Evolutionary Biology and Human Health

Author: DYBAS, CHERYL LYN

Source: BioScience, 57(9) : 729-734

Published By: American Institute of Biological Sciences

URL: https://doi.org/10.1641/B570903

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www.biosciencemag.org October 2007 / Vol. 57 No. 9 • BioScience 729

Biologists and physicians drew attention to the links between

evolutionary biology and human healthat this year’s annual American Institute ofBiological Sciences (AIBS) conference inWashington, DC. More than 250 scien-tists gathered in May to tease apart the relationships between Darwin’s origin-of-species thinking and modern-day

medicine.What they found were some ofthe most surprising connections onEarth, links that will lead to new para-digms in health care, the researchers hope,along with a few lessons learned.

Homo sapiens sapiens has come a longway over the last 10,000 years, movingfrom hunter-gatherers to today’s modern,high-tech society. Despite the many

cultural changes our species has gonethrough, however, the human body andits immune and other systems remainessentially unchanged from those of ourearly ancestors, says Randolph Nesse, aphysician and evolutionary biologist atthe University of Michigan–Ann Arbor.“The great mystery of medicine is thepresence, in a machine of exquisite

Evolutionary Biology and Human Health

C H E RY L LY N D Y B A S

The 2007 AIBS annual meeting focused on the importance of evolutionary biology in many aspects ofhealth science, such as understanding the human genome, the normal functions and malfunctions of

human genes, and the origin and evolution of infectious diseases.

Special Report

A Maasai shepherd moving his goats through Olduvai Gorge lives the way humanslived for much of their early history. The Maasai, who have relied on herding for

survival for thousands of years, have evolved the ability to make the enzyme lactasethroughout their lives. By applying evolutionary biology to medicine, scientists are

finding that many degenerative diseases can be better understood when humanadaptations are taken into consideration. Photograph: Ilya Raskin.

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730 BioScience • October 2007 / Vol. 57 No. 9 www.biosciencemag.org

design, of what seem to be flaws, frailties,and makeshift mechanisms that give riseto most disease. The question isn’t justhow do we get sick, it’s why?”The answer,he says, lies in the emerging field of evo-lutionary medicine.

Nesse and other speakers at the AIBSconference addressed this question.Each arrived at a similar conclusion:Evolutionary biologists and physiciansneed to join forces to create a new field ofDarwinian medicine. “Darwinian med-icine is still in its beginning stages,” saysRichard O’Grady, executive director of AIBS. “But it’s evolving at an ever-increasing rate. Evolutionary biology hassignificance for many areas of health andmedicine, not just those that arise frominfection.” Indeed, speakers at the meet-ing discussed ways in which evolutionarybiologists can collaborate with health-care professionals to better understanddiseases like cancer, heart disease, psy-chiatric disorders, and others.

Darwin’s theory of natural selection asthe explanation for the functional de-sign of organisms underlies how humanshave evolved disease responses.“There areadaptations by which we combat patho-gens, adaptations of pathogens thatcounter our adaptations, maladaptivebut necessary costs of our adaptations,and maladaptive mismatches betweenour body’s design and our current envi-ronment,” Nesse says.

Proximate, or near, questions probethe “what” and “how” of structure andmechanism, while evolutionary ques-tions ask “why” questions about originsand functions. Most medical researchseeks proximate explanations about howa part of the body works or how a diseasedisrupts a function. “The other half ofbiology, the half that tries to explain whatthings are for and how they got there,”Nesse says,“has been largely neglected inmedicine.”

“Doctors should be asking, ‘Why is abody vulnerable to this or that disease?’and ‘Why didn’t natural selection makethe body less vulnerable?’”Nesse believes.“A lightbulb would go on if they did, andthey’d recognize that another entire set ofquestions needs to be asked about everysingle disease.”

Decoding the human genome“It’s a spectacular, exciting time to be doing research in human genetics andgenomics,” said keynote speaker EricGreen, scientific director of the NationalHuman Genome Research Institute’s Division of Intramural Research.“Muchof this excitement is due to the ability todo more and more powerful sequence-based genome explorations.”

The Human Genome Project led to adraft sequence in 2001 and a complete sequence in 2003. “While we marvel atthese accomplishments,” said Green,“we’re also aware in the field of genomicsthat there’s an incredibly tough journeyahead, that of actually interpreting thehuman genome sequence, somethingthat even at a cursory level is going to takean unknown number of additional years.”

A great amount of attention, Greensaid, is now being focused on studyingnoncoding regions of the genome.“There’s a large [number] of noncodingfunctional sequences,”he said,“that act asregulatory elements to control the ex-pression of genes that mediate chromo-some replication, chromosome dynamics,and segregation and that function inways that aren’t even yet described intextbooks.”

Darwin knew nothing of DNA andnothing of genomes, Green said.“But heunderstood that evolution involved thiscontinual tinkering of all species’ blue-prints, if you will, and a constant attemptto change, to adapt to a change in envi-ronment.” This tinkering, scientists nowknow, involved trial-and-error processesthat led to major changes in the so-callednonessential, nonfunctional parts ofgenomes, with the essential, functionalcomponents tending to remain the same.“And so, left behind in all existing life-forms,” Green said, “in their genomes,are all sorts of clues about what could andcould not be tolerated with respect tochange. Evolution has left behind a legacyof successful and failed experiments, allscripted in the genomes of current life-forms.”

Green and his colleagues sequencesmall, targeted regions of the genome ina large number of vertebrate species.They then systematically compare thesesequences to the human reference se-quence to identify the most highly con-served regions in the human genome.“We’ve now targeted over 200 different re-gions of the human genome for suchstudies,” said Green, “but our flagshiptarget, for which [we have] data from 65vertebrate species, is a 1.8-megabase region of human chromosome 7. Thisis the region containing the gene that,when mutated, causes cystic fibrosis.”The secrets of this and other diseasesmay be hidden in the evolution of non-coding regions, Green said.

Besides understanding the importanceof the noncoding regions of our genome,Green said, there are some “exciting, newDNA technologies that are going tochange the face of sequence explo-ration...and lead to a whole new revolu-tion of how we might use sequenceexploration for answering all sorts ofquestions.”

Emerging virusesEdward Holmes of Penn State Universityreported that the ultimate reservoir ofthe SARS (severe acute respiratory syn-drome) virus is, in fact, the horseshoebat. In his talk on the evolution ofemerging viruses, Holmes said thatSARS is “an archetypical emerging virus.

Special Report

Randolph Nesse introduced the term“Darwinian medicine” with coauthor

George Williams in their 1995 book,Why We Get Sick: The New Science

of Darwinian Medicine. He spokeabout the relevance of evolutionary

biology to human health and theimportance of incorporating

evolutionary theory into medicine.Photograph: Carroll Photography.

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www.biosciencemag.org October 2007 / Vol. 57 No. 9 • BioScience 731

It’s a new pathogen that caused a newdisease. And its ultimate reservoir wasnot a human. It’s not the first, however,to develop in this way, and it won’t be the last.”

The science of looking at emergingviruses began in the 1980s with AIDS,Holmes said. “As an evolutionary biol-ogist, my interest in these viruses is, arethere rules we can develop to understandwhy some of them have emerged in hu-mans, while others haven’t? Why do wehave these particular ones and not themyriad of other infectious diseases thatcirculate in the animal kingdom?”

In fact, he said, there are rules. Thefirst, and simplest, is that almost allemerging infectious diseases caused byviruses are RNA viruses. “That’s impor-tant because RNA viruses evolve ex-tremely quickly. They lack any kind oferror correction mechanism. When theymutate, those errors are perpetuated.And their evolution rates, their muta-tion rates, are maybe six [orders of mag-nitude] higher than you see in mammalslike humans....That incredible evolu-tionary mutational power must in someway allow them to jump boundaries andget going in new hosts.”

The second rule, he said, is that if youlook closely at a list of emerging viruses,they can be categorized by how success-ful they’ve been in a new host species.When they jump from an animal to ahuman, how successful are they in a human? Evolution is the reason, saidHolmes, “for why lots of things crossover into humans, but very few estab-lish themselves as proper humanpathogens”with human-to-human trans-mission. AIDS is one of those that did.

There’s an ecological factor in whyAIDS became an epidemic, Holmes said.“The logging industry in West Africa ex-posed people to primates that carry the[viral] relative to HIV.And that change inproximity allowed HIV to jump fromnonhuman primates to humans. There’salways an ecological aspect to these emer-gences that we must know about” to un-derstand these viruses. Then there aregenetic factors determining why someviruses can emerge and some can’t, likehost susceptibility.

“It turns out there’s a very strongrule—the closer in evolutionary distancethe donor and the recipient species are,the more likely the virus will spread fromone to the other and successfullyemerge.... Fewer mutations are neededfor a primate virus to recognize cells inhumans and get itself going. So phy-logeny is really critical in understandingemergence.”

Holmes also said that with changingecology, “like deforestation and mega-cities, more and more [pathogens] willget into human populations.... If there’sone thing we learned from SARS, it’s thatwe have to have active disease surveil-lance and global cooperation.... Thatvirus was knocked out very quickly” be-cause it was controlled so well. “SARSwas an advertisement for global cooper-ation on disease.”

Rustom Antia of Emory Universityused the example of the myxoma virus inrabbits in Australia to talk about howpathogens emerge and why they harmtheir hosts. The rabbits were introducedinto Australia by European settlers. Therabbit population exploded, said Antia,and changed the ecology of the area byeating much of the native vegetation.“Then someone found that the same European rabbit species brought to SouthAmerica rapidly died of a myxoma infection,” he said. “So there was a sug-gestion that this virus could be used tocontrol [the rapidly expanding] rabbitpopulations in Australia.” So the myx-oma virus was introduced there.

A decline in Australia’s rabbit popula-tion took place, but the virus rapidlyevolved. As was shown in this virus inrabbits and in subsequent modeling stud-ies of other viruses in other hosts, Antiasaid, “the within-host dynamics of apathogen can be modeled as a sort ofrace between the pathogen growing andthe immune system [response that] itelicits, controlling the pathogen. Thepathogen elicits immunity, and immunitycontrols the pathogen.

“This basic framework shows the inter-action between the pathogen and the im-mune system, in the transmission of apathogen between an infected host andan uninfected host. The slowly growingpathogen grows and then gets killed bythe immune response before it reaches a high density. A very fast-growingpathogen, however, grows fast and thenkills the host. Transmission seems to happen most often at the intermediatelevels of virulence. At this level, thepathogen grows to a high density butdoesn’t kill the host,” increasing thechances for transmission.

Very simple models, he said, havehelped scientists look at the importanceof evolutionary changes in driving theemergence of pathogens. “Next we haveto bridge immunology and epidemiol-ogy,”Antia said.“That bridge will help usunderstand the evolution of virulence inpathogens and the emergence of thingslike drug resistance.”No matter what thepathogen, whether myxoma or influenza,he said,“we need to link within-host dy-

AIBS President Douglas Futuyma (left), professor in the Department of Ecology andEvolution at the State University of New York in Stony Brook, conducted

the meeting and introduced speakers, including Edward Holmes (center) and Eric Green. Photograph: Carroll Photography.

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732 BioScience • October 2007 / Vol. 57 No. 9 www.biosciencemag.org

namics to the transmission of a virus ina population to understand why parasitesharm their hosts.”

Computational methods for gene mapping How can scientists take in all the genetic variation they see within andbetween species and begin to patch it to-gether to understand the rules of howform and function have come togetherin various species? To address this ques-tion, Carlos Bustamante of Cornell Uni-versity analyzed human polymorphisms,and divergence data between humansand chimps, to identify genes that appearto be rapidly evolving and might be involved in recent human molecularevolution.

“Humans share a most recent com-mon ancestor, somewhere on the order ofabout 100,000 years ago, give or take,”saidBustamante. “And if we walk back fivemillion years ago, we’d find ourselves ina population very much like present-daychimpanzees. So how is it that we gofrom these hairy-looking things to thingsthat look like my wife and daughter, at areal level?”

The question, he said,“is really daunt-ing from a computational view, becausethere are so many changes, even fromour closest recent ancestors. So whichmutations and which kinds of genes areresponsible for the adaptive molecularevolution of our species? How much of

the genetic variation that we see withinhuman populations is functionally im-portant? How much of it is neutral? Howmuch is deleterious? And what types ofchanges and what types of genes may beinvolved in human disease?”

If humans and chimps are roughlyone percent divergent, said Bustamante,“that translates to somewhere on the order of 30 million nucleotide differ-ences. That’s 300,000 changes just in protein coding genes, 100,000 of whichare amino acid differences. And 100,000amino acids is something you can’t lookat one by one.” Then there’s the compli-cation that no one can guess how muchof noncoding DNA is important.

“So how do we do this? We need com-putational methods. Likewise, if we justfocus on humans, a pair of human chro-mosomes [is] on the order of 99.9 percentidentical, but it’s the different one-in-a-thousand base pair that translates to on the order of 10 million variablenucleotide sites in the human genome.”A person can’t figure out what everyamino acid change means, said Busta-mante, and computational methods arethe only answer.

A mitochondrial paradigm of diseaseEach one of us, though we think of our-selves as a single individual, is, in fact, acolony of a hundred trillion individualcells. And our cells have taken the evo-

lutionary strategy, said Douglas Wallaceof the University of California–Irvine, ofcreating a differentiation multicellular-ity, while inside each of these individu-als there is a colony of bacteria, knownas mitochondria. “So, in fact, the im-portant concept,” Wallace said, “is tonot think of ourselves as an entity, butto think of these different organisms asthey relate to achieving their ultimateevolutionary goal, which is to optimizethe probability that their genetic lin-eage will be retained from generation togeneration.”

Until now, said Wallace, “modernmedicine—classical medicine—has beenbased on the structural paradigm of dis-eases: tissue-specific functions, tissue-specific disease. But now we can say thatthere is another organism. This is themitochondrial organism, which has an energy paradigm. This is a holisticeffect but has differential tissue-specific effects.”

By studying energy flow through mitochondria,Wallace developed an evo-lutionary paradigm to understand med-icine at both the structural and theenergetic level.“So the mitochondria areabout energy, and life is about the inter-play between structure, energy, and in-formation. We humans have what wemight call an energy anatomy,” a way oflooking at our organs and our tissues,through the lens of energy flow throughmitochondria. Human degenerative dis-eases, like cancer or diabetes, and agingare intimately linked to our mitochon-dria, Wallace said.

“A significant part of our mitochon-drial DNA must have been adaptive,” hesaid, “allowing human ancestors to oc-cupy new environments. But some ofthese same variants, it’s beginning to turnout, are now important risk factors for awide range of common diseases.”

In our distant past, we needed to eatlarge amounts of hard-to-find salt andsugar to survive. Today, eating theamount of salt and sugar we’re still “pro-grammed for” can lead to high bloodpressure, or to diabetes and metabolicsyndrome. Our mitochondrial DNA didn’t get the memo: most of us aren’thunter-gatherers any longer.

Robert Fleischer (left), head of the Center for Conservation and EvolutionaryGenetics at the National Zoo, and Carlos Bustamante (center) listen as DouglasWallace answers a question during the discussion session on genes and genomics.

Photograph: Carroll Photography.

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Genetic variation and adaptationin AfricaBecause it’s thought that we all origi-nated in Africa, said Sarah Tishkoff of theUniversity of Maryland, “it’s critical forreconstructing our human origins tostudy disease processes there. We knowthat there is a huge amount of infec-tious disease in Africa, with HIV, TB,and malaria the three biggest killers. Soif we want to identify those variants thatare associated with either risk or pro-tection from these diseases, we need tolook in Africa.”

If we also want to find more effectivetreatments for ethnically diverse popu-lations, she said,“we need to be studyingvariants of genes in African populations.Think of it as a footprint that’s left behindwhen there is a strong selection for oneof these variants. If we can find those re-gions that are under selection, maybe wecan narrow down some of the variantsthat are important in disease.”

“For the past six years or so we’ve beengoing to Africa and collecting samples.Wenow have about 6500 samples that we’veisolated from about 100 different ethnicgroups,” she said. “We obtain detailedethnographic information about eachindividual, but in addition, we’re quite interested in obtaining phenotypic in-formation so that we can connect geno-type with phenotype and try to mapsome of these interesting traits.”

Tishkoff and colleagues have studiedfour of the hundred or so ethnic groupsin Africa: pygmies from Cameroon,East African pastoralists, East Africanhunter-gatherers, and a Bantu-speakinggroup. “They live in very different envi-ronments,” said Tishkoff,“and have verydifferent diets. They’ve been exposed todistinct pathogens, so we have every rea-son to think there could be very distinctadaptation going on in these differentpopulations, both for traits that are associated with disease and those thataren’t.”

Evolutionary dynamics of cancerIs genetic instability an early event andthe driving force of cancer progression,asks Martin Nowak of Harvard Univer-sity, or a late-stage by-product? “This isone of the biggest questions in cancer

genetics at the moment,” said Nowak.“Iwant to analyze mathematically the evo-lution that actually initiates the cancerprocess, and chromosomal instability isvery likely an extremely early event thatactually drives the process. I’m asking,What is the optimal mutation rate of acancer cell on the way to cancer pro-gression? Optimum for the cancer, thatis, not for the host.”

All our high-risk tissues, Nowak said,have developed in a way that allows us to avoid or delay the onset of cancer.Evolution has devised an attempt at sidestepping cancer: We have a largenumber of cells that divide, but thesecells are only replenished from a smallnumber of cells in a hierarchy—the stemcells.“Conventional cancer chemotherapykills all cells that divide,” said Nowak.“So you kill the cancer.And often you killthe patient. But you want to help the pa-tient to survive a tremendous amountof poison.

“So now we have molecular targetedtherapy that’s directed only at the cancercells. And imatinib, or Gleevec, is the firstmolecular targeted anticancer therapy

drug.... It’s highly effective as a treatmentof chronic myeloid leukemia.” Unfortu-nately, however, the leukemia stem cellpopulation is somehow spared byGleevec. “There’s no decline of the can-cer cell population that drives the dis-ease,” Nowak said. “The probability ofresistance is determined by the stem cellpopulation size at the start of therapy.The number of cell divisions that gener-ates the leukemia...leads to much higherlevels of resistance. Then it depends onthe mutation rate and the selective ad-vantage of resistance mutations—evenprior to treatment.”

Which brings us back to his thesis“that the major stake in the evolution ofmulticellularity was to make sure thatcancer does not happen too early, thatcells do what they’re supposed to do anddon’t just go crazy and divide.”

Melding evolutionary biology and medicineRegarded as a founder in the field ofDarwinian medicine, Neese said the field is really flowering now.“I think this meeting may be looked back upon as a

Pictured (from left) are discussion panelist Stephen O’Brien, of the National CancerInstitute, and plenary speakers Rustom Antia, Carlos Bustamante, Sarah Tishkoff,

and Martin Nowak. Photograph: Carroll Photography.

Special Report

Visit the AIBS Media Library for videos and audiorecordings of presentations made at AIBS annual

meetings from 2000 onward:

www.aibs.org/media-library

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milestone,”he said. Evolution is the foun-dation for all biology, Nesse explains,and its contributions to understandinginfectious disease and genetics are widelyrecognized, but its full potential for usein medicine has yet to be realized. Train-ing in evolutionary thinking, he main-tains, can help both biologists andphysicians ask important questions theymight not otherwise pose.

In his talk, Nesse related a tale of ahospital whose medical staff clearlyneeded to better understand evolution-ary medicine. “Several hospitals were rotating antibiotics, so they’d use one forsix months, then they’d all agree to useanother for the next six months, and another one for the next six months. Thisis the ideal way to create antibiotic re-sistance as fast as you can.”

Although anatomy, physiology, bio-chemistry, and embryology are recog-nized as basic sciences for medicine,evolutionary biology has not been. Futuredoctors, Nesse says, are generally nottaught evolutionary explanations for whyour bodies are vulnerable to certain kindsof failure. The narrowness of the birthcanal, the existence of wisdom teeth, and

the persistence of genes that cause bipo-lar disease and senescence all have theirorigins in our evolutionary history.

In an entire array of clinical and basicscience challenges, evolutionary biologyis turning out to be crucial. The evolutionof antibiotic resistance is becoming morewidely recognized, “but few appreciatehow competition among bacteria hasshaped an evolutionary arms race that hasbeen going on for hundreds of millionsof years,”wrote Nesse, Stephen Stearns ofYale University, and Gilbert Omenn of theUniversity of Michigan in an editorial inScience, “Medicine Needs Evolution”(24February 2006). “There is a growingrecognition that cough and fever are use-ful responses shaped by natural selec-tion, but knowing when to block themwill require studies grounded in anunderstanding of how selection shapedthe systems that regulate such defenses,and the compromises that had to bestruck.”

What actions would meld evolution-ary biology and medicine? Nesse liststhree: first, include questions about evo-lution on medical licensing tests, whichwould motivate medical school curricu-

lum committees to include evolutionarymedicine courses; second, ensure evolu-tionary expertise in agencies that fundbiomedical research; and third, incorpo-rate evolution into every relevant highschool, undergraduate, and graduatecourse.

These changes would help physiciansand biomedical researchers understandthat both the human body and itspathogens are not perfectly designed machines, but are evolving biological systems shaped by selection under theconstraints of trade-offs—trade-offs that produce specific compromises andvulnerabilities. Nesse offers a new twist onTheodosius Dobzhansky’s well-knownobservation: Nothing in medicine makessense except in the light of evolution.

Cheryl Lyn Dybas (e-mail:

cldybas@nasw.org) is a biologist and science

journalist who specializes in the environment

and health.

doi:10.1641/B570903Include this information when citing this material.

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