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The mathematician versus the malignancy

An engaging story about using mathematical models to improve chemotherapy.

 By Elie Dolgin

Nature Medicine 20, 460–463 (2014) doi:10.1038/nm0514-460 (open access)

The way in which people receive cancer therapy is pretty much the same as it’s been for decades: researchers determine the highest dose of a drug or treatment that does not cause unacceptable side effects; oncologists then administer that dose to patients on a standard timetable—usually daily tablets for oral chemotherapeutics and other pill-based regimens, infusions on a weekly schedule for injectable drugs and Monday-through-Friday treatments for radiation therapy.

Almost all current cancer therapies are given this way. And although the approach has undoubtedly extended countless patients’ lives, given that more than $80 billion is spent on cancer care in the US alone, it’s worth asking: are these schedules really yielding the best results for patients? And could alternative timetables produce better outcomes?

Franziska Michor hopes to answer these questions. Read more here

A report from the American Academy of Microbiology that is clear, short and engaging, and open access.

Executive Summary

Do you think the oncologists at a cutting-edge research hospital ever sit down with local farmers? Do you think the pharmaceutical researchers developing the next generation of anti-HIV drugs spend any time with the plant scientists working on the next generation of Roundup Ready soybeans?

If your answer to both questions is no, you would be mostly right. Even though all of these people are dealing with exactly the same evolutionary phenomena, they do not recognize themselves as a single scientific community and rarely get a chance to learn from each other. What they all have in common is that they are trying to eliminate an unwanted living entity – a cancer cell, a weed, a virus, an insect pest – but the treatments they develop eventually lose effectiveness because the target evolves resistance.

The emergence of resistance is a phenomenon with ancient evolutionary roots, Continue Reading »

Spermatogonial stem cells replicate and produce sperm throughout adult life, while oocyte precursors complete all of their mitotic cell divisions during fetal development and primary oocytes are arrested in meiosis at birth. Because many more rounds of cell division occur in spermatogenesis than in oogenesis, the incidence of germline mutations, and particularly of single base substitutions, is higher in sperm than in ova (Crow, 2000). Most single base substitutions occur roughly four or five times more frequently in sperm than in eggs, and the incidence of these mutations increases modestly with paternal age. Against this background, a handful of diseases, known as paternal age effect (PAE) diseases, stand out. PAE diseases, of which achondroplasia is the most common and best known, have several unusual features. Almost all (more than 95%) of the new mutations that cause these diseases occur in sperm; the incidence of these diseases increases significantly with paternal age, such that the fathers of affected patients are on average several years older than the fathers of unaffected babies in the same populations; and the genes underlying these diseases have unusually high apparent mutation rates. The mutations that cause PAE diseases are dominant, gain of function mutations in genes related to the RAS signal transduction pathway. Achondroplasia is due to mutations in fibroblast growth factor receptor 3 gene (FGFR3), while Costello syndrome, another PAE disease, is caused by mutations in the HRAS proto-oncogene. Continue Reading »

John W. Pepper, Barbara K. Dunn, Richard M. Fagerstrom, John K. Gohagan, and Nadarajen A. Vydelingum, “Using Systems Biology to Understand Cancer as an Evolutionary Process,” Journal of Evolutionary Medicine, vol. 2, Article ID 235678, 8 pages, 2014. doi:10.4303/jem/235678  (Open Access)

Abstract:  Unsatisfactory progress in cancer medicine and prevention calls for new research approaches. Research can broaden its view of cancer to include not only specific molecular elements, but also the process that explains their origin and dynamics. This process is Darwinian evolution of somatic cells. Applicable modeling techniques are available from process-oriented systems biology. We review relevant concepts and techniques, and their application to four key open questions in cancer prevention research. Helpful concepts are transferable from classical evolutionary biology and ecology, while useful techniques include computational agent-based modeling. The research questions we review include (1) why do benign neoplasms often progress to malignancy? (2) what is the chronological sequence of molecular events in cancer progression? (3) how can we find reliable molecular biomarkers for cancer? and (4) will evolved drug resistance stymie efforts at a long-term cancer chemoprevention? We conclude that molecular analysis can be usefully augmented with process-oriented systems biology to guide empirical research into the most productive directio

The Foundation for Evolution, Medicine, & Public Health announces the winner of the Omenn Prize for the best article published in 2013 on a topic related to evolution in the context of medicine and public health.  The Prize Committee, Allen Rodrigo (chair), Carl Bergstrom, and Sarah Tishkoff, considered 47 articles, and awarded the prize to 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

The first author, Ann Demogines, will receive the $5000 Prize.  She is a Research Associate in the Center for Systems and Synthetic Biology, College of Natural Sciences, University of Texas, Austin, where she works in the laboratory of Sara Sawyer.  The Foundation is grateful to Gilbert Omenn for making this prize possible.

 The Committee cited four other papers for Honorable Mention:

The Prize Committee’s Award Statement Is below Continue Reading »

A prion is a protein that can adopt a conformation other than the ‘standard’ functional conformation and this alternative conformation favors self-association. The aggregation-associated conformation can then be imposed on additional copies of the protein in the original conformation.  This self-templating mechanism for propagation is known primarily for causing neurodegenerative conditions in humans and in animals, such as kuru or Creutzfeldt-Jakob disease in humans or bovine spongiform encephalopathy (i.e., mad cow disease) in cattle.  Since this process of converting protein conformations can be transmitted from one animal to another or one person to another by some routes, such as cannibalism in the case of kuru, the name prion was created to indicate an infectious protein particle.  This concept of an infectious agent that involved no nucleic acid was the basis for the Nobel Prize in Physiology or Medicine awarded to Stanley Prusiner in 1997 (http://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/press.html). Continue Reading »

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Troubled sleep: Night waking, breastfeeding and parent–offspring conflict

A target article in Evolution, Medicine, and Public Health by David Haig on why infants cry at night, has  accompanying responses from Jim McKenna, Katie Hinde, Bernie Crespi, Patrick McNamara, and Jon Wilkins.  Open access

Abstract: Disrupted sleep is probably the most common complaint of parents with a new baby. Night waking increases in the second half of the first year of infant life and is more pronounced for breastfed infants. Sleep-related phenotypes of infants with Prader-Willi and Angelman syndromes suggest that imprinted genes of paternal origin promote greater wakefulness whereas imprinted genes of maternal origin favor more consolidated sleep. All these observations are consistent with a hypothesis that waking at night to suckle is an adaptation of infants to extend their mothers’ lactational amenorrhea, thus delaying the birth of a younger sib and enhancing infant survival.

This past December, science writer David Dobbs published an essay (2013) in the online magazine Aeon (aeon.co/magazine/) that purports to explain why the ‘selfish gene’ concept is outmoded and should be retired.  It elicited a good deal of commentary, and in early March, Aeon published responses (Sapolsky et al., 2014) to the original article from four individuals (two scientists, a genetic counselor, and a philosopher) as well as additional comments by Dobbs.  For those who are interested in this controversy, responses to the original Dobbs article were also posted elsewhere by Richard Dawkins (2013) and Jerry Coyne (2013a, b).  Below, I provide a sense of the arguments of Dobbs, the tenor of the criticisms of Dobbs’s piece, and selected other critiques of the gene-centric approach to evolution. Continue Reading »

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Crespi, B., Foster, K., & Úbeda, F. (2014). First principles of Hamiltonian medicine.
Philosophical Transactions of the Royal Society B: Biological Sciences, 369(1642). doi: 10.1098/rstb.2013.0366

We introduce the field of Hamiltonian medicine, which centres on the roles of genetic relatedness in human health and disease. Hamiltonian medicine represents the application of basic social-evolution theory, for interactions involving kinship, to core issues in medicine such as pathogens, cancer, optimal growth and mental illness. It encompasses three domains, which involve conflict and cooperation between: (i) microbes or cancer cells, within humans, (ii) genes expressed in humans, (iii) human individuals. A set of six core principles, based on these domains and their interfaces, serves to conceptually organize the field, and contextualize illustrative examples. The primary usefulness of Hamiltonian medicine is that, like Darwinian medicine more generally, it provides novel insights into what data will be productive to collect, to address important clinical and public health problems. Our synthesis of this nascent field is intended predominantly for evolutionary and behavioural biologists who aspire to address questions directly relevant to human health and disease.  More at PTRSB website 

The Cleveland Museum of Natural History invites applications for a postdoctoral fellow in Human Health and Evolutionary Medicine within the Division of Collections and Research.

The Museum is embarking on its Centennial Transformation Project, which will result in new exhibit galleries and research space.  As part of this project, a new gallery on human health is being created.  The museum seeks a postdoctoral fellow to help develop content and programs in the new human health gallery. Other duties will include managing content and coordinating with the exhibit design firm and a team of scientific advisors. The successful candidate will have a strong interest in public outreach and education and research experience in one of the following areas: 1) evolutionary medicine, 2) environmental health, 3) human biology, 4) human genetics.  The principal responsibility of the postdoctoral fellow will be exhibit-related activities, but research time can be negotiated depending on the fellow’s research program.  The position is for one year, starting July 1, 2014, but may be renewable for a second year.Applicants for this position should hold a M.D. or Ph.D. in a field related to human health (such as biochemistry, biological anthropology, cellular biology, genetics, immunology or physiology). The applicant should have a broad base of knowledge of human health, and demonstrated success in communicating science to the public is preferred.

The Cleveland region offers many opportunities for collaboration with other leading research programs at nearby institutions including Case Western Reserve University, University Hospitals, the Cleveland Clinic, Cleveland State University, and MetroHealth Hospitals, as well as a vibrant biotech community.   The museum itself also offers unique resources such as the Hamann-Todd Osteological Collection, a DNA laboratory, and the GreenCityBlueLake Institute.


Please send a cover letter, curriculum vitae, the names and contact information for three professional references in single PDF file to:
Human Resources
Cleveland Museum of Natural History
1 Wade Oval Drive, University Circle
Cleveland, Ohio 44106

 The list of people with an interest in evolution and medicine has been updated by Deryc Painter,  a graduate student in the Center for Biology and Society at ASU.  There are now 446 people on the list.

He began with the list from this site of self-identified medical professionals and research academics taking an evolutionary perspective to human health.  He added contributing authors and those cited in references from three recent textbooks of evolutionary medicine.  (Trevathan 1999, Stearns 1999, Perlman 2013)  He also added authors of articles in the 2010 special issue of Proceedings of the National Academy of Sciences on evolutionary medicine, and authors cited in Steve Stearns’ paper “Evolutionary Medicine: its scope, interest, and potential.  The resulting list provides a resource that should be very useful for connecting people in the field.  Please add your own information if it is not there already, and encourage other interested researchers, clinicians, and teachers to do the same.

  • Trevathan, W. R., Smith, E. O. & McKenna, J. J. 1999 Evolutionary medicine and health. New York, NY: Oxford University Press.
  • Stearns, S. C. 1999 Evolution in Health and Disease. New York, NY: Oxford University Press
  • Perlman, R. L. 2013 Evolution and Medicine. New York, NY: Oxford University Press.
  • Stearns, S. C. 2013.  Evolutionary Medicine: its scope, interest, and potential.  Proceedings of the Royal Society B. online  doi:10.1098/rspb.2012.1326

The 46 articles that were nominated  for the 2013 Omenn Prize are listed below.  The $5000 prize, sponsored by The Foundation for Evolution, Medicine, & Public Health, is made possible by a donation from Gilbert Omenn. Nominations closed on February 28, but the prize may be offered again next year.  The winner will be announced in April on the Foundation’s webpage and here at The Evolution, and Medicine Review.

To download the whole list click here     Omenn Prize articles EMR

To view the list, see below.

Continue Reading »

Geneticists have recognized for some time that many genes exhibit pleiotropy, meaning that one mutation can manifest in two or more distinguishable phenotypic effects. In a fascinating study recently published in Science [2014 Jan 10;343(6167):152-7. doi:10.1126/science.1246886], Joseph et al. offer evidence for an example of pleiotropy in which the distinct phenotypic effects associated with mutation of the POLR3A gene, which encodes a subunit (RPC1) of RNA polymerase III, are associated with two different diseases: one or another form of cancer and an autoimmune disease (scleroderma). Continue Reading »

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The prize is for the best 2013 paper in evolution, medicine, and public health. Deadline, Feb 28.  Details here. 

Greaves, Mel. (2014).Was skin cancer a selective force for black pigmentation in early hominin evolution?
Proceedings of the Royal Society B: Biological Sciences, 281(1781). doi: 10.1098/rspb.2013.2955  (open access)

Melanin provides a crucial filter for solar UV radiation and its genetically determined variation influences both skin pigmentation and risk of cancer. Genetic evidence suggests that the acquisition of a highly stable melanocortin 1 receptor allele promoting black pigmentation arose around the time of savannah colonization by hominins at some 1–2 Ma. The adaptive significance of dark skin is generally believed to be protection from UV damage but the pathologies that might have had a deleterious impact on survival and/or reproductive fitness, though much debated, are uncertain. Here, I suggest that data on age-associated cancer incidence and lethality in albinos living at low latitudes in both Africa and Central America support the contention that skin cancer could have provided a potent selective force for the emergence of black skin in early hominins.


          Open Rank (Job# 10655) Arizona State University School of Life Sciences

          Center for Evolution, Medicine & Public Health

Arizona State University is making a major commitment to developing the field of Evolutionary Medicine. There are plans to recruit up to eight faculty members for a new Center for Evolution, Medicine & Public Health headed by Dr. Randolph Nesse.

The Center and the School of Life Sciences invite applications for two open rank faculty positions for Cancer researchers with a preference for one associate/full and one assistant professor. Continue Reading »

Gallium-mediated siderophore quenching as an evolutionarily robust antibacterial treatment Adin Ross-Gillespie, Michael Weigert, Sam P. Brown, and Rolf Kümmerli EMPH
Published 30 January 2014, 10.1093/emph/eou003 

Background and objectives: Conventional antibiotics select strongly for resistance and are consequently losing efficacy worldwide. Extracellular quenching of shared virulence factors could represent a more promising strategy because (a) it reduces the available routes to resistance (since extracellular action precludes any mutations blocking a drug’s entry into cells or hastening its exit) and (b) it weakens selection for resistance, since fitness benefits to emergent mutants are diluted across all cells in a cooperative collective. Here, we tested this hypothesis empirically.

Methodology: We used gallium to quench the iron-scavenging siderophores secreted and shared among pathogenic Pseudomonas aeruginosa bacteria, and quantitatively monitored its effects on growth in vitro. We assayed virulence in acute infections of caterpillar hosts (Galleria mellonella), and tracked resistance emergence over time using experimental evolution.

Results: Gallium strongly inhibited bacterial growth in vitro, primarily via its siderophore quenching activity. Moreover, bacterial siderophore production peaked at intermediate gallium concentrations, indicating additional metabolic costs in this range. In vivo, gallium attenuated virulence and growth – even more so than in infections with siderophore-deficient strains. Crucially, while resistance soon evolved against conventional antibiotic treatments, gallium treatments retained their efficacy over time.

Conclusions: Extracellular quenching of bacterial public goods could offer an effective and evolutionarily robust control strategy.

A careful reading of the review of fever in “Fever: Friend or Foe?”, reveals the embarrassing deficiency in medical science’s understanding of how fever, much less anorexia, functions in infection. Since fever (as well as anorexia and other components of the acute-phase response) is induced by our own cytokines, it is virtually axiomatic that fever has been more beneficial than harmful on an evolutionary scale (since otherwise the response would have been deleted). As a “fan” of fever, I’ve compiled a list of six potential benefits of fever, each of which is found in the literature and has a reasonable experimental or theoretical basis (and each likely has some degree of correctness). Note that the first four are based on fever being a heat stressor. Have a look and then see my take on it.

Fever may work by:
1) directly harming pathogens,*
2) inducing apoptosis of infected cells (and neoplastic cells),
3) inducing host’s heat shock proteins to protect host cells during infection,
4) inducing heat shock proteins in pathogens—extracellular heat shock proteins activate immune responses as “danger signals”,
5) increasing efficacy of immune responses since they work better at slightly elevated temperatures,*
6) turning down the immune response by causing apoptosis of neutrophils and lymphocytes. Continue Reading »

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Last month, I completed teaching a graduate course for the tenth time.  After several years (in the early 1990’s) of thinking about launching a new alternate-year seminar course and then planning it, I began teaching PATH 480 in the fall of 1994.  The original name of the course, maintained through the first seven times I taught it, was: “Immunology, Evolution and Logic.”  Beginning in 2009, another faculty member, Derek Abbott, joined me in teaching the course, and the title was revised to: “Logical Dissection of Biomedical Investigations.”  In my portion of the course, I retained an emphasis on the relevance of logic and evolutionary principles to thinking about immune recognition and immune functioning more generally.  I focused class sessions on concepts and underlying assumptions critical to experimental investigations as well as on experimental design and data interpretation in articles reporting studies pertaining to immune recognition. Dr. Abbott has focused his portion of the course on the practical cognitive skills involved in reviewing papers and grant proposals pertaining primarily to innate immune signaling. Continue Reading »

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The Evolution, Medicine, & Public Health Foundation invites nominations for the Omenn Prize of $5000 to be awarded in April 2014 for the best  article published in 2013 in any scientific journal on a topic related to evolution in the context of medicine and public health.

The prize, provided by the generosity of Gilbert S Omenn, will be awarded to the first author of the winning article.  Nominations, including a brief statement in the body of the email (max. 250 words), a copy of the article (if distribution is permitted) or abstract and article link, must be submitted by 5pm, 28 February, 2014 US Eastern Standard Time to  OmennPrize@evolutionarymedicine.org . Authors are encouraged to nominate their own articles, but nominations of articles by others are also welcome.

Any relevant peer-reviewed article is eligible, but the prize is intended for work that uses evolutionary principles to advance understanding of a disease or disease process.  The prize committee will give priority to articles with implications for human health, but many basic science or theoretical articles have such implications.

The Prize Committee is chaired by Allen Rodrigo, and its members are Carl Bergstrom and Sarah Tishkoff.  Papers by committee members, their students and lab group members are not eligible, and articles by their co-authors or close associates are subject to special conditions.

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