Toward an evolutionary model of cancer: Considering the mechanisms that govern the fate of somatic mutations

Andrii I. Rozhok and James DeGregori

PNAS July 21, 2015 vol. 112 no. 298914-8921


Our understanding of cancer has greatly advanced since Nordling [Nordling CO (1953) Br J Cancer7(1):68–72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1–12] put forth the multistage model of carcinogenesis. However, a number of observations remain poorly understood from the standpoint of this paradigm in its contemporary state. These observations include the similar age-dependent exponential rise in incidence of cancers originating from stem/progenitor pools differing drastically in size, age-dependent cell division profiles, and compartmentalization. This common incidence pattern is characteristic of cancers requiring different numbers of oncogenic mutations, and it scales to very divergent life spans of mammalian species. Also, bigger mammals with larger underlying stem cell pools are not proportionally more prone to cancer, an observation known as Peto’s paradox. Here, we present a number of factors beyond the occurrence of oncogenic mutations that are unaccounted for in the current model of cancer development but should have significant impacts on cancer incidence. Furthermore, we propose a revision of the current understanding for how oncogenic and other functional somatic mutations affect cellular fitness. We present evidence, substantiated by evolutionary theory, demonstrating that fitness is a dynamic environment-dependent property of a phenotype and that oncogenic mutations should have vastly different fitness effects on somatic cells dependent on the tissue microenvironment in an age-dependent manner. Combined, this evidence provides a firm basis for understanding the age-dependent incidence of cancers as driven by age-altered systemic processes regulated above the cell level.

Selection shaped us to be endurance athletes…AND couch potatoes!

“Is Exercise Really Medicine? An Evolutionary Perspective:”
By Daniel E. Lieberman
Current Sports Medicine Reports 14, no. 4 (2015): 313–19.
Click here for the open access pdf

This superb short evolutionary analysis of the role of exercise in human health should be required reading for everyone interested in exercise and health…that is, all health professionals, and most of the rest of us us.  Lieberman shows that we were shaped to be endurance athletes by the benefits of chasing big game animals until they could go no further. But our ancestors also faced intermittent calorie shortages that shaped mechanisms to minimize unnecessary exercise, and to shrink unneeded tissues. Extensive daily exercise was so intrinsic to human life that the health benefits of exercise were never a selection force.

Several quotes offer eloquent summaries:

“The many mechanisms by which physical inactivity increases the risk of chronic, noninfectious diseases do not occur because physical activity evolved as an adaptation to prevent ill health, but instead, they evolved as adaptations to prevent excess capacity in individuals who were already active but energy limited.”  For instance, muscle loss conserves calories. (p. 317)

 “While exercise is an effective prescription to promote health, there is no minimum dose, no optimal dose, and no dose without risks or negative consequences.” (p. 313)

‘While physical activity is unquestionably a potent medicine, it never evolved for that role. Instead, humans’ evolutionary legacy as physically active endurance athletes on the margin of energy balance has resulted in a myriad of adaptive dose-response relationships in which the body uses stimuli from physical activity to adjust capacity to demand in order to maximize reproductive success. In addition, a chronic absence of moderate physical activity was so rare until recently that, from an evolutionary perspective, such levels of inactivity are not only abnormal but also cause pathology”  (p. 317)

In short, selection shaped us to be couch potatoes whenever possible, which now is almost always. And, the pathways from sedentary life to ill health are mostly adaptations that were useful for our ancestors, but often fatal today.


An evolutionary perspective helps evaluate the extent to which exercise is medicine and to explain the exercise paradox: why people tend to avoid exercise despite its benefits. Many lines of evidence indicate that humans evolved to be adapted for regular, moderate amounts of endurance physical activity into late age. However, because energy from food was limited, humans also were selected to avoid unnecessary exertion, and most anatomical and physiological systems evolved to require stimuli from physical activity to adjust capacity to demand. Consequently, selection never operated to cope with the long-term effects of chronic inactivity. However, because all adaptations involve trade-offs, there is no evolutionary-determined dose or type of physical activity that will optimize health. Furthermore, because humans evolved to be active for play or necessity, efforts to promote exercise will require altering environments in ways that nudge or even compel people to be active and to make exercise fun.

New articles in Evolution, Medicine & Public Health

After a long history of applying the sterile insect technique to suppress populations of disease vectors and agricultural pests, there is growing interest in using genetic engineering both to improve old methods and to enable new methods. The two goals of interventions are to suppress populations, possibly eradicating a species altogether, or to abolish the vector’s competence to transmit a parasite. New methods enabled by genetic engineering include the use of selfish genes toward either goal as well as a variety of killer-rescue systems that could be used for vector competence reduction. This paper reviews old and new methods with an emphasis on the potential for evolution of resistance to these strategies. Established methods of population suppression did not obviously face a problem from resistance evolution, but newer technologies might. Resistance to these newer interventions will often be mechanism-specific, and while it is too early to know where resistance evolution will become a problem, it is at least possible to propose properties of interventions that will be more or less effective in blocking resistance evolution.

John H McCullough
Clinical Brief:  Iron Restriction 
Full Text (PDF)

Amber Gigi Hoi and   Luseadra McKerracher
Clinical Brief:  Breastfeeding and infant growth 
Full Text (PDF)

Progress on reconstituting the depleted biome to prevent immune disorders

A review and update of an important topic

By William Parker and Rajendra A. Morey
Departments of Surgery (WP) and Psychiatry (RAM)
Duke University Medical Center, Durham, NC 27707

Historical Developments

The story of resolving immune dysfunction in Western society is one of uncovering a profound evolutionary mismatch. The story began 39 years ago when a parasitologist, John Turton, intentionally colonized himself with the human hookworm and eliminated his own hayfever [1].  Sadly, the story is littered with long pauses, and Turton’s observations went unappreciated for decades. The story took a new turn in the late 1980s when David Strachan pointed an accusing finger at some aspects of modern sanitation as being responsible for the plague of chronic immune disease affecting Western society [2]. Over the next 20 years, Strachan’s “hygiene hypothesis” evolved into “biome depletion theory” [3], as a large body of work identified the loss of biodiversity from the human body rather than hygiene, per se, as the underlying “evolutionary mismatch” [4, 5]. Graham Rook and others pointed toward the loss of eukaryotic symbionts in particular as being one of the most dramatic changes in the body’s ecosystem as a result of Westernization [6]. Further, a wide range of studies in animal models as well as a limited number of studies in humans pointed toward helminths as potential candidates for biological therapeutics that might alleviate the mismatch [6-8]. Given this information, a solution for chronic immune disease seemed apparent; enrich the depleted biome present in Westernized humans to eliminate pandemics of allergic, autoimmune, and other inflammatory-related diseases. The use of helminths appeared to be a very good place to start.

Recent Developments READ MORE »

Fighting HIV Evolution with an Evolved Therapeutic Agent: Phase I Dose Escalation Clinical Trial of a Potent Broadly Neutralizing Human Antibody

In previous commentaries (;;, I have discussed the critical role of extensive B-cell and immunoglobulin gene evolution in generating broadly neutralizing antibodies for HIV-1.  Of course, the unprecedented magnitude of antibody evolution necessary to achieve potent neutralization of a high percentage of HIV strains reflects the unprecedented evolutionary plasticity of HIV that originates in both high mutation and recombination rates for the HIV genome (Korber et al., 2001).  A new study by Caskey et al. (Nature, 2015) from the Nussenzweig Laboratory reports results for a first-in-human dose escalation phase I clinical trial of a human monoclonal antibody (mAb) specific for the HIV envelope (env) protein. READ MORE »

Ashley Montague on Anthropology and Medicine

Thanks to Holly Smith who provided a copy of a lovely little 1947 article in The Interne, by Ashley  Montague titled, Anthropology in Medicine.
Some quotes offer crucial historical perspective, such as: “Any suggestion that another course should be added to the already overcrowded medical curriculum will justly be viewed with alarm” He goes on to suggest that an anthropological perspective is crucial for physicians to have a view of the whole person in context, and to recognize individual variation as intrinsic to science and medicine.  Click here for the full pdf.

Montague 1947
Montague 1947
Montague titled,

MICROBIOTA Mother’s littlest helpers

By Katie Hinde and  Zachery T. Lewis
Science 26 June 2015:
DOI: 10.1126/science.aac7436 (not open access)

Commensal bacteria underlie, in part, our nutritional status, immune function, and psychological well-being. The trillions of beneficial microbes within our intestinal tract convert dietary nutrients, inhibit pathogen colonization, regulate immune processes, and produce neural signals (1, 2). Advances in our understanding of the importance of microbes have motivated the commercial development of products intended to boost “good” commensals and confer health benefits. Probiotic dietary supplements contain live beneficial microbes hoped to subsequently colonize the gut. Prebiotic nutrients are thought to enhance good gastrointestinal microflora by preferentially nourishing beneficial microbes. Even “psychobiotics” are being explored to ameliorate symptoms of psychiatric illness. These live organisms influence the brain through metabolites and neuroactive compounds in rodent models and preliminary human studies (3). How to most effectively be the landscape architects of our microbial community, however, often remains unclear. An opportunity to gain insights into how natural selection has shaped the coevolution of hosts and microbes can be found in mammalian mother-infant dyads, as our microbiota are ecologically engineered by mothers and breastmilk. Such insights can be leveraged to improve clinical management and nutritional technologies, enhancing human health not just in infancy, but across the life course (4, 5).  Read more (not open access)

Extent of Tumor Evolution as Assessed by Numbers of Nonsynonymous Somatic Mutations Correlates with the Effectiveness of Anti-Checkpoint Therapy

It would be hard to identify an approach to cancer treatment that has received more attention recently than anti-checkpoint therapy (Pollack, 2015).  This strategy for eliminating tumor cells is based on interfering with one or another pathway that inhibits the initial activation or functions of T cells, such as CD8+ cytotoxic T cells (CTL).  Activated tumor-specific CTL can directly kill their targets.  However, if copies of the T-cell surface molecule, PD-1, are bound by their physiological ligands on tumor cells, either PD-L1 or PD-L2, or other cells the ability of the T cell to perform its functions is substantially reduced.  A report published in Science (2015) by Rizvi et al. last month addresses the question of whether tumor mutation burden correlates with response to anti-checkpoint therapy for non-small cell lung cancer (NSCLC).


Causes and consequences of coagulation activation in sepsis: an evolutionary medicine perspective

By Maiara Marx Luz Fiusa, Marco Antonio Carvalho-Filho1, Joyce M Annichino-Bizzacchi and Erich V De Paula
Published in BMC Med. 2015 May 6;13(1):105. doi: 10.1186/s12916-015-0327-2. (open access)


BACKGROUND: Coagulation and innate immunity have been linked together for at least 450 million years of evolution. Sepsis, one of the world’s leading causes of death, is probably the condition in which this evolutionary link is more evident. However, the biological and the clinical relevance of this association have only recently gained the attention of the scientific community.

DISCUSSION: During sepsis, READ MORE »

Stearns – Medzhitov textbook to be published in August

Evolutionary Medicine 
Stephen C. Stearns, the Edward P Bass Professor of Ecology and Evolutionary Biology at Yale University
Ruslan Medzhitov, the David W. Wallace Professor of Immunobiology at Yale University School of Medicine and an Investigator with the Howard Hughes Medical Institute

This textbook is intended for use in undergraduate, graduate, medical school, and continuing medical education (CME) courses, aimed at both students and professionals in medicine and public health.  It discusses the evolution of patients and diseases, defenses and pathogens, cancer as an evolutionary process, vulnerabilities created by the evolution of reproduction, mismatch to modern environments, the evolution of mental disorders, and conflicts between the good of the individual patient and the welfare of the population (see brief Table of Contents below and detailed Table of Contents via the following link). This book’s professional illustrations and summaries of chapters and sections make its messages readily accessible.

To view Chapter 5 and the detailed Table of Contents visit the ‘Sample Content’ link: READ MORE »

A Functional Classification of Genomic Elements Informed by the Principles of Evolution

In an EMR commentary ( from March two years ago, I discussed issues related to the functional classification of genomic DNA sequences that arose in the context of claims from the ENCODE (ENCyclopedia Of DNA Elements) consortium.  A particular focus of that piece was an article by Graur and colleagues (2013) that offered an often humorous but rather stinging critique of the definition of “function” applied by the ENCODE authors to genomic DNA sequences.  Graur and two of his associates have now published (2015) an interesting and valuable functional classification of genomic sequences that is critically informed by their understanding of evolution. READ MORE »

Zurich EvMed meeting: Travel support available, Abstracts due NOW


Travel support for this meeting is available from Tri-CEM, the new evolutionary medicine Center at Duke University directed by Charlie Nunn.

The abstract deadline is NOW!

Evolutionary Medicine Conference: Interdisciplinary Perspectives on Human Health and Disease

July 30 – August 1, 2015
Institute of Evolutionary Medicine (IEM)
University of Zurich, Switzerland

This international conference will bring together distinguished keynote speakers as well as experts from different research areas (including medicine, anthropology, molecular/evolutionary biology, paleopathology, archaeology, epidemiology, and other fields) to debate the evolutionary origins of diseases and on how the knowledge of the past informs the present and the future. Furthermore, the specific implications of interdisciplinary research in the understanding and management of human health issues will be addressed.

All abstracts for mini-symposia, oral and poster presentations will be reviewed by a scientific committee and – when accepted – published in the Journal of Evolutionary Medicine. The best student abstract will be awarded a prize by the scientific committee. Students can also apply for a competitive travel grant.


This is the sister meeting to the recent meeting of the International Society for Evolution, Medicine and Public Health at Arizona State University’s Center for Evolution and Medicine 

An evolutionary strategy for treating metastases

Divergent and convergent evolution in metastases suggest treatment strategies based on specific metastatic sites

By Jessica J. Cunningham, Joel S. Brown, Thomas L. Vincent, and Robert A. Gatenby

In Evol Med Public Health published 20 March 2015, 10.1093/emph/eov006   (open access)

Abstract: Cancer cells, although maximally fit at their primary site, typically have lower fitness on the adaptive landscapes offered by the metastatic sites due to organ-specific variations in mesenchymal properties and signaling pathways. Clinically evident metastases will exhibit time-dependent divergence from the phenotypic mean of the primary population as the tumor cells evolve and adapt to their new circumstances. In contrast, tumors from different primary sites evolving on identical metastatic adaptive landscapes exhibit phenotypic convergence so that, for example, metastases in the liver from different primary tumors will evolve toward similar adaptive phenotypes. The combination of evolutionary divergence from the primary cancer phenotype and convergence towards similar adaptive strategies in the same tissue cause significant variations in treatment responses particularly for highly targeted therapies. This suggest that optimal therapies for disseminated cancer must take into account the site(s) of metastatic growth as well as the primary organ.

Chromosomal Catastrophe (Chromothripsis) Causing Curative Clonal Conquest

Last month, Murphy and colleagues (Cell, 2015) published a fascinating report about a patient with an immunodeficiency syndrome that underwent spontaneous resolution.  The mechanism for this remarkable outcome points to the importance of somatic cell selection and evolution in the origins, pathogenesis, and most dramatically in this case, elimination of disease. READ MORE »

Gil Omenn Prizes awarded at the ISEMPH meeting

Gil Omenn, Matthew Barber, Ann Demogines, & Randolph Nesse

The winners of the Gil Omenn Prize for 2013 and 2014 received recognition and their $5000 prize money at the inaugural meeting of the International Society for Evolution, Medicine & Public Health. Gil Omenn has just announced a major donation to the Society that will sustain the prize for at least three more years.  The prize is awarded for the best article published each year on a topic related to evolution in the context of medicine and public health in any journal.

Matthew Barber was awarded the 2014 Prize for his paper  “Escape from bacterial iron piracy through rapid evolution of transferrin” by Matthew Barber and Nels Elde from the University of Utah. The article appeared in Science 346:1362-6, 2014.
See more at:
Thanks to the prize committee: Sarah Tishkoff, Joe Alcock, Noah Rosenberg, and Alison Galvani

Ann Demogines was awarded the 2013 Prize for her paper  Dual Host-Virus Arms Races Shape an Essential Housekeeping Protein by Demogines A, Abraham J, Choe H, Farzan M, Sawyer SL (2013). PLoS Biol 11(5):e1001571. doi: 10.1371/journal.pbio.1001571
See more at:
Thanks to the Prize Committee, Allen Rodrigo (chair), Carl Bergstrom, and Sarah Tishkoff

Also, note that the Society now also sponsors the George C Williams Prize for the best article published in the Oxford Press journal, Evolution, Medicine, and Public Health



Live streaming of Thursday talks at ISEMPH meeting

The final program for the inaugural meeting of the International Society for Evolution, Medicine, & Public Health  is now online. 

All talks on Thursday March 19 will be live streamed at

The time zone is the same as California, so 3 hours earlier that EDT, and 7 hours earlier than London UK.


March 30 abstract deadline for Zurich EvMed meeting

The abstract deadline for the “Evolutionary Medicine Conference: Interdisciplinary Perspectives on Human Health and Disease” (Juli 30-August 1 2015 in Zurich, Switzerland) is approaching now:

– Abstract Deadline: March 30, 2015
– Early registration Deadline: May 31, 2015

Find all relevant information (abstract submission, registration, accommodation, etc.) on our official conference webpage:

Please get in contact with us if you have questions:

Thanks for sharing the event and the call for abstracts among your colleagues!

We would be happy to welcome you in Zurich soon…

Best wishes

Frank Rühli, Nicole Bender and Kaspar Staub (Conference Organisers)”

Omenn Prize for 2014 awarded for an article on iron piriacy by Barber and Elde

The Gilbert S. Omenn Prize is awarded by the International Society for Evolution, Medicine, and Public Health for best article published each year on a topic related to evolution in the context of medicine and public health.  The prize for 2014 goes to, “Escape from bacterial iron piracy through rapid evolution of transferrin” by Matthew Barber and Nels Elde from the University of Utah. The article appeared in Science 346:1362-6, 2014. First author Matthew Barber, a postdoctoral student, will receive the $5,000 prize and present a talk on March 21 at the 2015 ISEMPH meeting in Tempe Arizona.  The prize is made possible by a generous donation from Gilbert Omenn.

The Prize Committee—Sarah Tishkoff, Joe Alcock, Noah Rosenberg, and Alison Galvani—found the paper impressive in its scope, integrating phylogenetic, bioinformatic, and experimental approaches to show that primate hosts and bacterial pathogens causing diseases such as meningitis, gonorrhea, and influenza, have co-evolved in competition for a key growth-limiting nutrient: iron.  Barber & Elde show that natural selection during primate evolution produced specific functional adaptations in the iron-binding protein transferrin that prevent iron piracy by bacterial transferrin binding protein (TbpA). This result is a vivid illustration of the role that natural selection and “nutritional immunity” play in host-pathogen “arms races”, mediated by recurrent episodes of positive selection between hosts and pathogens.

Three papers were selected for honorable mention. They are listed below in alphabetical order.

Byars, Sean G., Stephen C. Stearns, and Jacobus J. Boomsma. “Opposite risk patterns for autism and schizophrenia are associated with normal variation in birth size: phenotypic support for hypothesized diametric gene-dosage effects.” Proceedings of the Royal Society B: Biological Sciences 281.1794 (2014): 20140604.

This article uses extensive health registry data from 1978 – 2009 in Denmark to demonstrate associations between birth weight and risk patterns for autism and schizophrenia.  They argue that their findings add support to the hypothesis that genomic conflict and imprinting may play a role in common diseases whose etiology has been difficult to unravel using standard approaches.

Pennings, Pleuni S., Sergey Kryazhimskiy, and John Wakeley. “Loss and recovery of genetic diversity in adapting populations of HIV.” PLoS genetics10.1 (2014): e1004000.

This article uses a population genetics approach to infer effective population size of HIV infections based on the prevalence of “hard and soft” selective sweeps. This study helps to explain actual patterns of drug resistance evolution in patients and suggests evolutionary principles for strategies to keep drug resistance to a minimum.

Warinner, Christina, et al. “Pathogens and host immunity in the ancient human oral cavity.” Nature genetics 46.4 (2014): 336-344.

This article characterizes the microbiota from dental calculus obtained from ~1000 year old human skeletons, observing pathogens associated with disease in modern populations and also antibiotic resistance genes prior to the use of antibiotics to treat disease.

Please join the Society in congratulating the authors of the winning and runner up articles. Nominations for next year’s prize will be received starting early in 2016.  The Society also sponsors the $5,000 George C. Williams Prize for the best paper published each year in the Society’s flagship journal, Evolution, Medicine and Public Health. All papers published in the journal in 2015 will have author’s fees waived and will be automatically entered into the Prize competition.




Human evolution and arsenic detoxification

Carina Schlebusch and colleagues just published an article in Molecular Biology and Evolution demonstrating human adaptation to the locally high arsenic levels in groundwater in the Argentine Andes. This work is the first to show a genetic adaptation that allows the detoxification of a environmental toxin (arsenic) in humans.

Title: Human adaptation to arsenic-rich environments

Abstract: “Adaptation drives genomic changes; however, evidence of specific adaptations in humans remains limited. We found that inhabitants of the northern Argentinean Andes, an arid region where elevated arsenic concentrations in available drinking water is common, have unique arsenic metabolism, with efficient methylation and excretion of the major metabolite dimethylated arsenic and a less excretion of the highly toxic monomethylated metabolite. We genotyped women from this population for 4,301,332 single nucleotide polymorphisms (SNPs) and found a strong association between the AS3MT (arsenic [+3 oxidation state] methyltransferase) gene and mono- and dimethylated arsenic in urine, suggesting that AS3MT functions as the major gene for arsenic metabolism in humans. READ MORE »

Altered Androgen Receptor Ligand Specificity in Prostate Cancer Cells Treated with an Androgen Biosynthesis Inhibitor

Carcinomas of the prostate are the most common cancers affecting men and a leading cause of male cancer deaths in the United States (CDC web site, Cancer Prevention and Control).  Given the unique association of the prostate with males, it makes sense that prosate carcinoma cells are often dependent for continued growth and proliferation on signaling by the androgen receptor, as andogens are primarily associated with physiological effects critical for male sexual development.  Therefore, therapies aimed at inhibiting either androgen synthesis or androgen receptor function make great sense. In a recent paper by Chen et al. (2014), Steven Balk and colleagues demonstrate that treatment of castration-resistant prostate cancer with a drug (abiraterone) that inhibits the production of androgens can select for mutant androgen receptors (AR) that more effectively recognize and get activated by a non-androgen. READ MORE »

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