in science publications around the entire world. With its incorporation eighteen months ago came a lot of attention and exposure. but the reason for its unprecedented growth is not as simple as a marketing strategy. It was the tenacity of its members. the distinct mission to unite. and the desire to influence the world that has made The Triple Helix the success it is today.

Last year was a greatyearforThe Triple Helix and all of its members. In 2006 we expanded our reach to three additional continents: Europe, Asia, and Australia. We brought our members together to promote the mission of this great organization with a national conference. We created strong relationships with multiple national organizations in the pursuit of interdisciplinary education. in total. we published more than 20.000 issues. Our voice was heard by not only our peers. but a younger generation that, like our own. aspires to be great leaders, and by those older than us who are proud of the success of future leaders.

With great success. The Triple Helix has also faced many challenges that confront all organizations of this size and magnitude. We have seen obstacles in international expansion, fundraising, major transitions, a nd more. In spite of these obstacles. thanks to the hard work of all members. The Triple Helix has continued to pursue its mission without faltering.

As nice as it is to look back at our success over the last year, it is essential that we look forward to the rest of 2007 and the many years to come. The Triple Helix does not plan to slow down. In 2007. we plan to implement a science policy division and inspire our audience to take part in science policy decision making. We will expand into several high schools as a part of our new high school publication. Expansion will continue internationally as our organization reaches thirty chapters and beyond. A new production site will be in place to assist with the growing number of issues produced. The Triple Helix will also print more than 45,000 issues on four continents. Various forums and conferences will be held on all four continents. and there will surely be much much more.

I want to personally thank all of you for your hard work and dedication. The Triple Helix in itself is a great idea. but none of this would be possible without the work you've put into this organization. It's an honor to work with so many great students and faculty around the world in the pursuit of creating a global forum for science in society. I look forward to working with all of you in yet another year of achievement.

Best regards.

Mizel Djukic Chief Executive Officer The Triple Helix, Inc.

Message from the Chapter President The publication of our inaugural issue marks just over half a year of success for The Triple Helix Cambridge since our launch in October. Success in writing and publishing seven finely-tuned a rtic les. Success that has attrac ted more than ten sponsors to pledge money towards our cause. Success that has d rawn in students from all disciplines -covering English, Moths, Economics and SPS- contributing to the truly interdiscip linary atmosphere already fostered by the collegiate system.

But our accomplishments are not just limited to Cambridge.

The Triple Helix Cambridge is already making an impac t on the international organization. From being the first branch fully established UK, to becoming the first ever UK branch to go to print. we are proud to carry Cambridge's reputation for success to what is arguably the highest level of international undergraduate journalism as we set the standard for the other international chapters.

We have the hard work and dedication of all those involved to thank for this, w ithout whom rea lizing these goals would not have been possible. Thanks, too. goes to you. the much overlooked reader. for picking up a copy!

On these firm foundations. may we continue to thrive in the legacy of high achievement for the year to come.

James Shepherd (Gonville and Caius) Founding President of The Triple Helix. Cambridge

2 THE TRIPLE HELIX Spring 2007

• ~ - - - - .... --~5

P&NN . . : - .. - .... -~ _....._ ____ ..._ ~ - ..__ -- ----·-"

Global Polio Eradication: Imminent or Impossible? Alyssa Sclafani

0 ver a decade before the new millennium, the World Health Organization p ledged its "gift from the twentieth to the twenty-first century" : the

worldwide eradication o f polio by the year 2000 (1]. In the late 1980s. polio infec ted more than 350,000 children every year and was endemic in more than 125 countries, making it a clear global health threat (2]. Given the humanitarian and scientific benefits o f eliminating poliomyelitis from the world's population. this Global Polio Eradication Initia tive seemed destined for success. The WHO was readi ly armed w ith two types of vaccinations. the Salk and the Sabin vaccines [3] . a nd in 1980 WHO officials had

deve loping countries lack the resources to p rovide immunization, refuse WHO aid due to fear. or have simply stopped d istri buting v accines as a resu lt o f governmenta l indolence. Vaccinations like the OPV have proved to be extremely effective , a nd have led to the virtual e limination of the d isease in the U.S. and o ther hig hly deve loped countries since the 1960s. Howeve r, po lio does remain preva lent in m any impoverished countries as a result of poor hygiene and lack of repeated immunization efforts [3]. OPV drops need to be administered in several doses to children under five , but in many cases multiple immunizat ions

are impossible d ue t o certified the elimination o f smallpox, proving the feasibility of eradicating a highly infectious disease [4]. However, more than six years afte r the deadline. the unfortunate reality is that a reemergence o f po lio remains possible . With significant obstacles

Polio does remain prevalent in many impoverished

countries as a result of poor hygiene and lack of repeated

immunization efforts

a n in su ffi cie nt supply o f vacc in es . improper storage o f the vaccine. or parental refusal to permit the ir chi ld's vaccination [5 ] . The latte r case occ urred t h roughou t Nigeria in mid -2003 when

yet to be overcome, experts d isagree on the p roper way to continue battl ing this disease.

It is not surprising tha t much is know n about the causes and symptoms of an infamous d isease like polio ; however. there are startlingly few ways to combat the disease itself other than w ith preventative vaccinations. Poliomyelitis is an in fectious viral d isease th a t is transmitted from person to person primarily via a fecaloral route. the result o f unsanitary living conditions. More specifically, polio is an en terovirus. meaning tha t it infects the gastrointestinal tract, where it can live and multiply for as long as seventeen weeks. The most serious consequences of the d isease, including paralysis, occur if infection reaches the Central Nervous System. If this occurs, the virus destroys the motor neurons of the spinal cord, prevents muscles from contracting, and eventually causes muscles to become flaccid and atrophied. In the most severe cases of brainstem infection. the brain may lose i ts ability to regula te such functio ns as breathing. heart rate, and blood pressure. ultimately leading to death. Once contracted, there is no specific treatment for polio. However, polio can b e averted through proper immunization. The WHO e mploys the Sabin Oral Polio Vaccine (OPV) . which contains live. weakened poliovirus and gives the rec ip ien t permanent, lifelong immunity to future infections (3].

Despite the damaging consequences of poliovirus and t he pervasive nature of this d isease. m a ny


rumors circula ted that the polio vaccine had been

contaminated w ith the AIDS virus and estrogen, the main ingredient in b irth control p ills (5]. As a result, many Nigeria ns be lieved th a t t he WHO's immunizat ion Initia t ive was a Western p lot to sicken and sterilize Muslim girls [5] . In the northern Nigerian state of Kana, a 1 0-month ban was placed on the polio vaccine when Islamic governmenta l authorities yielded to this fear [6]. Such actions added to the a lrea dy ca lamitous e ffect of the spreading poliovirus and caused major polit ical up heaval w ithin the Nigerian federal government [5]. Because of this interrupt ion in the immunization e ffort. between August 2003 and July 2005 the wild poliovirus (WPV) spread from Nigeria and infected eig hteen poliofree countries. Most of these countries had neglected their routine polio vaccination programs after a chieving polio -free sta tus, a nd the ir c itizens were there fore unprotected against transmission of the d isease [4] . Worryingly , many of these re-infe cted areas of A frica, Asia. and the Middle East include countries such as Sudan and Somalia. regions which are now so w ar-torn and d angerous tha t the WHO is unable to provide effective vaccination effo rts [7] . Nigeria remains. as of this past year. the greatest threat to the international spread of WPV. with more tha n 40% of targeted c hildren still not receiving immunizat ion in some areas [8].

The problem in Nigeria naturally raises questions about the interventional powers of the WHO a nd about the a ppropria te responses to countries that d o not

3

comply with international vaccination efforts. It stands to reason that when delinquent governments neglect their immunization programs, do not allocate proper funding, or, in the extreme, ban the vaccine itself, the WHO has a responsibility to protect other countries from the spread of the disease in accordance with its role as an international body and branch of the United Nations. However, forcing countries to adopt legislation requiring international vaccination programs often presents a serious political challenge. The typical U.N. retributive response to delinquency, i.e. the imposition of economic sanctions, would likely prove to be self-defeating, as it is

4

often a lack of proper funding that prevents impoverished countries from employing vaccination efforts in the first place.

Despite these various challenges and setbacks, it is undeniable that the effort of the WHO to end polio has led to great overall improve-ments and has dramatically lowered the global prevalence of this disease. Since the Global Polio Eradi-cation Initiative was launched in 1988, it has grown to become the "largest international health effort in history, operating in every country of the world " [2) . As of the end of 2005, Afghanistan, India, Nigeria, and Pakistan are the world's only four countries with endemic polio, as compared to 125 countries in 1988 [B). Efforts are underway in these countries to increase the numbers and quality of the supplementary immunization activities [8] . The overall result of the effort of the WHO is that the world's total number of polio cases was reduced to 1, 948 by 2005, as compared to an estimated 350,000 cases in 1988 [9). The incidence of polio has been reduced by more than 99%, and more than two billion children have been vaccinated [5] . Ultimately, some five million children have been saved from paralysis or death [5). Now, the question is whether eradication "once and for all" is a realistic goal.

With the WHO Initiative nearing its two-decade mark and with over $4 billion spent on the effort so far, many experts now contend that efforts should shift from trying to eradicate the disease to trying to control it (7, 9). It has been estimated that complete eradication would require another $1 .2 billion and then an additional three years of

precautionary follow-up [5, 9]. This is starkly different from the smallpox eradication effort, which cost only $1 00 million ( 1980 value) over the course of ten years (9). Another obstacle to polio eradication is that for every case of paralysis caused by polio, there are an additional 100-200 subclinical cases, which are mild forms of the disease in which no symptoms are detected [9). Since every infected person can pass on the disease regardless of its severity, there is therefore no way to monitor the trans-mission of these "invisible" poliovirus infections [9). In light of these difficulties, some experts assert that polio does not present as big a threat as certain other diseases


when viewed in the context of overall public health conditions in many developing countries [9]. WHO time and money, they argue, would be better spent by increasing the immunization efforts against diphtheria, pertussis, tetanus and

to reach their goal of global eradication, routine immunization against polio would need to continue indefinitely to prevent future outbreaks (7). If countries were to become remiss in their provision of routine

vaccination programs measles, and by researching possible vaccines for AIDS and malaria (9) . However, others question whether a world that could not defeat polio, even with the most comprehensive and well funded eradication effort in history, will have the stamina to try to eliminate these diseases [5].

Officials remain optimistic about the future, but stress that success is dependent upon continued public

support and full international participation in the WHO

eradication strategies

post-eradication, the world's population would become extremely susceptible to reinfection by new strains of poliovirus (7). It is clear that the world may continue to battle polio long into this twentyfirst century, and it is therefore essential that we do not allow apathy or

Despite recent criticism, the WHO remains committed to its goal of interrupting poliovirus transmission and is currently testing ways to improve the eradication effort. The development of different types of vaccines has long been considered a promising strategy, and the WHO has already begun to supplement its standard trivalent OPV vaccine with a more potent monovalent vaccine that would target one specific strain of poliovirus instead of all three strains [7, 10). Trivalent OPV confers unequal immunity against the three types of poliovirus, meaning that the recipient of the vaccine is protected against type 2 very effectively, but not as well protected against types 1 and 3 [ 11]. The typespecific monovalent vaccine would prevent weakened immunity by eliminating competition among the three strains of WPV, and would combat the continued circulation of types 1 and 3 in the most critical endemic areas [ 11]. Other encouraging strategies include testing a "birth dose" of OPV; scientists in the Indian state of Uttar Pradesh will study whether or not the administration of a dose within 72 hours of birth enhances immunity to poliovirus (7, 10]. The WHO also aims to increase the number of National Immunization Days and to continue to implement house-to-house "mop-up" campaigns in countries where polio remains endemic [10] . To further interrupt poliovirus transmission in these countries, the WHO is working to develop quicker diagnostic tests that would enable countries to recognize and respond more quickly to epidemics [7).

Officials remain optimistic about the future, but stress that success is dependent upon continued public support and full international participation in the WHO eradication strategies [7] . Given the tremendous obstacles facing the effort to eradicate polio, it would seem that the best course of action would be to implement some of these new strategies and technologies to first establish control over spreading WPV. This is not to say that po lio may never be completely eliminated; however, even if the WHO were


ignorance to undermine the potential for success promised by modern international vaccination efforts.

References: [1] World Health Assembly, Global eradication of poliomyelitis by the year 2000 (World Health Organization publication, WHA41.28). [2) Aylward eta/., Bulletin of the World Health Organization 83, 268 (2005) . [3) L. Bennington, in Gale Encyclopedia of Medicine , J. Longe, Ed. (Gale, Detroit. ed. 2, 2002), vol. 4, pp. 2648-2651. [4] D.L. Heymann, Bulletin of the World Health Organization 84, 82 (2006). [5] Dugger. Celia W. and Donald G. McNeil Jr. "Rumor, Fear and Fatigue Hinder Final Push to End Polio." New York Times 20 Mar. 2006: A 1. [6) "Polio Vaccinations Resume in Nigeria." New York Times 1 Aug. 2004: 1.3. [7) L. Roberts, Science 312, 832 (2006). (8) "Progress Toward Interruption of Wild Poliovirus Transmission-Worldwide", Morbidity and Mortality Weekly Report (Center for Disease ControL vol. 55, no. 16, April 28, 2006; www.cdc.gov/mmwr/PDF/wk/ mm55 16.pdf). [9) Arita et a/., Science 312, 852 (2006) . [10] World Health Organization, Global Polio Eradication Initiative Strategic Plan: 2004-2008 (WHO publication, 2003; www.polioeradication.org/content/publications/ 2004stratplan.pdf). [11] World Health Organization, Global Polio Eradication Initiative: Monovalent Oral Polio Vaccines Fact Sheet (WHO publication, 2003; www.polioeradication.org/ content/meetings/MediaMaterials_l20ctMediaEvent/ mOPVFactSheetfinai.200S.pdf).

Graphics References: : http://www.cdc.gov/NIP/global/images/ 02_lndia_giving_OPV.JPG .

5

Affective Forecasting and the Pursuit of Happiness

Katherine lane

When asked to state one's ultimate goals in life. many would list enjoying life- or some derivative thereof- high on their list. Often times. however.

people's desires and actions do not mesh. Recent research has established that. though

people may be in the pursuit of happiness. most of us do not seem to know what makes us happy, let alone how

6

to achieve it. Psychologists such as Harvard's Daniel Gilbert. Universi ty of Virginia' s Tim Wilson . Daniel Kahneman of Princeton. and even prominent economist George Loewenstein of Carnegie-Mellon all focus their academia on studying "happiness." or more specifica lly, how people predict what w ill make them happy or unhappy in comparison to their experienced emotion

after the event occurred . What they have found is that humans are vastly inept at anticipa ting their level of emotional alteration given an eve nt. t hereby overestimating the g lobal effect.

People a re re quired to make decisions every day, from when to g et out of bed in the morning and what to eat for lunch, to what career pa th to follow and whether or not to have children. Given the opportunity, I would hazard that many people would jump at the chance to look into the future and see where their life would lead. Interestingly enough though, t hey would d iscover that. w hile their specific situa t ions may b e d if feren t depending on the decisions they make. their level of happiness would be nearly identic al yet indep end ent o f the path chosen. Wilson and Gilbert state that people " routinely mispredic t how much pleasure or displeasure future events w ill bring and, as a result. sometimes work to bring about events that do not maximize their happiness" [9]. The following forecasting errors describe the processes of such miscalculations.

The Impact Bias The most prevalent o f the forecasting errors is impact b ias , wh ere p eople overestimate both the intensity and the duration o f their emotional reactions to future events. This bias is seen across a variety of populations (s tudents. p rofessors. medical pa tients) and a wide range of emotional e vents (d ormitory assignment, re ceiving tenure. losing a limb). What the various studies show is that people's effective emotional states return to their 'set points' after a much shorter time frame than antic ipated [6, 7, 9].


Hot-Cold Empathy Gaps Much of Loewenstein's work focuses on how people act d ifferent ly under the influence of what he terms "hot" and "cold " emotional sta tes. Loewenstein reveals that people in cold states - typical. rational circumstances -are incapable o f determining how they will behave in the future under a hot state -one of excitation, anxiety, courage. fear. etc [5] . This has significant impact on decision making, as these transient emotional states influence the fu ture consequences of such decisions. Loewenstein confirms that " these kinds of states have the abil ity to change us so profound ly that we ' re more different from ourselves in different states than we are from another person" [3] .

Focalism When making a ffective forecasts, people tend to focus extensive ly on th e specific occurrence (termed the focal event] and fail to consider the e ffect o f other life events that will inevitably occur a fter the focal event [11]. Experiments run by Wilson et al demonstrate this focalism hypothesis [ 11] . One such experiment had college students rate what their antic ipa ted feelings of overall happiness would be immedia te ly a fter their school won a big football game, as well as how frequently they would think about the game. Prior to making these predictions, a subgroup of participants were told to list what other events would occupy their time in the days succeeding the game. The results of this study indicate tha t the general tendency is for fans to overestimate how the outcome of the football game would influence their overall happiness. hence show-ing a durability bias; however, it was clear with the subgroup that the simple reminder of upcoming, regular-day activities in one 's

People are continually making decisions based on the valence, intensity and

durability of their predicted emotional states

life was enough to correct for this durability bias. Wilson et a l contribu te s th ese find ings to an a ffectiv e competition hypothesis whic h sta tes tha t everyday events take one 's mind o ff the focal event and produce affective reactions which may dilute the effects of the main event [11].

Immune Neglect The process of our body's white b lood cells fighting o ff any foreign invaders in our system thereby protecting our p hysica l h ea lth is a na log ous to the way our


psycho logical immune system protects our mental well being . When predicting the durability of an event. people tend to ignore t h eir high ly adaptive psychological immune system; in o ther words, they do not anticipate how quickly they wil l make sense of new or unexpected events once they occur [9]. The process occurs as follows: first, "people a ttend to events that are se lf-re levant bu t poorly u nders tood; " second, people "react emotiona lly to self-re levant. poorly understood events;" third. people "explain or make sense

Not only do people overestimate the impact of future events on their happiness, but they also reveal a retrospective impact

bias in overestimating the impact that past experiences had on

their happiness

of self-relevant, poorly understood events;" and finally, "by making sense of events. people adapt emotionally to them ... hence [the event] w ill lose some o f the emotiona l power t hat it had when it sti ll seemed extraordinary" [9]. This works both ways: decreasing p leasurable experiences by making sense of them while a lso decreasing the e ffects of negative events by p syc ho log ica l defenses such as rea soning . ra tion a lization, dissonance reduc tion, and positive illusions [8].

Retrospective Impact Bias Not only do people overestimate the impact of future events on the ir happiness, but they a lso reveal a retrospective impact bias in over-estimating the impact that past experiences had on their happiness [ 1 OJ . While people are able to accurately sta te the va lence of their past experience. they typically err in the intensity and duration of the specific reaction. This effect is primarily due to the "peaks and endings" of an experience which overrides the total event. Was the hockey game really that exciti ng. or was it just the one high light goal representing the entire game? This causes p roblems when trying to predic t the benefits received from future options: "peop le do not learn from experience tha t positive events are often less impacting than they an tic ipated , because they reca ll them as more impacting than they were " [ 1 0]. Furthermore, this re trospective bias also manipu la tes the memory of negative events . Peop le 's psychologica l immune system kicks in and continues to rationalize the past nega tive outcomes when recalling the event in the

7

present text [ 1 OJ. Finally, the tendency for people to "remember the best of times and the worst of times -rather than the most typical of times" [6] accentuates the retrospective impact bias: remembering atypical events and exaggerating the intensity and duration of these already uncharacteristic events to predict future outcomes and influence one's decision.

Implications of Use The concept of affective forecasting and its errors has many applications. People ore continually making decisions based on the valence. intensity and durability of their predicted emotional states. The tendency to remember and rely on uncharacteristic instances can have serious consequences. For instance, after the September 11th attacks the number of commercial airline passengers significantly decreased. The people who would typically use air transportation instead chose other methods such as automobile use, even though driving a cor is statistically more dangerous than flying: "the increase in automobile traffic occasioned by the September 11 attacks ultimately killed more people than did the attacks themselves" [9] . If people hod been rational about their decision-making many lives could have been saved.

Health core is another area in which affective forecasting could ploy a major role, especially in the arena of informed consent. The results of forecast-bias research suggest that the client would incorrectly predict their reac tion to major medical procedures. Most people do not consider how adept their psychological immune systems ore. As a result, they overestimate the effects of, soy, losing a limb and therefore choose the riskier procedure in order to save that limb [3].

So how does a person go about finding eternal happiness?

Perhaps most significant to everyday life, however, is the understanding that whether you chose option A or B is not going to make that much of a difference in the long run. Once a decision is mode and finalized, our psychological systems rationalize. reason, and convince us that the choice we made was in fact the best. Furthermore, if a distressing event befalls us, knowing that the single event w ill not leave us in a state of melancholy for ages is at least somewhat comforting.

So how does a person go about finding eternal happiness? In a research paper entitled the "Economic Consequences of Mispredicting Utility," Bruno Frey and Alois Stutzer differentiate between "intrinsic " attributes (spending time with family and friends, pursuing hobbies) and " extrinsic " attributes (sa lary, typica l consume r

8

goods) of options [2]. They propose tha t, in decision making, intrinsic attributes of activities are underestimated while the utility of extrinsic attributes is greatly overestimated. Furthermore, Frey and Stutzer conclude that people would be much happier if they placed a higher value on intrinsic a ttributes, as the value of these goods (family, friendship. community] maintains its subjective utility over time, while the utility of extrinsic goods wears off quickly [2].

The overall message one could derive from all of this, is to live consciously in the moment. enjoy life for its experiences , spend more t ime seeking h uman connections and know that, inevitably, your life w ill be characterized by an overall sense of happiness and well being.

References: [1] Elkman, P., Davidson. R. J., Ricard, M .. & Wallace, B.A. (2005). Buddhist and Psychological Perspective on Emotions and Well-Being. C urrent Directions in Psychological Science. 14. 59-63 [2] Frey, B. S., & Stutze r, A. (2004) . Eco nonmic Consequences of Mispredicting Utility (working paper no. 218). Institute for Empirical Research in Economics, University of Zurich. [3] Gertner, J. (2003) The Futile Pursuit of Happiness. http:/ /www. wjh .harvard .edu/ -dtg/Futile_Pursuit .htm [4] Gilbert, D. T., Lieb erman, M. D .. Morewedge, C. K., Wilson, T. D. {2004). The Peculiar Longevity of Things Not So Bod. Psychological Science. 15. 14-19 [5] Loewenstein, G., Schkode, D. (1997) Wouldn't it be nice ? Predicting Future Feelings. http:/ /elso.berkeley.edu/ eml/nsf97 /loewenstein.pdf [6] Morewedge, C. K., Gilbert, D. T., & Wilson, T. D. {2005) The Least Likely of Times: How Remembering the Past Biases Forecasts of the Future. Psychological Science. 16. 626-630 [7) Sanna, L. J., & Schwarz, N. (2004) . Integra ting Temporal Biases: The Interplay of Focal Thoughts and Accessibility Experiences. Psychological Science. 15, 47 4-481 [8) Wilson, T.D. , & Gilbert, D.T. Affective Forecasting. http: I /www. p eo p ie. v i r gin i o .e du / - t dw / Review.submitted.pd f [9] Wilson, T.D., & Gilbert, D.T., {2005). Affective Forecasting: Knowing What to Wont. Current Directions in Psychological Science. 14. 131-134 [10] Wilson, T.D., Meyers, J., & Gilbert, D.T. (2003). How Happy was I, Anywoys" A re trospective impact bias. Social Cognition , 21, 421-426 [11] Wilson, T.D., Wheatley, L Meyers, J.M., Gilbert, D.T., Axsom, D. {2000). Focolism: A Source of Durability Bias in Affective Forecasting. Journal of Personality and Social Psyc hology, 78, 82 1-836.

Graphics References: : Mlenny. File 2048842, iStockphoto.com. 4thApril2007.


Nanotoxicology: What You Can't See May Harm You

Uso1 Un

N owadoys, it seems as if technology is on a constant quest to make things smaller. From smaller MP3 players to smaller cell phones, the drive to minimize

is stronger than ever. Therefore . it is no surprise that the field of nanotechnology is developing at on incredibly fast pace; in fa c t, it is projected to become a $1 t ri llion market by 201 5 [ 1]. Nanotechnology involves the c rea ti on and development of nonomote rials , which ore materials w ith at least one dimension that is less than 1 OOnm. New nonomote rio ls are constant ly being engineered, but there are certain one s that ore commonly used inc lud ing meta l oxides, quantum dots, fullerenes, and carbon nanotubes. Titanium dioxides are used in cosmetics, fu lle renes in d ru g delivery systems, carbon nonotubes in display devices, and quantum dots in po ints and f luorescent bio log ica l labeling [2]. Over 600 nanobased raw and intermediate materials are already on the commercial market, and this number will only increase in the future [3].

Nanotechnology is not only receiving more attention because of its increasing areas of application, bu t a lso because it poses a potential health and environmental hazard. Current research has shown that nanomateriols have the potential to be toxic because their small size a llows them to eas ily be absorbe d and integrated into the body. With nanotec hnol ogy's

flexed is permeable to nonoportic les . For example, experiments performed with fluorescent partic les hove shown that flexed unbroken skin results in the penetration of 1 m m particles in to the dermis; this c learly

demonstrates that nonoporticles, which are 1 000 times smaller than 1 mm partic les, can also penetrate

flexed unbroken skin [4] . Experiments hove also confirmed tha t once nanoportic les break the skin barrier, they tend to localize in regional lymph nodes; whi le the exact transport mechanism is unknown, skin macrophoges and d endrit ic cells hove been implicated as possib le transfer agents. Both macrophoges and d endritic cells participate in immune system responses by taking up and processing antigens such as nonoportic les. They then

travel to lymph nodes and interac t with T lymphocytes [5]. The presence of

nanoporticles con change how these interactions occur and thus how the immune system fu nctions. Possib le

effects include allergic reac tions and decreased resistance to foreign bodies.

The respiratory tract is another portal of entry for nanoporticles. Whereas

larger particles inhaled say from pollution are only deposited in the upper a irways of

the respiratory system, nanoportic les hove been shown to deposit in the a lveolar area of the lung where gas exchange takes place. Because of this, they can readi ly tronslocate to extropulmonory sites by diffusing across the epithelia of the respiratory tract and into the bloodstream, w hich a llows them to generate

toxic responses for from their inevitably increasin g role in the future. more definitive research on nanotoxicology wi ll have to be done in order to c reate suitable regulations fo r and to ensure the safe use o f nonomoterials.

The risks nono mo terials pose o rig inate from th eir extremely small size ,

In addition to allowing easy access to the body, a

nanoparticle's small size can also increase its interaction with

biological tissues, potentially instigating more toxic effects

original place of deposition. In addi t ion t o

allowing easy access to the body, a nonoparticle 's small size can a lso increase its intera ction wi th biological tissues. potential ly instigating more toxic effects. As the size of a partic le decreases, its surface area increases, which leads to more potentially reac tive g roups being

which a llows them to readily enter the body and bypass its defenses. One of the main entry sites is the skin; broken skin is easily penetrated, and even unbroken skin when


d isplayed on its surface [6] . Thus, nonoparticles of a certain material may generate a toxic response whereas a larger particle of ·the same materia l wil l not. An important example o f this is the

9

creation of reactive oxygen species (ROS). Many nanoparticles contain transition metals on their surfaces that can form electron donor or acceptor active sites. For instance. experiments have shown that some of these active sites readily donate an e lectron to molecular oxygen to form the superoxide radical (0

2· ) .

0 2• vigorously reacts with hydrogen to form hydrogen peroxide (H,02). which then interacts with iron ions (Fe2• )

present in the body to generate hydroxyl radicals ( ·OH). a type of ROS [7]. Because of a nanoparticle 's large surface area to volume ratio. it tends to have more of these active sites per particle; therefore. nanoparticles create more ROS than their larger counterparts. An increase in ROS levels leads to oxidative stress. which causes damage to cell structures. Normally, the body provides protections against ROS by producing antioxidants and detoxifying enzymes. but when the level of oxidative stress gets too high. key cellular activities are disrupted as ROS levels increase unchecked. As more and more damage is sustained. cells eventually succumb to inflammation and cytotoxicity.

Nanoparticles can a lso penetrate the mitochondria and cause oxidative damage to its membranes. inducing the release of cell death factors [6. 8]. Other injuries to the body. such as protein denaturation. membrane damage. DNA damage, and the formation of foreign body granulomas may also occur due to nanomaterial interaction with cells.

Despite the increasing amount of available experimental data. no general conclusion can be drawn regarding the toxicity of nanomaterials. For example. not a ll engineered nanomaterials have been proven to negatively interact with cells. In an experiment done by injec ting 50nm m odel nanopartic les (MNP)

10

intraperitoneally into mice. the MNPs were found to be present in the brain. but did not seem to cause a toxic effect. This proves that although nanoparticles are small enough to penetrate barriers of the body, like the bloodbrain barrier. they may not be toxic in all cases [9). Another example of this involves the aforementioned ROS. ROS generation occurs only under certain conditions. such as UV exposure. For example. titanium dioxide, now used in sunscreens. can absorb a photon of light to give one of its valence electrons enough energy to "jump" to a higher energy level. This creates an electron "hole" at the nanoparticle's surface. which can then react with water or oxygen

to form various ROS [1 0]. However. this type of reaction only occurs when UV light is absorbed. Even though these exceptions and limitations cast some doubts on how

Despite the current stalemate in regulating nanotechnology,

most governments around the world are now beginning to recognize the rising need for

assessing its risks

truly toxic nonoporticles are under normal conditions. they are still far from being proven safe enough to use without restrictions.

The diversity of nanoparticles further complicates the question of toxicity. Conflicting findings on nonomaterial toxicity have been reported due to differences between synthetic nanoparticles, such as carbon nanotubes. and natural nanoporticles. such as diesel exhausts that are mostly generated by combustion. Whereas engineered nanomoterials are homogeneous in composition and size. natural nonoparticles are heterogeneous in composition and size and con exist in single or aggregated form [6]. Thus. not only is the size of the nanoparticle important in determining its toxicity. but other factors such as its origin and composition also ploy a role. Nonoporticles con enter the human body and interac t with it. but c learly more definitive research will hove to be done in order to


understand the extent of nanotoxicity as well as under what exact circumstances it occurs.

With the increasing prevalence of nanotechnology. specific regulations will be necessary to prevent any potential negative consequences of its use. such as the risks mentioned above. A clearly defined set of regulations has yet to be established for the production and use of nanomaterials because of the lack of a predictable pattern for nanotoxicity. Also. since the impact of nanotechnology is very broad. ranging from environmental effects to public health effects. many governmental departments have become involved in its regulation. which has made it even more difficult to come to one consensus on nanotoxicology. Another problem for regulating nanotechnology involves the fact that nanoparticles are not made out of new and never-before-seen materials. Currently in the US. the Toxic Substances Control Act (TSCA) is considered the primary legislation relevant to the possible negative implications of nanoparticles; however. in order to apply TSCA rules. it has to be determined whether nanomaterials are new chemicals or not. Since nanomaterials are simply scaled down versions of materials that were already on the TSCA list of chemicals. they can technically bypass EPA review and go straight to market [ 1 1) . This is just one example of the many difficulties in applying currently established safety laws to nanomateria ls.

Despite the current stalemate in regulating nanotechnology. most governments around the world are now beginning to recognize the rising need for assessing its risks. The first international nona-regulation conference was held in St. Gallen. Switzerland in 2005. It involved approximately 80 international representatives from industries. governmental organizations. and academia [4]. Not much has been decided yet. but this is the first step toward global cooperation in determining


nona-regulation. Domestically. the American National Standards Institute formed the Nanotechnology Standards Panel in 2004, which will be responsible for developing various standards in nanotechnology [2]. To progress toward a safe future where nanotechnology plays a role. more of these conferences and panels will have to be held in order to share research information and establish appropriate legal standards.

What does all this mean for the future of nanomaterials? With its broad applications. nanotechnology is here to stay. but a better understanding of nanotoxicology is clearly necessary. Workers in future nanotechnology industries may be exposed to toxic nanomaterials. and consumers may be exposed to those same nanomaterials through products that go on the market. Eventually. nanoparticles might end up in the environment. bioaccumulated by microorganisms in soil and water. In order to establish a set of regulatory rules that will satisfy both proponents and opponents of nanotechnology. future research must be directed toward answering questions such as these: What is the size threshold for nanotoxicity? What specific negative effects are invo lved in nanopartic le absorption? How do various nanomaterial c haracteristics affect nanotoxicity? How long does someone have to be exposed to nanoparticles before toxic effects take place? These are the types of mysteries that must be solved about nanoparticles before their safe use can be ensured .

References: [1] M. C. Roco. J. Nonoportic/e Research 5, 181 (2003). [2] E. E. Knowles Ill. Prof. Saf. 20. 20 (2006). [3] C. Meili. "None-Regulation" (The Innovation Society, St. Gallen. 2006). [4] S. S. Tinkle et ol .• Environ. Health Perspect. 111. 1201 (2003). [5] G. Oberdorster. E. Oberdorster. J. Oberdorster. Environ Health Perspect. 7, 823 (2005). [6] A Nel, T. Xio. L. Madler. N. Li, Science 311. 622 (2006). [7] D. B. Zorov. C. R. Filbum. L. Klotz. J. L. Zweier. S. J. Sollott. J. Exp. Med. 192. 1001 (2000). [8] A. D. Maynard. E. D. Kuempel. J. Nonoporticle Research 7. 587 (2005). [9] J. S. Kim. T. Yoon. K. Nom. Toxicol. Sci. 89. 338 (2005). (10) J. S. Tsu~ et ol .. Toxicol. Sci. 89. 42 (2006). (11] N. Lewinski, "Nanotechnology Poky and Environmental Regulatory Issues" (Washington lntemships for Students of Engineering. Washington. DC, 2005).

Graphical References: Page 9. dra_schwortz. File 3102126. iStockphoto.com. 4th April2007. Page 10. Dinev. I. File 3065005. iStockphoto.com. 4th April 2007. Page 11. Cooper, A File 3121356. iStockphoto.com. 4th , April2007.

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Edible Vaccines: Transgenic Plant Research Introduces New Vaccine Technology

SoJma!ii1~1ha A. Conroy

C ombining the best of modern biotechnology with molecular and cellular biology, scientists have recently come up with a new way to combat

disease: genetic reprogramming of plants causes each leaf or fruit to become a vaccine manufacturing system. Transgenic plants are genetically engineered using recombinant DNA techniques to create plants with novel characteristics. This is accomplished by introducing one or more genes of interest into a plant's genome through transformation. There are many economic advantages to developing transgenic plant biotechnology, including increased shelf life and quality of the plant, production of disease-resistant plants, and development of plants with herbic ide and pest resistance. Recently, the medical field has taken advantage of this new technology and the new area of transgenic plant research is flourishing. Plants that can produce vaccines are being considered for possible medical applications in diseases such as HIV, smallpox, the plague, and respiratory diseases.

Background As the risk of infectious diseases grows, it is becoming more and more of a necessity to address this issue, since the possible consequences have global implications. Currently, approximately one in three deaths occur from a communicable or contagious disease and about 75% of these deaths occur in developing countries [ 1]. Clearly, the need to develop inexpensive, easily transportable and effective vacc ines to treat " g lobal" disease is becoming increasingly urgent.

The original goal of genetic ally engineering plants to produ c e vaccines was to make advances in the biotechnology industry more accessible to the public. This continues

12

to be the primary objective of the bio technology and pharmaceutica l industry [2]. By c om bining medical science with p lant biology to create via b le a nd affordable pharmaceuticals, researchers have been able to take this challenge to a new level.

Because almost all widely used vac c ines for humans, with the single exception o f the oral polio vaccine, are limited to injections, an effort is being made to find other less expensive, safer, and less painful forms of delivery. Current vaccine development thus focuses on "subunit vaccines," pathogen-derived proteins tha t do not cause d isease the mselves, but ha ve the ability to elicit an immune response against the pa thogen [3]. In a sense, subu ni t va c cines are "safer" tha n conventional forms of vaccination simply b ecause they are free of the pathogen, w he re as conventional vaccines utilize the patho gen, in a weakened or killed form , in order to e li c i tan immun e res ponse [3] . Additionally, b ecause the mucosal immune system, made up of the


mucus membranes tha t line the mou th, gut, respiratory and reproductive passag es presents a first line of defense against pathogens, mucosal sub unit vacc ines have become a primary research area.

One o f the e arliest plant models that were used to test th e via bility o f p lant-based va ccines was the tobac co plant: it is easy to transform and expression of selected pro teins is easily assessed [4]. The selected protein ac cumulates in leaf t issue which can then be extrac ted [5]. More recent resea rch is focused on find ing other opt ions, including edib le plant species such as grains and vegetables.

Current Research Current resea rc h is targeting some o f the dea dliest d iseases w i th th is new

By combining p24 to lgA, the resulting fusion molecule would be direc ted to these surfaces and help to act as a first line of defense against infection. It was found that the combination of p24 1inked to certain a lpha chains of lgA served to increase expression of the p24 vaccine in the p lants [6] . Thus, by increasing p24 production, immunity is a lso increased.

In o rd er to assess the potential viability of this vaccine in animals, immuniza tion studies were then done using female mice to assess the effic acy o f the p24 vaccine [6]. The researchers analyzed spleen cells from the mice tha t had been immunized with the fusion molecule and from mice without the antigen. They found that a t a dosa ge of 1.5ig / mL T-cell production w as elevated in approximately 15 out of 20 mice that had

been immunized versus metho d o f vacc ina tion. One of the most pressing concerns toda y in th e medical f ield is the growing number of people infecte d w it h HIV-AIDS. There are nearly forty million c ases o f HIV worldwid e and most of t ho se in fected a re

Plant-derived antigens are essentially subunit vaccines that rely on a glycoprotein or a part of the pathogen that can elicit

an immune response

approximately 6 out of 20 mice that had not been immunized [6]. Because Dr. Obrego n 's stra tegy for enhanc ing recombina nt protein expression in p lants has been found to be successfuL further research is planne d to investiga te the possib il ity o f an

individuals from developing countries [6]. Because o f these worrying sta tistics, there is a growing need to d evelop an inexpensive and effective vaccine for HIV. Dr. Patricia Obregon and her colleagues a t St. George's Hospital at the University o f London have been working on a core protein of the Human Immunodeficiency Virus (HIV) called p24. This protein is one o f the four central proteins in the core of the HIV re trovirus and forms the "capsid" of the virus, the case in which the RNA genome of the virus is stored [7]. Importantly however, Obregon found that the immune system responds to increased levels o f p24 by consequently increasing its production of T-cells, white blood cells involved in immunity, that then ta rget the p24 capsid protein [6]. Because p24 is involved in eliciting an immune response to HIV infection, it is an imp ortant prote in to target when designing a va ccine for HIV.

One of the consistent problems in p lant-based vaccine research has been achieving a dequate levels of expression o f the targeted protein in the p lant. If protein levels are too low, the plant is not viable as a "production center" for vaccines. However, Dr. Obregon a nd her co lleag ues have discovered a wa y to significantly increase the levels of the HIV-1 p24 p rotein produced in tobacco plants. They accomplished this by fusing the HIV-1 p24 protein to part of a different protein, human immunog lobulin A (lgA) to c reate an entire ly new "fusion" molecu le [6] . lgA is an importan t secretory antibody that is localized to mucosa surfaces such as the mouth, respiratory tract and gastrointestinal tract.


antibody-antigen fusion molecule that could be used in designing new vaccines w ith specific immunological properties [6].

HIV is not the only disease to have a global impact by far. Two researchers a t the University of Illinois a t Urb ana-Champaign, Dr. Schuyler S. Karban, professor o f molecular genetics and biotechnology, and Dr. Dennis E. Buetow, professor emeritus o f physiology and plant biology, have been working on developing a p lantbased va ccine to combat human respiratory syncytial virus (RSV). A serious d isease, RS V causes lower respiratory tract infections d iseases in all age groups. Because o f a lack o f sanitation and an inad equate healthcare infrastruct ure th a t cause s a vailab le trea tment to be substandard, RSV is most severe in underdeveloped countries. Especially deadly in infants and small children, RSV is a leading cause of pneumonia and bronchiolitis, and because no vaccine is available , the infa nt morta lity rate is high [8] . Additiona lly, according to Dr. Buetow, "more severe RSV infections are being increasing ly noted in nursing homes and other g roup settings serving the e lderly, w ith pneumonia developing in u p to two -th irds of the pa ti en ts. " Commenting on the scope of the RSV virus, Dr. Karban expla ins that over 100,000 o f chi ldren that have been infected w ith RSV are hospitalized at a cost of over $350 million, and among these, nearly 4,500 result in fa talities. Dr. Karban goes on to explain that "currently , there is no vaccine for RSV, but in the past five years or so, there has been a treatment based on a recombinant protein

13

that is delivered as a shot." However, this treatment method is painful and tedious, with monthly shots lasting from October until March, the time where RSV is most prevalent. Additionally, each shot costs $1 ,000, eliminating this treatment as an option for many families. Because of the lack of options for this serious and deadly disease, Karban and Buetow have focused their research on creating a plant-based, orally delivered RSV vaccine.

According to Dr. Karban, plant-derived antigens are essentially subunit vaccines that rely on a glycoprotein or a part of the pathogen that can elicit an immune response. The difference between conventional vaccines and plant-derived vaccines is that conventional vaccines are based on utilizing the pathogen itself to elicit an immune response, while plant-derived antigens are free of the pathogen while still eliciting a similarly effective immune response. Buetow adds that conventional vaccines are generally made in insect or mammalian cell cultures, fertilized eggs or bacterial or yeast fermentation systems. Plant-derived vaccines are increasingly preferred because they do not include any animal-related contaminants. Additionally, humans are not affected by most plant viruses and so any potential contaminants should no t pose any problems.

Both Dr . Karban and Dr. Buetow agree that since the mucosal immune system is the "first line of defense" against disease. especially RSV, an edible vaccine is the most promising area of research. Says Buetow, "It appears useful also to have orallyadministere d p lant-derived vaccines that produce significant levels of serum antibodies for potentially longlasting and/or permanent protection. Our orally-fed, tomato-derived RSV vaccine produces both mucosal and serum antibodies." Karban adds that "For the longest time, immunologists have focused on the humoral immune system, but only recently in the past few years that there is has been an interest in focusing on the mucosal immune system and understanding the mechanisms and receptors invo lved in mucosal immunity."

Tobacco has generally been the test plant of choice because of its viability; however, the health concerns associated with tobacco have eliminated this choice as an e dible vaccine-producing p lant. Instead,

14

researchers are looking at other fruit-producing plants. Because tomatoes are inexpensive, edible, and one of the largest and most economically important produce groups, they are an excellen t plant to use for the production of and dispersal of a vaccine.

Buetow has t hus focused h is researc h on developing an RSV vaccine in tomato fru it. RSV infects living organisms through the use of two proteins, G and F, on its surface. The G protein allows the virus to a ttach itself to a cell and the F protein causes the infected host cell to fuse to another infected cell. facilitating the

dispersion of the v irus from cell to cell [9 ]. According to Buetow, "the fru it has been genetically transformed with the viral gene for the antigenic F-protein of RSV. The transformed fruit produces the F-protein," he says, adding that "mice fed these transformed tomatoes develop both mucosal and serum antibodies against RSV." Because o f this , Buetow says, there is a greater potential for the d evelopment of plantderived vaccines th at can be used to control b oth human and animal diseases.

Benefits and Concerns Although a plant-based vaccination system is still in the testing stages, scientists like Dr. Karban and Dr. Buetow are hopeful that they will soon be able to see t he ir v is ion come to fruition. Buetow estimates that a plant-based vaccination system

may be fully operational in the US w ithin five to seven years while Karban notes that there are a number of plant-derived therapeutic products out in the market right now.

There is no ques t ion that p la nt-based edible vaccines have many benefits. One of the major advantages is the quick harvesting time. Within a matter of days, the plant can be infected, the relevant protein produced, and the plant harvested. Additionally, plants with edible fruits that provide a direct target for the antigen, such as tomatoes, apples and other fruits and vegeta bles, can be produced on a large scale , increasing production and lowering the cost per dose [10].

However, some processing w ill be necessary to convert plant derived vaccines into an edible form. Dr. Buetow says that since the levels of vaccine that are c urrently being produced in edible plants are not sufficient to provide lasting immunity, the solution would


be to develop a liquid or a d ried extract o f the p lants containing the vaccine. This would provide high enough amounts of the vaccine to ensure a protective immune response.

Dr. Charles Arntzen, co-director of the Center for Infectious Diseases and Vaccinology at Arizona State University, is one of the leading experts in the field of plant-based vaccines. Dr. Arntzen 's vision , and the primary focus of his research, is to c reate new, oral vaccines for developing nations. Dr. Arntzen says that "If we could develop less expensive manufacturing systems that cou ld be adopted into develop ing countries, we could also begin to expand the robust production of a new genetically engineered generation of vaccines." Because of the g reat potential of edible vaccines, Dr. Arntzen has done several studies on the economic feasibility of p lant-based, edible vaccines. He estimated that the cost range of goods needed per dose of a plant-derived hepatitis B vaccine is $0.04 to $0.1 0. The study found that once packaged, the total cost per vaccine would be approximately $0.13 whereas currently, the lowest price for this same vaccine produced in the traditional manner is $0.30, more than twice the cost [11 ]. Furthermore, because of advancements in biotechnology, it is now possible to produce multi-antigen vaccines through multiple gene splicing techniques and mixing d ifferent plant-derived vaccines [ 11 ].

The processing technique is simple . According to Dr. Arntzen, a screw press. such as those used to c rush grapes in the wine industry, will compress p lant tissue to excrete juices containing the vaccine proteins. A mesh filter is then used to eliminate the bulk material. Since the vaccine proteins stay soluble. they are able to be filtered through the mesh. Another smaller. mesh filter is used to retain the protein a nd the vaccine can then be concentrated at this step and washed with a buffer to eliminate small, unwanted molecules. The resulting highly concentrated protein paste can be collected, dried to stabilize it. and then d istributed in capsule form.

Another important benefit is that ora l vaccines are much safer than injecta b le vacc ina tions. Because injectable vaccinations require the use of expensive hypodermic needles, delivering a vaccine orally will bypass this cost in addition to eliminating the concern of cross contamination of blood products, a serious risk in developing countries where needles are often reused.

Human testing is stil l in the early stages and there have been only five Phase 1 human trials. In these studies, human volunteers were fed raw potatoes or lettuce expressing the e nterotoxin B subunit from E. coli [ 12. 13]. However, Dr. Arntzen remains upbeat, saying that "all have been successfu l from the standpoint that the proteins that were delivered in the tissue provoked the proper response in the human subjects, i.e. the subjects produced both mucosal and serum antibodies against the toxic B subunit."


Yet eve n w ith all o f these benefits, there is still the concern about how the public will react to the idea of consuming genetically modified foods. Dr. Amanda Walmsley, Research Fello w a t Monash Unive rsity in Melbourne, has been researching plant-made vaccines for over nine years and has performed public surveys regarding the use of genetically modified, ora lly delivered , p la nt -made vaccines. According to Walmsley, the idea is generally well-received: "If people can see the common good that a genetically modified organism can give . they are usually receptive to the idea." This acceptance is partly due to the fact that there are many safety regulations involved in making genetic ally modified vaccines. "So long as a ll of the pharmaceutica l an d agric ultura l regu la t ions a re adhe red to with regards to making a p lant-made vaccine , and we make sure we adhere to the regulations to the le tter, there shou ld be no ethical concerns regarding this technology," says Walmsley.

However, there are still some risks that need to be met to gain regula tory approval for the new vaccines. A risk factor that must b e met with plant-made vaccines is the potentia l to contaminate other, non-genetica lly modified pl ants. Because many p lan ts are windpollinated, this could c reate a potential hazard in gene spread. There are several stra tegies in p lace for the containment o f transgenic c rops. A commonly used strategy is "spa tia l isolation" where transgenic c rops are p ia nted in greenhouses to prevent polle n transfe r outside the area of production. In addition, some groups are using plant viruses to carry the gene for a vaccine; as they rep licate in the leaf. they produce the desired protein. This strategy prevents the genes from getting into the p lant's DNA. and there fore cannot lead to release of pollen with the vaccine genes. Since viruses mutate as they rep lica te. a strict qua lity contro l mechanism is needed to be sure that the vaccine is exact ly the correct protein. Because of the cost of this quality contro l, the preferred a lterna tive is to use transgenic plants that incorporate the gene of interest into the nuclear chromosome. This gene may undergo subsequent mutation, but it is only one cell out of billions o f cells in the p lant and thus the mutational frequency of genes in the nuclear chromosome is very low.

Additiona lly, anothe r potentia l problem is the question of whether or not plant-based vaccines w ill weaken the immune system. Dr. Arntzen explains that through a biological process called "tolerization, " our immune response against proteins is shut down. This process has been studied in deta il in many medical immunology laboratories. Arntzen explains that the proteins being designed as p lant-based vaccines are not soluble protein, and as such are very unlikely to have negative effects. He emphasizes, however, that testing of a ll protein-based o ra l vaccines from any source inc luding plants w ill very likely require tes t ing for

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to lerance induction be fore the Food and Drug Administratio n will grant a lic ense to p roduce the vaccine commercially

Lastly, some have raised concern over the possibility of_ over-vaccination. Dr. Arntzen believes that a lthough th1s should not prove to be a problem, a requirement for licensure o f this new method is going to require evidence that overdosing on the vaccine would be impossible. " In ord er to satisfy vaccine licensure , a rigorous downstream method to make uniform dosage and qua lity control standards will no doubt be developed," says Dr. Arntzen, adding that "while this may add some cost. we will end up with products that will be in a pill or capsule form, which will make plant-made vaccines just like any other oral vaccine, from the user's perspective."

However, as Walmsley points out. the biggest challenge is not overcoming public misgivings about plant-based vaccines but in moving the idea past "proof of principle" and into clinica l testing stages. To date, there has only been six phase I human trials performed using plant-based vaccines. According to Walmsley, "phase I tria ls are conducted on limited numb er of healthy people, usually less than fifty, and test the general sa fe ty and lack of adverse e ffects o f the vaccine," adding that because there are four different phases of trials "we' re a long way off just yet." Arntzen points out that the cost of moving vaccines through licensure is the biggest drawback at p resent. since the academic groups who have pioneered the use of plants for developing world vaccines do not hove access to the hundreds of millions of dollars needed for complete testing to gain vaccine licensure. He notes that the recently approved Cervical Cancer vaccine that two companies are introducing cost over $1 Billion to get from concept to market.

Yet the growing threa t of g lobal d isease, made potently c lear by the HIV-AIDS crisis in African countries and the smallpox threat here at home, continues to work as a driving force motivating researchers like Arntzen, Karban, Buetow and Walmsley to search for increasingly crucial results. But as is a lways the case with research, progress is slow. Says Karban " ... we still have more work to do."

References: [1 ) A.D. Lopez, C.C.J.L. Murray. The Global Burden of Disease, 1990-2020. Nature Medicine, November, 1998; 4(11 ), 1241-1243. [2) C.J. Arntzen, T.S. Mar. Pla nts and Human Health: Delivery of Vaccines via Transgenic Plants. Molecularfarming.com, 2002; http:// www.molecularfarming.com/ediblevaccine.html. [3) Karban, S., Personal communication. [4) S. J. Streatfield. Plant-based Vaccines for Animo/ Health. Rev. sci. tech. Off. Int. Epiz .. 2005; 24(1) , 189-1 99. [5) H.S. Mason, R. Chikwamba, L. Santi. R.T. Mahoney, C.J.

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Arntzen. Antigen d elivery systems: Transgenic plants for muc osa l vaccines. Mucosal Immunology, 3rd Edition. Section D. Mucosal Vaccines (McGhee JR, Mestecky JF, Eds) Elsevier Science, London, 2004, pp . 1053-1060. [6) P. Obregon, e t. al. HIV-1 p24-immunoglob ulin Fusion molecule: A New Strategy for Plant-Based Protein Production. Plant Biotechnology JournaL (2006) 4, pp . 195-207. [7) T. Sterling et a l. (2002) H/V- 1 p24 and Disease Progression. J Infect Dis 186:11 81-11 85. [8) S.S. Karban, S.F. Krasnyanski, D.E. Buetow. Foods as Production and Delivery Vehicles for Human Vaccines. Journal of the American College of Nutrition, 2002; 21 : 212S-217S. [9] G. Bolt, L.O. Pedersen, H.H. Birkeslund. Cleavage of the Respiratory Syncytial Virus Fusion Protein is Required for its Surface Expression: Role of Furin, Virus Research, 2000 June; 68( 1 ): 25-33. [10] C.J . Arntzen, B. Dodet, S. Plotkin. Plant-derived Vaccines and Antibodies: Potential and Limitations, Vaccine, 2005, 23(15): (1753-1 756). [11] C.J. Arntzen, R. Mahoney. Plant-derived Vaccines: Cost of Production, (Center for Infec tious Diseases and Vacc ino logy, Biodes ign Inst itu te, Arizona Sta te University, 2006) , http:/ /www.biodesign.asu.edu/assets/ p d fs/id v-p rova cs/ Pia nt -derived-Vo ccines-C ost -ofProduction.pd f. [1 2] Kapusta e t a l., A Plant-derived Edible Vaccine against Hepatitis B Virus, The FASEB Journal. 1999; 13:1769-1799. [1 3] Y. Thanava lo, Y. Yang, P. Lyons, H.S. Mason, C.J. Arntzen. lmmunogenicity of Transgenic Plant-Derived Hepatitis B Surface Antigen , Proc. Natl. Aced. Sci., USA vol. 92, 3358-3361. 2005.

Other Sources: • D. Herzfeld, K. Orvis, T. Riordan, H. Zaleski. M. Zeller. Edible Antib iotic s in Food Crop , Bioethics@ Iowa Sta te University, June 6, 2003. http:/ /www.bioethics.iastate. edu/ c lassroom/ edibleva ccines .html. • D.D. Kirk, K. Mcintosh. Social Acceptance of Plant-Mode Vaccines: Indications from a Public Survey. AgBioForum, 2005, 8(4): 228-234. • W.H.R. Langridge. Edible Vaccines. Scientific American. 283 (2000): 66-71. • B. Sylvester. Are Edible Vaccines the Wove of the Future? Medical Post. 37 (2001 ): 29. • D.E.Buetow and S.S. Karbon. Transgenic p lants producing viral and bacterial antigens. AgbiotechNet. 2000, vol.2, pp.1 -6.

Graphics References: Page 9: Micka, D. File 892075, iStockphoto.com. 4th April 2007. Page 11: http: //www .ars.usda .gov / is/ AR / archives/ sep00/tomato0900.htm


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Out of Sight, Out of Mind: Medical Breakthroughs that Never Reach the Third World

Shreyas Muku1111d

I n recent years, there has been growing media criticism levelled a t the heads of big pharmaceutical firms. Whilst most will lose interest in the repea ted ly touted

'evils of big ph arm a ', the large-sca le rea lity of the situation is both surprising and a larming.

Representing less than one sixth of the g lobal population, the US, EU and Japan together account for 90% of the global pharmaceutical market [1] at current exchange rates and it is here that this €500 billion-dollar global industry focuses its attention and its research. With 40% of revenues controlled by just 1 0 companies [2]. those decisions are further consolidated into a few

The trend of corporate disinterest is apparent as only 10% of HIV

vaccine funding originates from commercial organisations

boardrooms and further divorced from the reality of lives in the Third World.

Neglected Diseases Malaria, leishmaniasis (kala-azar) and AIDS, together are responsible for over 5 million annual deaths worldwide with over 95% of sufferers living in the developing world [3). There is no widespread, proven vaccine availab le for any of them and the limited treatment a vailable is far too expensive for the vast majority of sufferers, with a recent UNDP Human Developmen t Report placing

approximately half of the world 's population under the $2-a-day poverty line.

In addition, there are several complicating factors. Foremost among these is t he rise of AIDS, which compromises the immune system of sufferers and leaves an ever-increasing number of people vulnerable to the other diseases. Many existing antiretroviro l drugs to counter HIV and anti-parasitic measures to tackle malaria have become progressively less effective in the face of resistance developing in their respective pathogens.

By for the most prevalent of these d iseases in the West is AIDS. Following extensive international lobbying by NGOs in recent years, some progress has been made. Funding for an HIV vaccine has doubled in the last halfd ecad e to o ver €600 million [4), with various experimental protein, DNA and vira l vector vaccines shown to be effective in animals and in human tissue culture. The trend of corporate disinterest is apparent as only 10% of HIV vaccine funding orig inates from commercial organisa tions. With increasing recognition of this disinterest. conditions such as malaria , tuberculosis and several other tropical afflictions, which receive even less commercial attention than HIV I AIDS, have been collectively dubbed 'neglected diseases ' .

Disparities If there has been a modest expansion in AIDS research, there has been a verita b le explosion in funding for cancer therapy and countermeasures for cardiovascular diseases, which are by far the most prevalent causes of death in the developed world . To illustrate this, we can look a t the story of two drugs, tackling diseases that a ffect people on opposite ends of the income spectrum.

How the figures stack up. Comparison of drug research and development investment

Investment

Global private R&D expenditure (2005) Military Budget of the United States of America (2006)

Global private healthcare R&D expenditure (2005) Sales of LDL-reduclng drug, lip itor (2005)

Pfizer: Tota l Profit (2005) Pfizer: Tota l R&D expenditure (2005)

US Cosmetic Surgery Products Industry (2005) Phase Ill tria ls, torceptrapib

Cancer Research UK research investment (2005) Global Commercial Investment in HIV vaccines (2005)

Global Public Funding in Private-Public Partnerships for Neglected Diseases (2005)


Expenditure /€ 37 1 b illion 350 billion 73 billion 9.7 billion 6.4 billion 6.3 billion 1.3 billion

650 million 317 million 60 million

33 million

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Pfizer's newly developed product, torcetrapib. has been shown to reduce the chance of heart disease by affecting the transport of cholesterol in the blood.

Cholesterol is a key precursor for the vast majority of human steroid hormones (such as cortisol and testosterone) and is

Since then. a d rug has been sought to inhibit the a c tivity of CETP and in 2004, torcetrapib was succ essful ly demonstrated by Pfizer scientists in human patients. In early 2006. less than two decades after the concept was developed. investment inc luded €9 0 million fo r a

manufacturing p la nt involved in controlling the fluidity of plasma membranes in our cells. Owing to its low solubility in water (which forms the bulk of blood plasma), cholesterol is transported in several specialised

The disparity between medicine for the rich and medicine

expansion in Ireland a nd €650 million o n the Phase Ill c linical trials involving 25,000 pat ients [5]. In spite of this massive investment and rapid develop ment

for the poor has been extreme for the past century

p ro cess , t he trials

particles, which are forms of lipoproteins. Low Density Lipoproteins, or LDLs, and High Density Lipoproteins. HDLs. are two such protein-fat constructs designed for carrying low solubility compounds from the liver to other tissues. High concentrations of larger LDLs have long been associated with cholesterol deposition leading to atherosclerosis, which greatly increases the risk of heart attack. HDLs, on the other hand. have been associated with redu c tion in cholesterol deposition.

In 1990, a study was carried out on five Japanese famili e s who lacked the ability to synthesise the Cholesteryl Ester Transfer Protein (CETP). This mutation reduced the rate of cholesterol transfer out of HDLs, thus maintaining a higher HDL c oncentration in the blood and lowering the incidence o f heart disease.

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demonstrated t ha t patients rece1v1ng the drug experienced an unexpectedly high mortality rate compared to the control sample. The product was wi thdrawn by Pfizer in January upon presentation of the results.

At the other e nd of the scale, paromomycin. an aminoglycoside antibiotic, has been known to be an effective anti-parasitic compound since it was isolated in 1959. Although the precise mechanism of action is unclear. p aromomycin is no w known to inh ibit the synt hesis o f pro t eins in t he p arasite. Leishma nia donovani, the main cause o f kalo-ozor. The drug was briefly sold for ora l-use in humans and subsequently abandoned due to a la ck of pro fitability. It has rema ined unmarketable for 41 years [6).

The disparity b etween medicine for the rich and medicine for the poor has b een extreme for the past

century. According to a recent p ublication in the medical journal , Th e Lancet, from 1975 to 2004, 1556 'N ew Chemical Ent ities ', d istinc t n ew d rug s, were licensed by US Food and Dru g Admin istra ti on [7) . This inc lud e d a mere 21 treatments for 'neglected d iseases ' . inc luding 3 for th e g loba lly resu rgent strains o f tuberculosis and eight for malaria.

The Age of Philanthropy With Warren Buffe t ' s recent d onation o f most o f his w ealth , th e Bill & Melinda Ga tes Found a tion has b ecome the worl d ' s best-funde d charity, w ith an endowment in excess o f $30 billion [8). Essentia lly cons tructed upon the


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riches of two men, one of the organisation's core goals is to tackle diseases endemic to the poorest populatio ns of the world .

In fac t. one o f the organisation's successes was an attempt to salvage paromomycin . In July 2000, the Institute for One World Hea lth was founded in the United States as the world 's first non-profit pharmaceuticals development company. It rapidly ac quired the rights to paromomycin , found a ma nufacturing p artner in the Indian pharma ce uticals industry a nd. within 4 yea rs. c arried out a successful p ho se Ill trial.

The organisation has since received €11 5 million of Gates Founda tion fundin g and e xpects t o ma rk e t a comp le t e t reatmen t sche m e for $ 10. al tho ugh eve n t his is considered rela t ively expensive for the most impoverished victims o f Kala-ozar [9).

Indeed, a similar story is emerging conceming artemisinin, a c omp onent o f a Chinese herbal remedy, which was singled out for d e velopment by the Chinese military in 1972. but poorly investigated by pharmaceutica ls compa nies. Most exist ing anti-ma laria ls currently recommended by the WHO, ore synthetic derivatives of this compound and one of the main anti-ma larial prophylactics licensed is mefloq uine. which was the latest in a series of d rugs developed in the 1970's by the US military to prevent

Of the 700,000 people in developing countries receiving antiretroviral drugs, half rely on

the Indian generics industry

t roops b eing taken out of action, demonstra ting the importance of political will in the progress of medical research.

Unfortunately, even with lead development driven by the need for e fficient armies, most of the existing treatments lie for beyond the economic means of those in need , due to the exp ense of artificial synthesis or extraction from plant sources. The possib le development o f g eneti ca lly modifie d yeast stra ins capab le o f artemisinin biosynthesis has recently been presented as a che aper alternative by the Institute for OneWo rld Health. in collabora tion with researchers in Synthetic Biology at the University o f California. Berkeley.


Overpricing and Generics Of course. there are diseases

w hich grave ly a ffect the g loba l population as a whole and as a result

the products developed and sold in the West can. in theory. benefit the rest of the

world . Howe ver, as mentioned before, m edical products sold a t Western prices are scarcely accessible to a signific ant proportion of Third World populations.

When a company's patent on a compound expires, o ther m anufac turers c an introduce near-identica l competing produc ts, which ore not b randed in the same way. known as 'generic' d rugs. Data from the US market shows that. on average . b y the entry o f a second competitor into a market. the mean product price w ill have drop ped by 46% [1 0) .

How ever. accord ing to t he US Fe d e ra l Drug Authority, patents typ ically expire twenty years a fter being fi led and generics ma y only be sold in the US after this t ime ha s passed. The result is a relatively long-term and unregula ted monopolies on the la test d rugs.

The time taken for competitors to enter any given market depends on the willingness of the judiciary to protect the intellec tual property o f the patent holder. India and Brazil are among the few countries with both an advanced chemical industry to support high-quality generics m a nu facture as well as a sympath e tic judiciary to allow earlier competition in the market. In sp ite of a recent change in law to improve protection of patent holders, the Ind ian ge ne rics ind ustry has become a majo r supplie r of low-cost medic ine in developing countries , reducing p rices b y up to a hundred-fold from equivalent brand-products. Of the

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700,000 people in developing countries receiving antiretroviral drugs, half rely on the Indian generics industry [11].1n the recent past. Indian courts have held in favour of generics pharmaceutical companies and even the US federal court of appeals ruled to effectively curtail a patent on Pfizer's most lucrative drug, Lipitor, allowing India's largest generics manufacturer. Ranbaxy, to move in 15 months earlier than expected [12].

Alongside the support of the Indian courts, Ranbaxy has become a target for Private-Public Partnerships, such as that set up by the Medicines for Malaria Venture (MMV), another organisation that has received Gates grants. Ranbaxy is now on the verge of commercialising a new low-cost artemisinin alternative, a project which was accelerated by the MMV-brokered transfer of research on synthetic peroxides from Roche.

This year, the government of Thailand followed suit, in a move that has attracted much criticism from pharmaceutical multinationals. The purchase of a generic alternative to the antiretroviral Koletra is expected to allow five times as many people to obtain the drug from the government compared to the current distribution regime under Sanofi-Aventis. The Thai support will boost generics manufacturers in India and odd to growing lobby at the WTO for the licensing of generics in the case of national health emergencies.

The main argument directed against generics manufacture rs is that they ultimately prevent a sustainable research model for drug development. On average the sunk cost for developing a new compound is, rather controversially, estimated to be in excess of €800 million [13] and for such expenditure to be made, investors must feel confident that these costs will be recouped . Indeed, Pfizer's failed torcetrapib, although uniquely well funded, illustrates the need for high prices on cholesterol-reducing drugs. In fac t, with much concern over upcoming patent exp iries, Pfizer intends to axe 10.000 jobs by the end of 2008 and AstroZeneco have recently announced plans for a 5% reduction in its global workforce.

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At first it seems to be reasonable cri t icism that the research model is 'short-circuited' by generics firms, however, one must reconsider the arguments previously presented; first ly, that few in the Third World can afford even the less expensive brand products a t their current prices, and secondly, that the income from these markets make up a m inor port of the global re venue o f pharmaceuticals organisations. As a result, t he introduction of a cheaper generic drug into the market of a developing country would have little effect on the global revenue of major companies and present minimal financial threat. In fact, the multinational may be so insensitive to the sale of generic drugs in developing countries that their introduction may not even translate to a significan t price d rop in the original b randed product. An extreme example to illustrate this comes from the International Dispensary Associa tion, a nonprofit group based in the Netherlands, which has been selling medical and healthcare supplies at affordable prices for almost three decades. The organisation provides chemo t herapeutic agents, such a s doxorubicin, to the South American market for as low as 0.1% of the price of the branded d rug in that market [14].

A further point has been often made by observing that the combined profits o f the 1 0 largest multinational pharmaceuticals companies totalled €28.6 billion in 2004, some €1.8 billion more than the net profit of the remaining 490 companies in the Fortune 500 listing [1 5]. Over decodes of acquisitions and o rganic growth, drugs companies have swollen into g iants from First World sales and even today many firms enjoy double-digi t growth in sales and profits. As such, even the predicted drop in soles revenue expected with patent expiry around 2010 does not justify the withholding of d rugs in much poorer countries. The question of public-health policy that arises is whether the risk of losing future research from f inancia lly robust MNCs is w orth obstructing low-cost drugs from reaching the millions of sufferers in need today.

A hope for the future? The example set by

the Gates Foundation and a new wove of ventures bode well for engendering a stronger spiri t of phila nthropy in a world w here . a ccording to Fo rbes, in March, the world' s 793 billionaires controlled $2.6 trillion, a sum that is comparable to the GOP of the 840 millionstrong African c ontinent [ 16]. However. a recen t


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study published by the Wellcome Trust estimated that, as of April 2005, of the funding received and pledged to Private-Pub li c Pa rtnerships focused on d rug development for 'neglected d iseases ', over 78% had come from philanthropic organisations [17].

An R&D model so hea vily dependent on such funding can scarcely be considered robust. However, the long- term heal thcare revo lution he ralded by p hilanthropic organisations may be as much a result of their truly global view of medical care as due to their financ ial support. Their advent may finally enable us to make globally proportionate advanc es in healthcare .

The development of smaller companies, w hose main market is the p oor, operating through Private-Public partnerships suc h as MMV, could also indicate a new pri va te-sector p arad igm with a lowe r cost d rug development pipe line. Impro vement of links w i th academia will also be crucial to d e velop a p aralle l healthcare produc ts industry. developing drugs for Third World diseases, sold at prices a ffordable in the Third World and becoming less dependent on the research of 'big pharma' and the royalties that they seek to exact.

There do remain long-term threats as well however and one can not expec t this new and now more realisable model to be the perfect cure to the ailments of free-market medical care. The impoverished are among the most vulnerable of people especially when in critical health and multinationa l pharmaceutica l companies , heroes of the recent past, have been charge d with nu me rous a llegations of i llegal a nd premature c lini c al tria ls. Kee ping t his in mind , a nightmare scenario can be envisaged where generics companies lead a new era of profiteering in the name of the poor, selling c ompromised products, perha ps tested on humans w ithout consent. at prices affordable only to the new middle classes of emerging economies, excluding the most impoverished yet a gain.

Only time will tell whether principles shall endure, but having the financia l clout of Bill Gates. Warren Buffet and those o f their ilk to support researc h con only be an adva ntage for n ow in o n otherwise mass ive ly underfunded field.

Shreyas Mukund is a 3'd year reading Natural Sciences (Chemistry} at Christ 's C ollege, Cambridge.

References [ 1] IMS Health Inc [2] Forbes [3] World Health Organis a tion [4] HIV Vaccines and Microbicides Resource Tracking Working Group (2006) "Adding It All Up : HIV Vaccine and Microbicide Development Funding." [5] Pfize r Inc [6] Inst itute for OneWorld Health [7] Ch irac P, Torre e le E (2006) "Globa l framework


on essentia l health R&D." The Lancet 367 9522 1560-1561 [8] Bi ll & Melinda Gates Foundation [9] Institu te for OneWorld Health [ 1 OJ US Federa l Drug Authori ty, Office o f Generic Drugs. Ana lysis of reta il sa les 1999-2004 based on data from IMS Health Inc [ 11] Medecins sons Fron tieres [ 12] CNN [13] DiMas i J, Hansen R. G rabowski H (2002) "The price of innovatio n: n ew esti mates of drug development costs." Journal of Hel th Economics. 22 2 1 51-185. [ 14] Ministerio de Sa lud del Peru (Peruvia n health ministry) and International Dispensary Association (2003). [ 1 5] Fortune 500 listing (Fortune Magazine) [16] Forbes and the CIA World Factbook [17] Moran M, Ropars A. Guzman J. Diaz J, Garrison C (2005) The new landscape of neglected disease drug development. Lond on School of Economics and the Wellcome Trust

Graphics References Page 18: Asiseeit. File 2406728, iStockphoto.com. 4th April 2007. Page 19: Lee, P. Rle 1544327, iStockphoto.com. 4th April 2007. Page 20: Burley. File 2367011, iStockphoto.com. 4th April 2007. Page 21: Nijs, M. File 2051524, iStockphoto.com. 4th April 2007.

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The Future of Biofuels Thor111as K~uyverr

A t present. the vast majority of our energy comes from fossil fuels. In the UK, 73% of our electricity is generated from fossil fuels, mainly coal and gas

[1]. and 97% of non-electric energy is supplied by oil and gas [2]. Burning these fuels releases carbon dioxide into the atmosphere, which is now thought to lead to global warming. More pressing, however, are the political implications of our dependence on fossil fuels, particularly oil, which is the source of many vehicle fuels. In the current political and environmental atmosphere, we are looking towards new sources of fuel. Biofuels seem to hold the answer to many reservations over alternative fuels. Could this be the answer to Britain's energy crisis?

Part of the problem with fossil fuels is due to the political implications of their international market. Oil reserves are very unevenly distributed, and a relative ly small group of nations, particularly in th e Middle East, supply a relatively large proportion of the world's oil. About 70% [3] of the oil exports made worldwide are by countries which are m e mbers of the Organisation of Petroleum Exporting Countries (OPEC) - affording th e m a significant degree of co ntrol over oil prices [4]. Given the inexorabl e link b e tween GOP and oil use (see Figure 1}, this is a political m i n e fi e I d : t h e

6,000,

...... c. "C ..c ...... 1:

.Q c. E :::1

"' 1: 0 u 0

0 GOP (Billions US$)

Figure 1: Oil consumption related to GOP [6]

economies of powerful countries can b e great ly affected by other nations over wh ich they have li ttle or no political in f lue nce. This is especially true since the nations which make up OPEC include many whic h are not traditionally allied with the first world, such as Iran, Iraq and Venezuela. For this reason, in January 2006, US President George Bush announced that the US

Biofuels seem to hold the answer to many reservations over alternative

fuels. Could this be the answer to Britain's energy crisis?

would, through technology, find rep lacements for at least 75% of the oil it imports from the Middle East by 2025 (5].

So how can we alleviate this problem? The answer seems simple: find other energy sources. Unfortunately, the main alternatives have many problems of their own. Nuclear power, although supplying 77% of the French and 23% of our own energy usage [7] , is very unpopular

due to a number o f high-profile a ccidents and the problems o f storing nuclear waste . Renewable energy sources h ave g reater public appeal. Their drawbacks inc lude being expensive (Figure 2} and intermittent - sources such as w ind and solar power are a t the mercy of the elements - and caus ing other environmental damage such as disruption of b ird populations by w ind farms [8] .

Furthe rmore , we cannot normally use electricity as a fuel for vehicles. Electric cars suffer from the limita t ions o f battery technology, and hydrogen fuel cells still have significant technical hurd les to overcome [ 1 0] . Either technology would also require a

4500 significant shift in infrastructure and car design.

This is w here b iofuels offe r

Data points represent countries, linear trend line added. No te that the U.S.A. and China are not shown on this graph

promising results. In the 1970s, th e Bra zi li an Governmen t started the Programa Nacional do

22 THE TRIPLE HELIX Spring 2007

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Wave

Wind - offshore

Wind -onshore

Nuclear

ccs

Gas

0 2 4 5 e 7

Cost (p/ kWh)

Figure 2: Government estimates of 2020 energy costs from different sources [9] Only wind can compete economically with natural gas [the current cheap est option). Note that estimates for solar power is not shown here - these are in the range 10-16 p / kWh

Alcoa/, to promote the use of e thanol from fermented sugar-cone to fuel cars [1 1]. New engines can be built to run on a variety o f ethanol-petrol mixtures, or p ure fuels- all new cars in the U.S.A. are now des ig n ed to accept fuel containing up to 1 0% ethanol. The sugar cane con be easily grown, and is carbon neutral on being burnt [an equal amount of C0 2 is released as it took up from the atmosphere to grow) . As an a dded bonus, fewer o ther pollutants are released than are by burning p etrol.

All was not perfect, however. Ethanol p roduction tokes a significant amount of land - Brazil is estimated to use 4.5 million hectares growing sugar cone , of which some 55% is used to c reate ethanol [12]. In spite of this vast use of land, the scheme is currently only producing some 282,000 barrels per day, compared to Brazil's consumption of around 2. 1 million barrels of oil per d ay [13] . More importantly, much of this land is used only for sugar cane, to the exclusion of all other p lants, a socalled monoculture. This situation, a lready familiar from food c rops, is ecologica lly disastrous, as it reduces biodiversity. Also, the traditional method of burning fields to clear them after harvesting has, when used on this scale, had serious impac ts on air quality in sugar-growing areas [14].


To some extent, these problems con be solved by more e ffi cient agri cu ltu re. With a fa irly generous estimate for improved efficiency, the previously quoted figure of 282,000 barrels per day may be generated from only 1 million hectares. This might seem impressive, but if this w ere to replace the US 's daily consumption o f 20,300,000 barrels of oil [15]. it would need to be scaled up to 71 million hectares, over 40% of the c urrent land area which America uses to grow crops. This would stil l replace neither the US's annual natural gas use of over 600 billion cubic metres, nor its annual consumption o f over one billion tonnes of coal [16] .

One major area for improvement is in the efficiency of using the plant matter. Of the total biomass of a sugar cane, th e m ajo rity is c e llu lose, which cannot b e fermented by traditional means. One possible avenue for major efficiency improvements is cellulosic ethanol. This involves breaking down ce llulo se, a polymer of sugars, into its individual un it s, which can the n be fermented to give ethanol [17] . While only a few plants store significant amounts of sugar, cellulose is a major structural component of a ll p lants, so the range o f potential row materials that could be used is for greater.

Another means by which biomass can be processed is gasification . Biomass is p artly burnt in such a way that

23

.· CAMBRIDGE

it releases a mixture of carbon dioxide and hydrogen, which can be burnt or fed into a fuel cell. One difficulty with this is that it requires careful filtering to remove impurities such as ash from the mixture . Alternatively,

Of the total biomass of a sugar cane, the majority is cellulose, which cannot be fermented by

traditional means

gas can be produced by allowing anaerobic bacteria to digest biomass and produce methane, which is the main component of natural gas. In general, biological methods of processing are cheaper- as they run at low temperatures and pressures, without expensive catalysts - but slower, which puts them at an industrial disadvantage.

A third technology that is c urrently being d eveloped is known as the Thermal Conversion Process. It can potentially make use of a wide variety of waste substances - an experimental p lant in Missouri runs on sla ughterhouse waste [18]. By a combination o f heat and pressure. the material is chemica lly transformed into a substance similar to oil. This can be used directly in generators. or further refined for use in vehic les, while the waste materials from the process can be made into fertilisers.

24

As mentioned above, one major potent ial problem with biofuels is the need for land to grow the fuel crops. This poses both ecological problems - there are, for example, concerns that rainforest in Indonesia may be cleared to make way for palm oil plantations [ 19] and social/economic concerns. A rapid transition to biofuels might make it economically favourable to g row energy crops instead of food crops, in areas where people are starving [20] . As b iofuels become more widespread and more profitable, the market p ressures to g row them will become stronger. It is vital that we address this problem in advance, rather than waiting for it to become reality . One possibility is an international reg ula t ion or agreement not to grow energy crops where the land could be used to produce food for the starving. This could be difficult to enforce, however, and risks excluding developing nations from the biofuel industry. Perhaps it is more realis tic to concentrate on technologies -including those describ ed above - which do not re ly on a specific part o f a speci fic plant . Food crops could then b e grown as a priority, and the inedib le parts processed to make biofuels.

Another concern is whether biofuels are actually energetically viable. Some observers have calculated that the energy in an amount of a biofuel such as ethanol is less than the energy required to produce it [21] . The implic ation of this is that more fossil fuels are used to produce the biofuels, which can then only be pro fitably grown in t he presence of government subsid ies. Furthermore, carbon dioxide emissions (and other greenhouse gases) would therefore be higher than they


CAMBRIDGE

are when using fossil fuels d irectly. Recently, however, a number o f studies have refuted this view, suggesting that bio fuels do in fact yield more energy than is used in their product ion [22] . That biofuefs can be produced loca lly , ra ther than imported , is a major poli tica l incentive, as it would diminish the economic control OPEC nations currently w ield over oil-importing nations [23] .

Biofuels, although they cannot be the solution to all our energy problems, may at least be able

to play a part in that solution

History teaches us that no answer to the energy c ris is is w ithout its problems, and hence we should avoid presenting bio fuels as a utopian vision. We should by no means. however, totally shun them in our search for energy sources. Biofuels, a lthough they cannot be the solution to a ll our energy problems, may at least be able to p lay a part in tha t solution, especia lly with new technologies allowing us to extract energy from wha t would otherwise be waste products.

Thomas Kluyver is a 1'1 year reading Natural Sciences at Pe terhouse. Cambridge.

References: [1] 2001 figures from ONS - http:/ /www.statislics.gov.uk/ ST ATBASE/ssdataset .asp? vlnk= 7286 [2] 2005 figures from the DTI Digest of UK Energy Statistics 2006 [3] Calculated from CIA World Factbook Figures [4] See for example http:/ / news.bbc.co.uk/1 /hi/business/ 6080734.stm [5] State of the Union Address, 31 January 2006 [6] Data from the CIA World Factbook [7] 2001 figures from ONS - http:/ /www.statistics.gov .uk/ ST A TBAS E/ssdataset. asp?vl nk= 7286 [8] See for example ht tp :/ / news.bbc.co.uk/ I / hi/world/ europe/51 08666.stm [9] The Energy Review, Cabinet Office, 2006 [I 0] http:/ /www.eere.energy.gov /hydrogenandfuel cells/ mypp/pdfs/ fuel_cells.pdf [11] http:/ /www.eia.doe.gov /emeu/cabs/brazenv.html [1 2] Rgures from UNICA. The Union of Sugar-cane Growers [1 3] 2005-6 figures, US Department o f Energy http :/ I www.eia.doe.gov /emeu/cabs/Brazii/Oil.html [1 4] fPC Issue Brief 20, October 2006, Specific Environmental Effects of Trade Liberalization: Sugar CIA World Factbook [1 5] Coal consumption figure from U.S. Energy Information Administration http://www.eia.doe.gov/ cneaf/coal/page/ special/feature .html [16] For example http://www.iogen.ca/cellulose _ethanol/


what_is_ ethanol/process.html DISCOVER Vol. 27 No. 04 [17]http: //www.foe.co.uk/campaigns/ b iodiversity/ case_studies/palm_oil/ [18]http:/ /envinnment. guardian.co.uk/climate change/story I 0 .. 18291 72.00.html [ 19] Ethanol Production Using Com. Switchgrass, and Wood ... -Pimentel D, Patzek T - March 2005 -Natural Resources Research 14: 65-76 [20] Ethanol can contribute to energy and environmental goals - Farrell AE, Plevin RJ, Turner BT, Jones AD, O'Hare M. Kammen DM - January 2006 - Science 31 1 (57 60):506-8 [21] Environmental. economic, and energetic costs and benefits of biodiesel and ethanol biofuels - Hill J, Nelson E. Tilman D. Polasky S, Tiffany D.- July 2006- Proc Noll Acad Sci U SA. 103(30):11206-10 [22] Energy and emission benefits of a lternative transportation liquid fuels derived from switchgrass: a fue l life cycle assessment - Wu M, Wu Y. Wang M - July/August 2006 -Biotechnol Prog. 22(4):1012-24 [23] See for example http://www1.eere.energy.gov/biomass/ initiative_sheet.pdf. Page 6 (U.S. Department of Energy)

Graphics Refrences: Page 22: [6] above Page 23: [9] above Page 24: West. M and West. M. File 2540153, iStockphoto.com. 4th April 2007. Page 25: Leigh. K and Shepherd, J. On behalf ofTTH Cambridge.

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CAMBRIDGE

The British BSE Crisis - A Case Study of the Role of Science in Mass Hysteria

Snmoti1 Me~derrns

0 n March 20'h 1996, the Secretory of State for Health, Stephen Dorrell, reported to the House of Commons on evidence of a possible link between a new

variant of Creutzfeldt-Jocob disease (vCJD). a fatal neurological disease, and Bovine Spongiform Encephalopathy (BSE) [1] . The media took up the story with incendiary headlines - 'We've Already Eaten 1.000.000 Mod Cows' [2], 'I cannot rule out 500,000 cases' [3] - resulting in widespread public hysteria. European legislation reacted with a complete bon of British cattle and bovine products [4]. and a marked drop in beef consumption was seen across Europe [5]. Defeatist statements from senior officials such as, 'We considered killing all 11.8 million cattle - the entire notional herd' [6] fuelled the panic further.

A decode later however. public hysteria has subsided and the European export bon has ended [7]. Reflecting upon the c risis yields on astonishing

26

discrepancy between the actual number of human fatalit ies caused by vCJ D and the bleak picture presented by the media at the time. Until December 2005, only 153 people in the UK had died of vC JD. with the peaking of this epidemic in the year 2000 with 28 deaths. In 2005, only 5 deaths from vCJD were confirmed [8).

Before the Secretory of State for Health mode his statement. officials made strong efforts to play down the risk of contracting vCJD from British beef. The now infamous 'beef is safe' quote from Agriculture Minister John Gummer in 1990, who stressed his point by posing with his daughter eating a beef burger. was meant to allay public fears [9) . In the same year Chief Medical Officer Sir Donald Acheson reassured the public that, 'Beef con be eaten safely by everyone. both adults and children, including patients in hospital', disregarding the early warnings of other scientists at the time [ 1 0] .

What is the justification for the huge divergence between early statements claiming there was minimal risk from vCJD and the later alarming assertions that triggered the 'BSE c risis ' and the ensuing public hysteria? Certainly, newspapers seek headlines that capture the public attention, and politicians ore under pressure to make their stance clear. Nevertheless, as the BSE crisis demonstrates. when science is so heavily involved in determining public policy, conclusions about a situation are not always so easily discerned. The polarization of opinion throughout the BSE crisis illustrates the danger of the oversimplification of falsifiable scientific evidence.

The public needs to be informed about possible threats, and creating a pretense of absolute sa fety is as dangerous as overemphosising the risk. Yet the hysteria was such that at the height of the BSE crisis. on overage, two British farmers committed suicide per week [ 11) . Whilst suicide rates for formers ore generally high, could some of these deaths hove been prevented by a less frenzied public and press and a more consistent scientific voice? [1 2]

The scientific publication in Th e Lancet that prompted the BSE crisis in 1996 was in fact a very re asonably worded report: 'We believe that our observation of a previously unrecognised variant of CJD ( ... ) is a cause for great concern. That it is due to exposure to the BSE agent is perhaps the most plausible interpretation of our findings. ( ... )If there is a causal link then. given the potentially long and widespread exposure to the BSE agent, further cases of this new


CAMBRIDGE

;

variant of CJD are likely to arise.' [13) Whilst the report directly identifies the serious nature of the scientific findings, it by no means sensotionalises the threat from CJD. If the media and officials were to follow this more considered and reasoned style of reporting, it would certainly help to ovoid moss hysteria and anxiety.

Yet the public reaction to scientific findings is often unpredictable. For example. the number of people in the UK dying from salmonella. another food-borne disease, is approximately 40 - more than the vCJD cases even at the height of the epidemic [14]- yet these deaths hove not spurred widespread hysteria. Further, it is ironic that some smokers in countries that hove not seen a single vCJD case continued smoking but did not toke the risk of eating beef. despite the fact that, '( ... ) In developed countries as a whole, tobacco is responsible for 24% of all male deaths and 7% of all female deaths ( .. . )' [ 15). It is not only the actual disease burden or risk to health that is responsible for hysteria , but the officially presented and publicly perceived risk.

It is one of the roles of science to identify and investigate such risks. In April 1988 John Wilesmith found that the route of BSE infection was feeding ruminantderived protein (also known as meat and bone meal MBM) to ruminants (16). This led to a ban of MBM in the UK in 1988 two years a fter the identification of BSE. Yet when the first cases of vCJD appeared it was very difficult for scientists to estimate the number of cases to come, as the incubation period was not known [17] . It was therefore impossible to know whether the 1 0 cases reported in The Lancet resulted from exposure to BSE during the early 1980s or the late 80s and early 90s. If the former hod been the case. the incidence of vCJD could hove climbed much higher than it actually did. At the time, all scientists could do was try to estimate the extent of the impact of BSE/vCJD using available data. and even today there is still debate about the exact nature of the infectious agent of BSE and vCJD [ 18) [ 19). For there is more than one form of the protein present in vC JD, and in the human population, the different variants of this protein seem to influence susceptibility to vCJD. Due to this polymorphism we may actually see another wove o f vCJD cases, potentially resulting in more deaths than we hove seen in the post [20]. The prion agent (protein particle) of vCJD has also been found in the appendices of otherwise healthy people [21). There is also concern about the disease being spread with in the human population by direct transmission [22].

The BSE crisis is a striking example of public fear of on incalculable risk of infection with a potentially devastating outcome. Sadly, we see the pattern of 'food hysterias' repeated again and again- 'Scottish farmed salmon' is full of cancer toxins" [23] - and these recent headlines con cause as much public fear as those surrounding BSE in 1996. The public must learn and accept


that it is not possible to exactly assess on unknown risk. It was not possible for BSE and will not be possible for future hazards like avian flu (H5N1) or GM-food. as science con only give estimates with varying degrees of uncertainty. As a result, there must be a point when scientific investigation ends and policy begins, as suggested by the BSE inquiry that investigated the crisis: 'Scientists were expected to provide all the answers. where sometimes this was not their proper role' [24].

So what is the role of science when it comes to communicating scientific information? I argue that in

Decisions that concern the public must therefore not only be grounded in scientific evidence, but must also

leave room for new findings and new avenues of research

addition to providing the public with research and discoveries, scientists should promote a critical way of thinking. Questioning one's own theories, accepting that we do not know things for certain, comparing different risks and always referring to the best data available could prevent future hysterias and reduce the possibility of grossly underestimating threats.

This new way of approaching uncertainty is required because o f the enormo us potential for science to create unwarranted public fear and anxiety. In 1998, The Lancet, the very some scientific journal tha t published the connection between BSE and vCJD, publi shed an article by Dr. Andrew Wakefield suggesting a possible association between the MMR vaccine and Autism [25]. Though the study was quickly criticized and the current scientific data strongly dismisses a link between the MMR vaccine and Autism [26) the public damage it caused still persists. Friedriches et AI. (2006) have c ome to the conclusion that 'Measles

27

· CAMBRIDGE

susceptibility has increased significantly in nursery children' due to adverse publicity on MMR vaccine uptake [27).

As experience has illustrated. and as most scientists are aware. scientific conclusions can be fallible. Decisions that concern the public must therefore not only be grounded in scientific evidence. but must also leave room for new findings and new avenues of research. As for BSE. a recent report on the discovery of a prion mutation in cattle and the identification of 'atypical scrapie' [28) suggests that the 'story' is not over yet. Recent research indicates that BSE and vCJD might be with us for a long time. and other potentially devastating health risks will most likely come up in the future. Learning from the mistakes made during the BSE crisis is therefore vital. Ideally in the future. scientists will more actively involve themselves with the presentation of their findings by the government and in the media. and the public will think more critically before altering their behavior in response to a perceived risk.

Simon M elderis is a 3•d year reading Medicine at Churchill College. Camb ridge.

References: [ 1) Crown copyright 2000. 'The BSE Inquiry'. The report. Volume 16. Reference Material 1, BSE chronology. October, 2006: http ://www.bseinquiry.gov.uk. [2) Daily Mirror. March 20th, 1996. [3) Pattison, John. Quoted by Daily Mirror. March 21st. 1996. [4) European Union legislation Decision 96/239/EC. March 27th, 1996. [ 5) Pickelsimer. C.. Wahl T. 'Mad Cow Disease: Implications For World Trade'. Washington State University: Impact Center Information series USA. 2002. [6] The Independent. March 21st, 1996. [7] European Commission. Press Room. Press Releases MEM0/06/108. 'BSE: Lifting restrictions on the trade of cattle and beef from the UK'. Brussels: March 8th. 2006. [8] Andrews, N. 'Incidence of variant Creutzfeldt-Jakob disease onsets and deaths in the UK. January 1994 -December 2005' . Edinburgh: The National Creutzfeld tJakob Disease Surveillance Unit. 19th January, 2006. [9] Crown copyright 2000. Ibid. [1 OJ Acheson, D. Sir. 'The BSE Inquiry' . The report, Statement No 251. October. 2006: http://www.bseinquiry.gov.uk. [ 11] 'Stress and suicide in th e country '. BBC News . September 14th, 1999. [12] Thomas, H.V., Lewis. G .. Thomas, D.R., Salmon. R.L .. Chalmers, R.M .. Coleman. T.J .. Kench, S.M .. Morgan-Capner, P .. Meadows, D., Sillis, M .. Softley, P. 'Mental health of British farmers'. Occup Environ Med. March, 2003; 60(3):181-5; discussion 185-6 [12) Will, R.G., Ironside, J.W., Zeidler. M .. Cousens. S.N .. Estibeiro. K., Alperovitch, A .. Poser. S., Pocchiari, M .. Hofman. A.. Smith, P.G. 'A new variant of CreutzfeldtJakob disease in the UK'. The Lancet. 1996; 347: 921- 25.

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[13) Adak. G.K., Meakins, S.M .. Yip, H., Lopman, B.A., O'Brien. S.J. 'Disease risks from foods, England and Wales. 1996-2000.' Emerg Infect Dis. March. 2005; 11 (3):365-72 [14) Peto, R., Lopez, A.D .. Bareham. J .. Thun. M., Heath. C. Jr. Doll, R. 'Mortality from smoking worldwide.' Br Med Bull. January 1996; 52(1):12-21. [15] Wilesmith, J.W., Wells, G.A., Cranwell, M.P .. Ryan. J.B . 'Bovine spongiform e ncepha lopathy: epidemiological studies.' Vet Rec. December 17th. 1988; 123(25) :638-44. [16) Zeidler. M .. Ironside, J.W. 'The new variant o f CreutzfeldtJokob disease.' Rev Sci Tech. April. 2000; 19(1):98-120 BSE science. [17] Saborio, G.P .. Permanne. B .. Solo. C. 'Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding'. Nature. 2001; 810"813. [18) Monuelidis. L. 'A 25 nm virion is the likely cause of transmissible spongiform encephalopathies.' J Cell Biochem. October 16th. 2006. [19) Peden, A.H .. Head, M.W .. Ritchie. D.L .. Bell, J.E .. Ironside. J.W. 'Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient.' The Lancet. Aug 7th. 2004; 364(9433):527-9. [20) Llewelyn, C.A.. Hewitt, P.E .. Knight. R.S .. Amar, K., Cousens. S .. Mackenzie. J., Will, R.G. 'Possible transmission of variant Creutzfeld t-Jakob disease by blood transfusion ' . The Lancet. February 7th. 2004; 363(9407) :417 [21) Bishop, M.T., Hart. P .. Aitchison. L .. Boybutt. H.N., Plinston, C .. Thomson. V .. Tuzi. N.L .. Head. M.W .. Ironside, J.W .. Will, R.G .. Monson. J.C. 'Predicting susceptibility and incubation time of human-to-human transmission of vCJD '. The Lancet. May, 2006; 5(5) :393-8 [22]Noture. October. 2006; http://www.nature.com/nature/ joumal/v408/n6808/fuJJ/408003aO.html. [23) Crown copyright 2CXX1 'The BSE Inquiry'. The report. October. 2006: http:/ /www.bseinquiry.gov. uk. [24) Wakefield. A.J .. Murch, S.H .. Anthony, A., Linnell, J .. Casson. D.M .. Malik, M .. Berelowitz. M .. Dhillon. A.P., Thomson, M.A., Harvey, P., Volentine, A., Davies, S.E .. Walker-Smith. J.A. 'Ileallymp hoid-nodular hyperp lasia, non-specific colitis. and pervasive developmental disorder in children' . The Lancet. February 28th. 1998; 351 (9 1 03) :637-41 . [25] Taylor. B. 'Vaccines and the changing epidemiology of autism.' Child Care Health Dev. September. 2006. [26] Friederichs. V .. Cameron, J.C., Robertson, C. ' Impact of adverse publicity on MMR vaccine uptake: a population based analysis of vaccine uptake records for one million children. bom 1987-2004'. Arch Dis Child. June, 2006. [27] Baron. T., Biocobe. A. G., Arsoc, J.N .. Benestod, S., Groschup, M.H. 'Atypical transmissible spongiform encephalopathies (TSEs) in ruminants '. Vaccine . November 13th, 2006.

Graphics References Page 26. Mlenny. File 1880406, iStockphoto.com, 4th April 2007 Page 27. Gagne, L. File 2684387, iStockphoto.com, 4th April 2007.


The Importance of Memory AVJduy lee

I I M emory is a way of holding on to the things you Jove, the things you are. the things you never want to lose."

How much does the memory of the human brain contribute to c reating the sense o f self?

What ro le does autobiographical memory p lay in making us who we o re?

The importance o f the capacity of the brain to store and retrieve information is undisputed by any student having to deal with a demanding university course. Yet the concept of memory is still very muc h understated -to many, the function of memory is limited to our 'working memories' , where we lament the inabilities of our brains to cope wi th the massive amounts of knowledge this Information -Techno logy age brings with i t, or the appointment that simply 'slipped my mind'.

We often, however,

believe we are, but also contributes to the construc ts of our personality.

Perhaps the best way in which the importance of the autobiographical memory could be demonstrated is via examination of the very disorders in which it is a ffected. Most clinical omnesios tend to be caused by t issue d amage or concussive injury. Otherwise. in the absence o f brain tissue damage, funct ional memory loss might occur. This is characterized by a significant memory loss a ttributab le to a sing le instigating event or process. w ithout any accompanying brain tissue injury [2].

Essentially, autobiographical memory performs two functions, the first being in providing facts tha t allow us to interact accurately with society. This c learly bears great importance: amnesiacs. for example those with Alzheimer' s disease, some-times lose the ability to

recognize those who are overlook a second -'autobiographical' - form of memory. Anyone who has had to review for on exam realizes how hard it is to consciously remember something. so how is it tha t we con seeming ly automatically remember t e lephone numbers. or where we live? Simply, the brain is a ble to retain information about self -

Anyone who has had to review for an exam realizes how hard it

is to consciously remember something, so how is it that we can seemingly automatically

remember telephone numbers, or where we live?

most beloved to them. This changes a large part of who they ore - the ir inability to recall even the slightes t deta i l about those who used to be most intimately known to them con be both emotionally and mentally crippling. This is a lso devastating fo r re la tives, who slowly find that their loved one has

semantic, self-re levant facts and e vents in our post which leave last ing impressions: so-called ' flashbulb memories' [1).

But what is the importance o f autobiographical memory to man? If one were to propose that it were responsible for creating the entire en tity th a t is the personality, there would be opposit ion from many folds. Indeed. the 'personality'. or 'self ' . is something in which the whole consistently appears to be greater than the sum of its parts - there is a lways on elusive , abstract, non-quantitative factor that cannot be grasped. but which some attribute to ephemeral qualities such as spirituality. This Io tter concept might seem impossible to define, but a c lose description of the 'spirit and soul ' might be the conscience and mentality that g ives a p erson his sense of living, his ideals and beliefs w ith regards to his place in the world. However, such a quality cannot be a ttained w ithout f irst possess ing a firm memory of a ll essentia l in formation rela ting to se lf. Hence. it seems reas ona b le to state tha t su ch information not only creates the self-image of who we


becom e a stronger, memories of shared bonds and relationships eventually e roded. Hollywood a nd soaps love to magnify the trauma of memory loss: the Bourne Identity sees Matt Damon struggling to recall his secret agent life and in Total Recall. Arnold Schwarzenegger is asked why he wonts to remember his post. His answe r: "To be myself again" . While drama tends to exaggerate, the trauma of memory loss is real and documented in many a moving account [3) .

Interesting ly, amnesia is frequent ly observed coupled with a great tendency to confabulate - the patient unconsciously replacing fac t w ith fantasy. For examp le . Baddeley and Wilson [4] discuss the case of a rood occident patient. R.J . who hod suffered bilateral brain damage and consequently a loss of memory of any sort w ith regards to self.

When presented w ith evidence of his life prior to the occident, such as a wedding photograph. R.J concocted detailed . f requently non sens ica l explanations - 'tha t chop [in the wedding p hoto] certainly looks like me, but it 's not me !'. In a svmewhot

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cruel joke. his confabulations often vaguely touched the shadows of what his past life had been - his explanation for pushing a wheelchair-bound fellow patient down the road had been that he was bringing him to view a sewage plant that he was 'helping to construct', when in actual fact he had once been involved in such a project as a civil engineer. though in a completely different location and setting. While it borders on pointless moralistic debate to argue whether

his amnesiac life after the accident can b e considered meaning fully, it certainly does not go beyond reason to state that the very essence of his being had changed. For he could no longer appropriately relate to the things which had held significance to him in the past. nor rely on a 'reservoir of experiences' to help determine where his life had brought him thus far.

However, in the age where using nasal sprays containing the hormone oxytocin appears to make people trust you. and feelings of love and adoration can be reduced to dopamine highs. some might argue

30

that the forging of relationships might simply be the result o f biochemical attractions rather than any sort of need to share common experiences and memories. Even if that may be the case. one cannot argue with the fact that simply recalling a pleasant shared experience with a loved one brings forth those familiar 'fuzzy' feelings of warmth and happiness. Chemically-mediated or not. the recollection of the stored memory of the person clearly contributes to creating a lasting and pleasing

relationship. In some cases of autism. it is found that memory can be impaired, affecting the abilities of the autistic patient to identify the relationship of peers with self and hence in interacting normally wi th peers in social situations. Without the memories of the fac ts that define the parameters of relationships and roles we partake in this life. it is hard to imagine anyone being comfortable with his or her concept of self.

The second crucial part of autobiographical memory lies in episodic recall - what Brown and Kulik appropriately labelled 'flashbulb memories'. Think of what you were doing when you first heard the breaking news of 9/1 1 in 2001. and you will probably be able to rec all it. in a lmost photographic detail. Some bits of the memory might be slightly unc lear. for example. you might not be able to remember what coloured socks you were wearing (or indeed. if you

were wearing any). but you would almost certainly be able to remember how you first heard the news - the incredible image of the planes flying straight for the towers on the television - or wha t your first reactions were. This would be even more so, if one had been personally affected in any way by the event in question. Some events are routine and their memories tend to fade in significance. while others that create g reat e motional upheaval or genera te substantial consequences a re like ly to be reiterated in our conversations and thoughts over and over. As a result


. . ·· cAIV\·sRIDGE - • 0 • .: • - .... •·~. - •••• •, _, - ~· ..

these memories are often subject to distortions and influenc es from our emotional reactions and personal perceptions of the ways in which the event unfolds.

Whilst the way in which autobiographical memory is created is largely unknown. it appears that during sleep and dreaming. we seem to process the events that have occurred during the day.ln her book on d reams and their e ffects on consciousness, sc ience reporter Andrea Rock holds forth tha t dreaming a llows us to sieve out and record bits that could have significant influence on our person. We then attempt to piece these bits together with any relevant past experiences. This construction of a 'database' of sorts a llows us to understand and preempt future situations and predict our beha viours in them. The importance of event recollection simply cannot be undermined. simply because the wealth of experiences that a person creates and draws upon throughout his life can be defining in producing the reactions or responses that c harac terize his behaviour in varying situations. essentia lly crafting his personality.

Curiously enough, the events thot we tend to forget also play an important role - Linton regularly entered events into a diary and in 1975 did a study in whic h she tested her ability to remember these entries (4] . She found that there was a tendency to forget the less pleasant inc idents more rapidly than the rest. Again. this appears to be related to an ability of the brain to 'deconstruc t' harmful events during sleep - could it be that the brain has developed a protective mechanism; giving us the capacity to remember important events. while also the talent to gradually eradicate unpleasant moments that cause us emotional hurt from ourimmediote recollections? This perhaps gives us scientific reason to wont to edit the adage 'time heals all wounds' to 'sleep heals all wounds'.

Cogito, ergo sum." ("I think, therefore I am.") All those years ago, Descartes had condensed the very purpose of existence and self into the ability to think. Yet now, one wonders if it should have been "Memor, ergo sum." ("I recall. therefore I am.") instead.

Audry Lee is a 2nd year reading Medicine at Queens' College, Cambridge.


References: (1] Flashbulb Memories; Brown and Kulik. Cognition. 5 (1977) 73-99 [2] Schaefer and Kihlstrom. 1989 [3] Reader's Digest. 'Forget Me Not' by Jon Goodwin: http:// w ww. rd. comIc on tent I o p en Con t e nt . do? contentld=26958&pagelndex=O [4]Human Memory, Theory and Practice. Alan Baddeley, p227

Additional Sources: • Handbook of Memory Disorders. Alan D. Baddeley. Barbara A. Wilson. Fraser N. Watts. 1995 • Mental Processes. Longuet-Higgins, 1987 • http:/ /66.51.173.96/Philosophy/existence.htm; Steven Gislason. MD. Existence and the Human Mind • http:/ /www.oldondsold.com/ortic les 19 /psychoonolysis-8.shtml Antiques Digest. 1920 • The Pattern of Intact and Impaired Memory Functions in Autism. Nancy J. Minshew. Gerald Goldstein. J. Child Psycho!. Psychiat. Vol. 42. No.8 • The New Scientist: http:/ /www.newscientist.com/orticle/ dn9981-instant-expert-love-.html • The Mind At Night. The New Science of How and Why We Dream. Andrea Rock. March 2004, Basic Books

Graphics References: Page 30: Pantazescu. P. Rle 2664965. iStockphoto.com. 4th April2007. Page 31: Anthony, C. File 1052257, iStockphoto.com. 4th April 2007.

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. CAMBRIDGE

The Ethics of Placebo Trials in Different Economic Contexts

l?waful Ravi

II M edical progress is based on research which ultimately rests in part on experimentation involving human subjects." [1] This is

paragraph 4 of the World Medical Association (WMA) Declaration of Helsinki, which provides guidelines for medical research involving human subjects. There has been, is and always will be a need for clinical research in medicine. primarily because of the presence of incurable diseases, such as HIV I AIDS today. Only palliative treatments are available for these diseases. merely delaying the onset of life-threatening sequelae. Moreover. overuse of antibiotics has led

Is it right that some patients are not given the potentially curative

treatment?

to the evolution of multi-drug resistant bacteria. notably Methicillin Resistant Staphylococcus aureus (MRSA); this brings a requirement to produce new antibiotics.

In research. a pla-c ebo is required to show effectiveness of a new therapy. Two groups of patients are compared: one rece iving placebo, the other receiving the treatment under trial. The classical view of placebo as a sugar pill is a misconception. as the WMA forbids plac ebo to be anything othe r than the "best c urrent practice "[2] for the c ondition. Hence, placebos are the current, typical treatment used. against which the new treatment is compared. The use of a plac ebo brings one major ethical question: since all doctors make an o ath of beneficence to patients. is it right that some patients are not given th e potentially c urative treatment?

The ethi c al iss ues surrounding the use o f placebo are demonstrated in the example of a recent trial o f a m e th od o f p re ventin g transmission of HIV from mo ther

32

to baby. World Health Organisation (WHO) guidelines [3] state that " best current pract ice" is a regimen of three drugs given to the pregnant woman: nevirapine, azidothymidine and lamivudine. These have been shown [4] to significantly decrease HIV transmission from mother to baby. However, in many parts of the world, especially sub-Saharan Africa, resources are limited and this three-drug regimen cannot be afforded.

Consequently, researchers proposed treating HIVpositive pregnant women in these regio ns wi t h nevirapine alone. However, t he Food and Drug Administration (FDA)- the regulatory agency for cl inical trials in the USA- refused to sanc tion such a method in the USA due to ethical concerns centred on paragraph 29 of the Declara tion of Helsinki, w hich emphasises that a placebo-controlled trial must only b e used in th e absence of existing proven therapy [2] .

The above argument is based upon the theory of clinical equipoise. This exists whe never "at least a re asonable minority of medical professionals believe the experimental trea tment w ould be as g ood as, or better than, the standard trea tment." [5] Effectively, it prohibits r e se arch ers knowi n gly wit hholding effec tiv e tre atme nt from the p lacebo gro up. In th e nevirapine t rial. as the three-drug combina tion had already been shown to be the then current "best practice," withholding the drugs, and replacing them with nevirapine alone would violate clinical equip oise.

The trial w as ul timately conducted in Uganda u nd e r t he authority of the Ugandan g overnment. The fact that the trial was sanctioned by the Ugandan g overnment. b ut not b y t he FDA , suggests that the Ugandan governm ent afford s i ts pop ula tion lower ethical standards by no t adhering to cli ni c al eq uipoise . However, to what extent is t his justifie d? Th e p otential b enefits of the single-drug regimen being shown to be e ffective in reducing HIV transmission from mother to baby are huge: in a country as poor


CAMBRIDGE

as Uganda (GOP / capita of $1 500) . [6] a cheap, e ffec tive single-drug reg imen would sa ve tho usands o f lives. considering that the prevalence of HIV in Uganda is as high as 17%. [7] This could be said to o ffset the pote ntial ethical infringement.

And what did the FDA make of this balance? In sp ite of this benefit to Ugandan populations, should the FDA have stood by and let a US lab take advantage of Uganda's lower ethical standards? Whether or not the FDA should have, it could not have intervened directly as i t has no jurisdiction in Ug and a . So was it the

Was it the responsibility of the researchers to not contravene their own ethical guidelines in another

country?

responsibility of the researchers to not contrave ne their own ethical guidelines in another country?

A potential solution to these problems is to bring into operat ion an interna tional ethical 'code of cond uct' o r standard regulations. so as to ensure tha t the definit ion o f p lac ebo is universally recognised. This would effective ly take the FDA d efinit ion and put it into internationa l law . Whilst idealistic . this degree of harmonisation would he lp end concerns over the exploit a t ion of vulnerab le third-world patients. This having b een said, would this perhaps be harmful for the very reasons that the nevirapine trial was considere d e thical? The international law would not be able to accomm oda te the need s of le ss economically d eveloped countries.

From an economic perspective, this would most likely lead to a situation where the riche st and most politically powerful na tions set the ethical standards for the rest o f the world. if one assumes that economic ally d eveloped powers have less pressing needs for t rials that may violate clinical equipoise. This is undemocratic and problematic because different countries have different needs or hop es from a c linical trial. Referring to the HIV 1 AIDS example. the sing le-drug regimen trial would not be permitted anywhere in the world due to a bse nce o f c lin ical equ ipoise based on US o r UK standards; yet. there is a possible need for this trial in poorer nations. In fact, results from the tria l have shown that nevirapine reduces HIV transmission from mother to baby 41% bet ter than azidothymidine a lone [8]. whilst costi ng approxima te ly 70 t imes less. This has clear benefits to resource-poor na tions fighting the spread o f HIV/AIDS.

This is demonstrative o f a further reaching general principle. that there would a lso be great difficulty in logistically applying this across d ifferent nations, with


different cultures. This is demonstra ted by the recent scandal involving the South Korean researcher. Dr Hwang Woo-suk, who . among other transgressions, was found to have used eggs from female members o f his resea rch team. This is culturally acce ptable in South Korea but is seen as morally wrong in the USA. Yet. in other aspects o f g amete donation, such as state funding of gamete supply (i.e. egg and sperm donation), which is condoned by the USA and considered unethical by South Korea . the scientific world . as a whole, does not raise quest ions a bout American cond uct. This again skew s the b a lanc e of power for development o f interna tional law.

It is important to apprecia te that there is a huge re quirement for c linical research today, and this means that p lacebo c ontrols ha ve to be used . There are legitimate moral concerns over usage of a p lacebo, especially in relation to its use in d ifferent countries. Neverthe l ess , in m y opinion , p rovid ing that appropriate regulation and legislation ensure that the p lacebo is always "best current practice ", p lacebocontrolled tria ls are essential for the development of medical knowledge.

Praful Ravi is a I'' year reading Medicine at Christ's Co/lege. Cambridge.

References: [1 ] World Medical Association Declaration o f Helsinki. (Paragraph 4], 2004. [2] World Medical Associa tion Declaration of Helsinki. (Paragraph 29], 2004. [3] Table 3, World Health Organisation: Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants in resource-limited settings: towards universal access, August 2006. [4] " Ef f icacy o f three short cou rse re g imens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa and Uganda : a randomised. double-blind p lacebo-controlled triaL Petra Study Team." Lance t 2002, 359 (9313) [5] Food and Drug Administration, www.fda.gov/opacom/ morechoices/ fed996.htm [6] www.c ia .gov/cia/publications/ factbook/ rankorder/ 2004rank.html [7] Na tional Guidance and Empowerment Network. www.ngen.or.ug [8] "Intrapartum and neonata l single-dose nevirapine compared with zidovudine for prevention o f mother-tochild transmission of HIV-1 in Kampala , Uganda: 18-month follow-up of the HIVNET 012 randomised trial." Lancet 2003, 362: 859-867.

Graphics References: Page 32: Prill. A. File 2490797, iStockphoto.com. 4th April2007.

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Taking Off- The Implications of Mass Space Tourism M~cho.1e ~a fwee~arnd

0 n a clear night when the Moon is full, look a little to the left of the Mare Tranquilitis. Here on the rim of a crater. with a stunning view both of the surrounding

moonscape and back down to the Earth. would be the ultima te location for a holiday villa or hotel. Space tourism is a concept no longer reseNed just for the Jetsons - since American entrepreneur Denis nto became the first space tourist in 2001, the industry has. quite literally, taken off. The award of the Ansari X-Prize to Burt Rutan's company. Scaled Composites demonstrated the feasibility of commercial space travel and private companies. such as Richard Branson's Virgin Galactic, plan to begin commercial flights by 2008. Virgin claims that over 29000 deposits have already been placed for its proposed sub-orbital flights. and predicts that within twelve years of operation some 50 000-100 000 o f us will have visited space on a Virgin Galac tic flight. Those who set their sights a little higher can look to companies such as Space Adventures. already respons ible fo r ta king lito . Mark Shuttleworth and Gregory Olsen to the Internationa l Space Station (ISS) , offering orbital flights. now with additional spacewalks. and even a proposed rou nd trip to the Moo n. It's a holiday w ith a sui tably astronomical price-tag, a trip to the ISS starting at $20 million, rising to a sky-high $100 million for a lunar fly-by [ 11]. Increasingly. companies are taking the view that the promised financial returns justify the intimidating initial investment. and the industry is thereby generating its own momentum as we move ever closer to mass space tourism.

With these developments comes an urgent need for clear legal regulation of space tourism. to resolve issues of liability, property rights and the legal status of space tourists. The unique. and significant. costs and risks inherent in space travel make this a tric ky balancing act - w hilst c lear safeguards are needed. over-regulation could ground the industry. Already, for example. US technology transfer regulations have held up licensing agreements between Virgin Galactic and Scaled Composites to utilise the technology behind SpaceShipOne, resulting in a two-year push back of the company 's operating timetable.

With these developments comes an urgent need for clear legal

regulation of space tourism

Almost all of the treaties relating to space, developed by the UN, were formulated during the Cold War when few countries possessed space programmes. Certainly, the

34

concept of space tourism is not inc luded; indeed it is not fully c lear whether space tourists fall into the category of 'astronaut' and are thus subject to treaties such as the 1968 Rescue Agreement [3] . Under these treaties. outer

space possesses a unique status as res communis -'Common Heritage for Mankind' - and, as such, activities taking place in space are not subject to control by a particular State (body or nation) . Interestingly, this approach is based on the Antarctic Treaty (1961) regulating the use of the only area on Earth which is similarly uninhabited and unclaimed by one single nation. On what basis. then. can we decide what a c tivities are acceptable in space? Up until now, 'product placement' in space has taken the form of a gimmick - Russian cosmonaut Mikhail Tyurin recently hit the world's longest golf d rive, an estimated one million miles around the Earth, on a spacewalk from the ISS [ 13) . Whilst stunts like these have generally been cause for amusement. can we be sure that there would be not significant opposition to widespread astronomical advertising. or an intergalactic tussle over celestial casinos or planetary package tours?

This 'common heritage' status also m a ke s th e prospects look a little shaky for a hotel on the Moon - the 1979 Moon Agreement expressly stating that the surface (and subsurface) 'shall [not] become property of any State, international ... or national organization ... or of any natural person' [3). Should some form of leasehold arrangement


be formulated. and if so. which bodies will regulate property distribution?

There is also the issue of protecting the celestial environment- the retrieval from the Moon of stowaway E. coli bacteria from the Apollo 12 mission illustrates the fact that any human activity in space will unavoidably risk contaminating and

privileges to Japanese businessman Daisuke Enomoto for unspecified medical reasons. even though he had undergone the requisite mission training. Making this even more pressing is the fact that currently, space tourists have no recourse for compensation under the Liability Convention (formulated in 1972) [3) . It is imperative to

resolve these legal issues polluting space. Currently, NASA estimates that there are 5500 tonnes of 'space junk ' in Earth orbit (14] -p osing b o th a pollution problem, and hazard for c urrent and future tourist and scientific spacecraft.

Any human activity in space will unavoidably risk

contaminating and polluting space

before the first loads of space day-trippers start packing their cameras and spacesuits.

And what of the impact o f space tourism upon 'traditional' scientific

Whilst it is not believed that current space activities have an environmental impact significant relative to, say, that of a nation [8], studies have not yet considered the effects of an increase in space traffic due to leisure flights.

Prospects on the drawing board, albeit far-off. for eventually altering the surface of Mars into a habitable environment. so-called terraforming. take these environmental concerns to a whole new level. From science fiction writers to scientists such as Stephen Hawking and Paul Davies. it has been suggested that in the event of ecological disaster on Earth, humans will need to escape to colonies in space. Even if reality does not turn out to be quite so dramatic. we clearly cannot afford to repeat our environmental mistakes on such a vast and even more fragile stage.

That two of the five original space shuttles have been lost in only 11 5 flights highlights the dangers inherent in space trave l. It would be reckless to proceed much farther without the implementation of minimum safety standards and regulation within the industry. What would, for example. be the required pre-flight training? The three tourists who have thus far visited the ISS have undergone a six month training period, inc lud ing the operation (a lthough not practice) of the spacecraft. Preparation for a spacewalk would involve an additional 190 training hours. but what of Virg in's three hour suborbital flights?

It seems obvious that prospective space tourists should undergo stringent pre-flight medical evaluation. Precedent has b een set b y the Russian Federal Space Agency. on whose flights lito, Shu ttleworth and Olsen traveled, who refused flight


pursuits in space? Certainly, space tourism has the potential to inspire interest and generate funding for scientific space missions; Olsen d escribed "motivating a s many young people as I can to go into science and moths" (9] as the primary objective of his flight. and Shuttleworth performed experiments relating to HIV research during his time on the ISS.

The scientific and engineering challenges posed by space tourism in themselves generate great opportunity for research. fuelled by the promise of massive returns once tourism begins in earnest. A case in point is the regeneration of Russia 's Yuri Gagarin Cosmonaut Training Centre, Star City (at which nto, Shuttleworth and Olsen trained) and plans are already in place to construct spaceports in Dubai. Singapore and New Mexico for the launch of commercial tourist spacecraft.

Somewhat ironically, however. it is very immediate and massive financial returns that are of the most concern to 'traditional' sp ace scientists. who face the diversion of funding away from scient ific research to commercial applications. Already scientists often wait for years to have th eir scientific sate lli tes launched or experiments performed aboard the ISS. We have recently seen the

35

· CAMBRIDGE . ~-, . ~~ . . ... ,~1

cancellation or indefinite postponement of several 'lessglamorous' NASA missions- to the outer Solar System. for example. and the Constellation-X satellites to search for gravitational waves- and the slashing of research funding (the astrobiology budget alone reduced by 50%)[1 5] in order to accommodate the Bush Administration 's call for human exploration of the Moon and Mars. Some scientists argue that such manned scientific missions are themselves a pointless expenditure- in the light of the hugely successful unmanned exploration performed, for example. by the Spirit and Opportunity Mars rovers. and the Huygens probe to Saturn's moon Titan. It seems given that the additional costs of providing for tourism might raise the - already astronomical- costs of manned space travel even further. Since in terms of commercial return. (for an analysis of which. see for example [1 6]) it is an easy choice between the tourists and the test tubes. we face the danger that national space programmes will follow suit in a bid to compete with the private sector for the tourist dollar.

Addressing the legal, environmental and scientific concerns raised by space tourism is vital while the industry is still in its nascent phase. With its obvious momentum. however, it seems clear that whatever the outstanding issues. the sky is no longer the limit for space tourism. Watch out for the signs of a new lunar hotel on a c lear night in the not-too-distant future.

Michaela Freeland is a 2nd year reading Mathematics a t Newnham College, Cambridge.

References: [1] Crales J 'hsde Russb's Space Can,::l', BBC New.;, 9'' AugJ;t 2:Xl6 [2] Fides J 'Space Tourists Offered Walkabout', BBC News, 21 '' July 2006

36

[3) Freeland S 'Up, Up and .. . Back: The Emergence of Space Tourism and Its Impact on the lntemational Law of Outer Space', Chicago Journal of International Law. Vol. 6 No. 1, Summer 2CXJ5 [4) Klotz I 'New Mexico Lands Space Business'. BBC News. 15'11

December 2005 [5] Klotz I 'Fortune Smles on Space Race Sponsor', BBC News. 23'd August 2006 [6] Klotz I'US Export Rules Frustrate Vrgin', BBC News, ~ May 2CXJ5 (7] Redfern M 'Human Spaceffght Goes Commerical'. BBC News. 21 ~ March 2006 [8] Rice E E 'Energy Impact Assessment of NASA's past. present and future space launch vehicles, Joumol of Energy 2. 1978 p 182 [9] 'Q&A: Thrd Space Tourist', BBC News. 4'h May 2004 [10] 'Thousands Keen for Space ffght'. BBC News, 28"' February 2005 [ 11 ] 'Moon VISit Trip Set for Uft-Dff'. BBC News. 1 0" August 2005 [12) 'US DrawsUpSpaceTourism Rules'. BBC News. 1'' August2006 [13] 'Astronauts Whack Golf BaD and Outfit Station in Spacewalk', Space Daiy. 2Jd November 2006 [14) NASA Orbital Debris Program Office- orbitaldebris. jsc.nasa.gov [15] NASA FY 2007 Budget and 2006 Strategic Plan- nasa.gov/ about/budget [16] Alege, P Spitier P WeDs D 'Space Tourism Business Model- the Virgin Galactic Approac h' geocities.com/ innovating_competitively/aerospace/Virgin-Galactic.pdf

Graphics References: Page 34: Pacheco. R. File 2252139, iStockphoto.com. 4th April 2007. Page 35: Luecke. L. File 790801 . iStockphoto.com. 4th April 2007. Page 36: Evans, J. File 1887528, iStockphoto.com. ·4th April 2007.


CAMBRIDGE

Responsibility to the Truth: The MMR Scandal and Scientific Fraud

James Shepherd

U nsettlingly, it seems that a minority of scientists will lie about the results they produce. Whilst scientific fraud does not appear to be widespread, with low

estimates placing the number of scientists engaging in fraud at 1 in 10,000 and those turning a blind eye to it at 1 in 100 [1]. this figure is still worrying. One person can do

evidence that there is no cause for concern[5] . The reverberations from this were , and still are, alarming: either the informed public lost faith in the scientific method or the uninformed public acted on ignorance of the balance of evidence.

As more and more evidence emerged that a huge amount of damage. Whatever draws people in - the glory. the money or because they put their gut feeling before evidence- it seems that this is a problem that the scientific community will face for years to c ome.

--------------------- Wakefield's findings were

No causal link was established between MMR

likely to be wrong, support for his findings and conc lusions ebbed. The paper was disowned by The Lancet follow ing retraction of support from ten of its co-authors [6] . In their retraction they

vaccines and autism as the data were insufficient

Using the notorious MMR vaccine case as an example of potential scientific misconduct. this article w ill investigate the ways in w hich scientists may misrepresent their data, the effects of this and how they might be prevented from doing so.

In 1998, a doctor working at the Royal Free Hospital in the UK organised a press conference at which he claimed that a triple-vaccine given to young children was dangerous. The doctor was Dr Andrew Wakefield, the vaccine MMR and the danger a risk of developing a form of autism. The basis of the c laim was a paper w ritten by Wakefield published in The Lancet which claimed that t here was a 'possible relation' between autism. bowel disease and MMR, adding it could not prove an association [2].

This announcement caused panic within the UK over the safety of MMR and since there has been a drop in vaccination rates to as low as 60% in some areas with the number of measles cases now the greatest they have been in twenty years [3.4]. It has taken eight years for public confidence to return to favouring the triplevaccine, in spite of many studies sh owing strong


admitted "no causal link was established between MMR vaccines and autism as the data were insufficient" [7].

Furthermore, it was found tha t Wakefield had received funding from those with a conflict of interest in discovering an autism-MMR link, the lawyers who were suing for damages following an MMR vaccination. This source of funding was not declared prior to publication [8].

The paper was withdrawn due to complaints from fellow scientists that called its accuracy into question. Checking that a paper is accurate is the principle behind peer review. w hic h happens when a paper is submitted, prior to publication. It is not. however. designed to stop scientists from misleading journals about their sources of

funding, something that led to the scientific community trying to

introduce counter-measures to tigh t en up potential conflicts of interest, but this was not enough to stop some scientists starting to lose faith in this method of monitoring scientists [9].

Even so, there are a lso cases w here peer review has failed to do what it sets out to do. This was especially true following stories of fabricated evidence such as the cases of Korea's Woo Suk Hwang, an e minent therapeutic c loning scientist.

37

. CAMBRIDGE

and MIT associate professor and immunologist, Luk Van Parijs, both of whom have been accused of data fabrication [1 0, 11]. Hwang's most famous fabrication was that of using false DNA fingerprinting data to show that allegedly cloned cells were genetically identical to their donors, whilst the extent of Van Parijs's fraud is unknownMIT have thus far refused to reveal which of his published articles are known to contain falsified data.

It is important to note that falsifying data was something that Wakefield did not do - he merely embellished its interpretation.

This failure largely stems from the fact that peer review can only do so much to check the accuracy of results, short of actually doing the experiments again. Therefore , the system largely relies on scientists themselves not to misrepresent their results - either to other scientists or the public. In many ways, this represents a universal moral code within science- those who do not adhere to the scientific method can expect to be ostracised by their colleagues - effectively scientists are policed by scientists.

38

Luckily, peer pressure also exists in the form o f training people in so-called ' research ethics', required of universities in the US by the National Institutes o f Health (NIH) [12]. a very large funding body. It is these

Should those shown to be untrustworthy get a second

chance?

same universities, however. that stand accused of pressuring academics into producing publicat ions to the extent that they encourage fraud [13]. Obviously, it's a fine line to draw with funding being so v ital to the entire process and competition is very strong for a limited pool of money. For example, whilst individual labs do not usually disclose exact figures. a typical Unviersity Pathology department receives funding in the millions of pounds (14] .

So what other roles can the funding b ody take in reducing fraud? One way is to threaten to withhold funds if labs do not undertake steps to detect and reduce fraud, as in Germany [1 5]. These regulations were put in place by the main funding body there. Deu tsche Forschungsgemeinshaft (DFG) - establishing the lnstitut fOr Forschungsinformation und Qualita tssicherung (Institute for Research In formation and Qua lity Assurance) as an 'auxiliary facility of the research' [16]. Closer to home, the General Medical Council (GMC). a UK regulatory body. charged Wakefield with publishing inadequately founded research and finding wrongful means of funding. effectively punishing him for his professional conduct in the matter of MMR [17]. This seems strange on the face of it: why not charge him for covering up his conflict of interest. or for misleading the public? It is probably because the GMC has limited power to regulate these p roblems.

The fact that the GMC did not charge Wakefield for misleading the public, whether out of a lack of power or not, means that the debate of how to prevent this kind of issue from arising in the future was not raised. On the one hand, the effects of w hat he said were devastating to public health. but surely it could be argued that scientists should be allowed to alert their colleagues, and the public, of potentia l danger? Is it right that governing or funding bodies should have control over what their scientists announce or research? Across the Atlantic, Ja mes Hansen, a n eminent c limatologist, has claimed that he has been gagged by his funding body (possibly indicative of a larger effort to quieten climate change scientists in the USA) [ 18, 19]. Another such example is the non-disclosure of th e Seroxat adult suicidality trials. which revealed Seroxat was more dangerous than previously thought. This was a


CAMBRIDGE

blow to the pharmaceutical ind ustry, undermining the trust placed in them by the Food and Drug Administration (FDA) [20] . In both cases, it is contended that the funding body is wrong in gagging its scientists, but th inking of the consequences of Wakefield's announcement. is it too risky to not exert any control?

Whether it is funding bodies or fellow scientists that watch for fraud, it is possible that some people still do not care about these issues. The disgraced Wakefield still researches at a facility called Thoughtful House in the US and Hwang still runs a priva tely funded g roup in Korea [21, 22].1t seems as long as they produce results and publications then no-one minds too much. This is dangerous- should those shown to be untrustworthy get a second c hance? Surely scientists who are 'good' and 'decent' , in the majority, need to take a stand against those who simply are not conforming, lest scientis ts themselves lose faith in the credibility o f scientific work.

This raises a very problematic consideration: what about the chance of reform? Much like c riminals who stray from the legal path are let back into society. should the same be true for errant scientists? If there was a better way of catching fraudsters before they do the tremendous amount of damage those mentioned ha ve done to their fields, then this would be a good way of proceeding.

With this idea l in sig ht, some sc ie ntists have called for an interna tional bod y to run c hecks on sc ie ntists wo rldw id e [23]. Bu t o f course, t he se investigations wi ll ta ke mone y and scientists away from research at the fron tiers. It seems sad that we can ' t trust a minority within the scientific community to tell the truth, to each other or to the public, and that this damages not only the credibility of good work but also the funding for such work.

Given that incidents such as the MMR case a lso have such an impact on the public, it seems strange that they do not get involved with checking the honesty' of scientists. Science's fragile public image is difficult to main ta in in charged atmospheres fuelled by mass hysteria. This might be because the flow of informa tion between scientists is particularly contentious concerning scandals such as MMR. The problem here is two-fold: it is difficult for the scientist to transmit the information to the public, and the public finds this information difficult to receive and assimilate in a useful way.

Transmission of informa tion can e ither go via media or politicians, b ut these routes are fraught with


problems. The media is prone to abuse and bias and politicians can be construed to be 'towing the party line '. as in the 'Hansen Global Warming ' case above .

So wha t stops scientists from expounding their views t hemselves ? This wou ld effec tive ly make them politicians. and would risk them fo rming conclusions befo re gatherin g t he evidence. It would g ive credence to those scientists who feel temp ted to search for evidence to back up a gut feeling, rather than to accurately analyse the data they collect. Furthermore. just as politicians and their personal (or party) agendas

Science's fragile public image is difficult to maintain in

charged atmospheres fuelled by mass hysteria

are stereotypically d istrusted, so might scientists be when playing this role? Surely this is inconsistent with the objectivity of science as a discipline?

Sadly, the problems with communication also lie on the receiving end with the public and their d istrust in or misconception of the scientific method. If scientists are to accurately communicate the intricate risks and threats associated with their research, then the public must undertake to appreciate the idea of scientific objectivity and to avoid being overly swayed by large threats with either infinitesimally small or disproven risks.

James Shepherd is a 2nd year reading Natural Sciences at Gonville and Caius College. Cambridge.

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· CAMBRIDGE

References: ( 1] Steneck, N H. Assessing the risks of pubficly funded research. Cited in Science. 290,5497 (2CXXJ): 1662-1663. (2] Wakefield, A J. eto/.lleal-lymphoid-nodularhyperplasia, nonspecific cofilis, and pervasive developmental disorder in children. 7he Lancet. 351:9103. (1998). (3] BBC News. MMR researchers issue retraction. Thursday, 4 March 2004. [ 4] BBC News. UK 'in grip of measles outbreak'. Wednesday, 14 June 2006. [ 5] BBC News. Confidence 'returning in MMR jab' . Thursday, 28 September 2006. ( 6] BBC News. MMR researchers issue retraction. Thursday, 4 March 2004. [7] NewScientist.com news service. Controversial MMR and autism study retracted. Thursday, 4 March 2004. (8] BBC News. MMR doctor 'to face GMC charges'. Monday, 12 June 2006. (9] Coghlan, A. Medical editors to take tougher line. New Scientist. 2439. (2004). [10] Couzin, J. MIT Terminates Researcher Over Data Fabrication. Science. 310:5749. (2005): 758. [11] ScienceNOWDailyNews, AAAS. South Korean Team's Remaining Human Stem Cell Claim Demoished. 10 January 2006. 12] Kennedy, D. More Questions About Research

Misconduct. Science. 297:5578 (2002) : 13. [ 13] Lewin, R. Pressure to publish leads to increase in fraud. New Scientist. 1815 (1992) .

40

[ 14] Cambridge University Laboratory Leader. private communication [ 15] Bottanci, A. Germany Gets in Step With Scientific Misconduct Rules. Science. 296:5574 (2002). [16] www.forschungsinfo.de/ [ 17] BBC News. MMR doctor 'to face GMC charges'. Monday, 12 June 2006. [ 18] Pearce, F. Climate change pecial: State of denial. New Scientist. 2576. (2006). [ 19] Fry. C. Inquiry into c laims of US g lobal warming research censorship. Guardian Unlimited. 2 November 2006 [20] Jofre, S. Seroxat makes adults suicidal too. BBC News. 15 May 2006. (21] Thoughtful House Website. Dr. Andrew Wakefield. http://www.thoughtfulhouse.org . [22] ScienceNOW Daily News, AAAS. Hwang Returns to the Lab. 23 August 2006. (23] Willaims, N. Editors Seek Ways to Cope With Fraud. Science. 278:1221. ( 1997).

Graphics References: Page 37: Diaz, J MG. Rle 2539802. iStockphoto.com. 4th April 2007 Page 38: Mcbrugg. Rle 2803712, istockphoto.com. 4th April 2007 Page 39: McBrugg. Rle 2769373, istockphoto.com. 4th April 2007 Page 40: Leigh, K and Shepherd J. On behalf ofTTH Cambridge.


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