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“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