“Biological sagacity of pathogens: the biggest

challenge to human intelligence”

Esther OrozcoUniversity of Mexico City

"The single biggest threat to man's dominance on the planet is the virus”.

Joshua Lederberg, Nobel Prize 1958

Enviromental changes lead to biological modifications in living organisms

Adaptative Capacities lies on

•Mutations•New DNA acquisition•Epigenetic Events•Phenotypic Changes

Evolution

Ancestral human migrations

• Capacity to adapt is a conservative element and necessary for evolution • Migration and adaptive capacities have been fundamental characteristics

of human beings since it’s origins in Africa about 130 thousand years before present (YBP).

MAMMAG, University of California, Irvine

170-130 YBP

51-39 YBP

12-15 YBP

73-56 YBP

70-65 YBP

Esther OrozcoUniversity of Mexico City

Changes in sucrose, lactose and mannose metabolism, skin pigmentation and fertility genes

Africa

Europe

Asia(middle/east)

OceaniaAmerica

Adaptative capacities drive genetic changes

Exons (protein, rRNA, tRNA (1.5%)

Changes with higher impact occur in 1.5% of the genome.

3,200 million bp: 99.9 % similar in all individuals

Esther OrozcoUniversity of Mexico City

Human being is surrounded by organisms with adaptative capacities

VirusBacteria ProtozoaFungiPlantsAnimals

pathogenspathogens

Benefic organismsBenefic organisms

Non-harmfulmicroorganismsNon-harmfulmicroorganisms

VirusBacteria ProtozoaFungi

pathogensNon-harmful microorganismsNon-harmful microorganisms

VirusBacteria ProtozoaFungi

Emerging and Re-emerging Diseasesprovoke changes in our genome, in economy and in social and individual behaviour

Circular genome map of IP32953 and comparison with Y. pestis CO92

Chain P S G et al. PNAS 2004;101:13826-13831

©2004 by National Academy of Sciences

Circular genome map of IP32953 and comparison with Y. pestis CO92. (A) Genome of IP32953. (B) Genome of CO92. (A and B) Circle 1 (from center outward), G+C content; circles 2 and 3, all genes coded by function (forward and reverse strand); circle 4, GC skew (G–C/G+C); circles 5 and 6, genome divided into locally colinear blocks (when IP32953 and CO92 are compared with one another); each block is distinguished by a unique color (black segments within colored blocks represent regions specific to that genome in the comparison), and the orientation of each block is indicated by strand; [circle 5, –ve strand; circle 6, +ve strand); circle 7, locations of IS elements (IS100 is blue, IS285 is red, IS1661 is green, and IS1541 is magenta)]. In A, the gray highlighted region near the 12 o'clock position indicates the proposed IP32953 inversion (see text), whereas the remainder of the genome denotes the stable “ancestral” arrangement that has prevailed through the present. B illustrates the complexity of the molecular events that gave rise to the inversions or translocations in the Y. pestis genome first proposed (16) solely on the basis of the dramatic shifts in G/C skew (gray highlights serotypes I, II, and III), but now extended through whole-genome comparison. For example, gray highlight II is composed of three distinct blocks, two that are derived from distinct places within the same replichore (origin to terminus half), whereas the third block originated from the other replichore (light blue block).

• pPCP1 and pMT1 plasmids• chromosomal genes adapted to new functions

Yersinia pseudotuberculosis Yersinia pestis20,000 years

causative of bubonic plague

Triumph of Death by Peter Bruegel (the elder)

European bubonic plague (1347)

First register: 541 bc Esther OrozcoUniversity of Mexico City

Emerging and re-emerging diseases around the world

Esther OrozcoUniversity of Mexico City

Infections are leading cause of death

Esther OrozcoUniversity of Mexico City

• Infectious diseases provoke biological answers of our organisms but they also are important selective forces on our genomes

Ej: distinct susceptibility to infections by different individuals:Immunity, genetic differences

Pathogens Human beings

Esther OrozcoUniversity of Mexico City

• Our history have also been shaped by continuous interactions with the world of microbes

Pathogens Human beings

Esther OrozcoUniversity of Mexico City

Conquest of Aztec Empire (1521)

Smallpox in the Mexico-Tenochtitlan siege. Florentine code, book XII f. 53v.

The Spanish conquest of the Aztec Empire had smallpox as his best allied.

15 million Aztecs died because of smallpox during the Spanish conquest. This event, facilitated the defeat and disappearance of the Aztec civilization.

Sánchez-Yáñez, et al. Smallpox in the conquest of Mexico

New disease in AmericaLack of immune defenses

Esther OrozcoUniversity of Mexico City

• 1786 Edward Jenner discovered the variola vaccine

•1803 Carlos IV send from La Coruña, España, the “Real and Philantropic Expedition of Variola

Vaccine”. The vaccine was carried from Spain to America in the bodies of 22 live children

• He gave the order that the vaccine can not be the object of commerce or particular benefits

• 1980 WHO declares the world free of smallpox (two centuries after the discovery of vaccine)

o City

1,138,006 bp

A night with Venus and a life with Mercurio”

Wolfgang Amadeus Mozart (1756-791) ?Ludwig van Beethoven (1770-1827) ?Franz Schubert (1797-1828) ?Edgar Allan Poe (1809-1849) ?Abraham Lincoln (1809-1865) ?Charles Darwin (1809-1882) ?Robert Schumann (1810-1856) ?Charles Baudelaire (1821-1867) ?Al Capone (1899-1947)

Simón Bolivar. (1783-1830) ?Cristóbal Colón (1451-1520) ?Alberto Durero (1471-1528) ?Hernán Cortés (1485-1547 ?Enrique VIII (1491-1547) ?María Estuardo (1516-1558) ? Iván el Terrible (1530-1584) ?Isabel I (1533-1603) ?

T.pallidum?

‘?

Spirochete100 Million years

T.pallidum: 100,000 years

from America or from Rusia?

12 million new cases around the world (WHO)

Source: Deborah Hayden: Genius, madness and the mysteries of syphilis. 2003, Basic Books

Esther OrozcoUniversity of Mexico City

Where the microorganisms causative of infection

diseasescome from?

Wolfe et al (2007) Nature 447: 279

Zoonosis: Main origin of human infections

HIV Origen

Sangha River Congo River Kinshasa River Around the worldCentral Africa, 1930 (Wolfe et al, 2007)

35 million people live with HIV three million people are killed by HIV/AIDS

100 nmLimphocyte T CD4

Human genome:3 200 000 000 bp

HIV-1 Genome:9749 nucleotides

15 m

HIV genoma (cDNA)

Mutation rate: About 10.3 x 109 virions are produced per day. These have a half life of 5.7 hours and a fixed mutation rate of 3 x 10-5 per base per replication cycle. This means that at least one mutation may occur in each nucleotide of HIV in a day.

HIV

RN

A genom

e

Migration has influenced the transformation of HIV/AIDS in a pandemic issue

The flu pandemic 1918-1919(50 million people killed)

National Museum of Health and Medicine (USA).

Epidemiology of Amoebiasis

In Mexico:• 2,057,198 cases intestinal

amoebiasis• 9394 cases of hepatic abscesses

50 million people around the world are infected with this parasite

Entamoeba histolytica

Esther OrozcoUniversity of Mexico City

Ehadh112 Ehadh112 Ehcp112Ehcp112 --

188 188 1338 1338 2061 bp2061 bp

5’5’ 3’3’55’’

Liver from animals immunized with Ehcpadh DNA and challenged with virulent trophozoites

Genes forming the Ehcpadh complex

0 1

cp/adh

healthyanimals 0 10 1

cp/adh

ccontrol

cp/adhcp/adh

vector

cp/adhcp/adh

Toward a vaccine against Entamoeba histolytica

Esther OrozcoUnivestity of Mexico City

Strategies to defeat microorganisms causing emerging andre-emerging diseases

Dorothy Mary Crowfoot Hodgkin (El Cairo, Imperio Británico 1910 - Shiptons-on-Stour, Inglaterra 1994) Nobel Prize Laureate 1964

1875 John Tyndall1915-1927 Clodomiro Clorito PicadoTwight1928 Alexander Fleming

Esther OrozcoUniversity of Mexico City

Time will come when people can buy penicillin in the pharmacy. Then, ignorant people will expose bacteria to non lethal antibiotic doses causing the emergence of drug-resistant bacteriaAlexander FlemingNobel, 1945

penicillium

Discovering of Antibiotics and emerging of drug-resistant strains

Antibiotic Discovering Resistant Strains

penicillin 1928/1943 1946

streptomycin 1943/1945 1959

cephalosporin 1945/1964 1968

tetracycline 1953 1948

eritotromycin 1952 1988

meticilin 1960 1961

ampicillin 1961 1973

Palumbi (2001) The Evolution Explosion (Norton & Co., New York)

Drug resistant strains appear due to Natural Selection

Drug resistant bacteria are selected very fast

Dobzhansky 1950 Esther OrozcoUnivesisty of Mexico City

antibiotic

Drug resistance in Entamoeba histolytica

P-glycoprotein: Discovered in Cancer cells (MDR)

Pgp normal function: detoxification

Pgp gene

GENE AMPLIFICATION

emetine

E. histolytica has at least six EhPgp genesDrug resistance mutants over express EhPGP proteinDrug resistance mutants present resistance to multiple drugs

Esther OrozcoUniversity of Mexico City

Conclusions:

• Genetics and genomics of pathogens allow them to survive

human body defenses and defeat human intelligence

They evade immune response and drug action

To win the battle we need: i) advanced knowledge on their biological mechanisms to develop better diagnostic methods, vaccines and new drugs

• Challenges are opportunities for social and economic development

Through biotechnology, genomics, proteomics, molecular biology, etc., etc.

Education, education and education

Who will win this war?

We can win many battles but never the war

MutationsNew DNA acquisitionEpigenetic EventsPhenotyipic Changes

Evolution

Microorganisms have also won many battles but never the war

Adaptation to Survive