In a recent blog post (http://evmed.asu.edu/blog/evolutionary-medicine-top-ten-questions), Randy Nesse suggests that the presentations and discussions at the second annual conference of the International Society for Evolution, Medicine, and Public Health (ISEMPH) were

“… instigated 25 years ago as George Williams and I discussed and grappled with how evolution could be useful for medicine, and what to call the enterprise.”

In her chapter (Bentley, 2016) introducing the just published book, “Evolutionary Thinking in Medicine: from Research to Policy and Practice,” the author acknowledges activity that can be considered evolutionary medicine in the years prior to 1991 but confines it to before roughly 1940.  Following the end of World War II, Professor Bentley finds little to no evidence of significant work in the field until the 1990s.  Unfortunately, these claims disregard substantial numbers of evolution-related studies that either influenced fundamental understanding of human health and disease or affected medical practice.

Some of these publications from the period of 1945 to 1990 described seminal and extremely influential studies that appeared in high-profile medical or biomedical research journals.  In fact, a few of these publications led to Nobel Prizes or were associated with future Nobel laureates or other extremely eminent biomedical investigators.  They should be regarded as informative and important examples of evolutionary medicine.  This lack of recognition seems to reflect both the limitations that can arise from a field that embraces fairly disparate disciplines and the particular disciplinary affiliations characterizing individuals critically involved in the reinvigoration, since 1990, of evolutionary medicine as an explicitly-recognized domain of inquiry.

This situation reminds me, as best as I can recollect, of Horace Freeland Judson’s comments in his history of molecular biology, “The Eighth Day of Creation” (1979), about the multiple research traditions, whose practitioners had different primary interests and research goals, that together brought into being what we now regard as molecular biology.  For example, there were structural biologists who applied X-ray crystallography to biological macromolecules such as proteins and nucleic acids in the quest to determine three-dimensional structures and relate them to function.  A fairly distinct group of investigators were intensely interested in how genes functioned, a question they initially explored primarily in bacteria and their viruses.  The majority of members of these two groups were not necessarily, initially at least, well versed in the accomplishments of the individuals in the other group.

So with respect to Randy Nesse’s suggestion that all of the talks at the second annual conference of the ISEMPH can be traced back to his 1991 article with George Williams (Q Rev Biol.), I cannot agree completely.  My presentation, and the other talks in the same session on “Somatic Cell Mutation, Selection, and Evolution in Health and Disease,” can arguably trace their primary intellectual sources of inspiration, if that is not too grandiose a term, back well before 1991.  Of course, we would not have been presenting these talks at the particular place and time we did present them without the existence of the ISEMPH and all of the substantial work that preceded the creation of the society and made possible this particular conference.

So, below I provide a number of examples of important studies published after 1945 but before 1991, limited mostly to those of particular relevance to my career, in which evolutionary principles or concepts played a critical role in explaining or understanding phenomena of clear and arguably major medical significance.  The insights embodied in the corresponding publications were the impetus for many subsequent and important contributions involving evolution and medicine.  In addition, there were many other lines of research from this period that related to both evolution and medicine that I will not cite here.  Thus, the studies I do cite below are intended to be illustrative.

I am an immunologist with interests extending back many years in immunity, host-pathogen interactions, genetics, molecular biology, and evolution.  No later than the early 1970’s, I began to read about the field of immunology, and I encountered the clonal selection theory of acquired immunity, which still provides an important conceptual framework for immunologists, although with a variety of refinements and modifications.  Sir Frank Macfarlane Burnet of Australia formulated this theory in the late 1950’s (1957, 1959).  At roughly the same time and possibly even slightly ahead of Burnet, David Talmage, an American, put forward very similar concepts (1957, 1959).  Both scientists explicitly embraced an evolutionary framework to explain the human antibody response, as made explicit in the following sentences from Talmage’s 1957 article:

“The process of selection requires the selective multiplication of a few species out of a diverse population.  As a working hypothesis it is tempting to consider that one of the multiplying units in the antibody response is the cell itself.”

Their shared concept was that the antibody-producing cells, which we now call B lymphocytes and plasma cells, varied genetically (within the same body) in ways that influenced recognition of foreign molecules, termed “antigens.”  On the basis of differential abilities to respond to antigen, some B cells had a survival and proliferative advantage.  The result was that antigen that found its way into the body exerted a selective “pressure” on the body’s lymphocyte population promoting the evolution of that population of cells and favoring specifically those B cells with antigen-specific receptors able to effectively bind that antigen.  Such phenomena clearly represented somatic cell evolution and were obviously of relevance to immunity against human pathogens and presumably also of importance for numerous immunologically-mediated diseases.  In other words, the study of immune responses was part of evolutionary medicine.

Given this background, it never occurred to me to doubt that evolution was relevant to medicine.  But other aspects of my education and training similarly led me to view the relationship between evolution and medicine as unsurprising.

While pursuing medical and graduate degrees at the University of Pennsylvania between 1975 and 1981, I became aware of Peter C. Nowell (a physician and receipient of the Lasker Award in 1998), a faculty member in the Pathology Department who became well-known for first describing the Philadelphia chromosome in 1960 and fully documenting it in 1961 (Nowell and Hungerford, Science) a hallmark of chronic myelogenous leukemia and an early example of a cytogenetic alteration that conferred a proliferative advantage on the malignant cells (as shown later).  Of equal importance, in 1976, Dr. Nowell published an article in Science on tumorigenesis that was entitled: “The clonal evolution of tumor cell populations.”  The last sentence of the abstract makes undeniably clear the author’s belief that evolutionary principles were relevant to and needed to be applied to understanding and treating clinical cancer:

“More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.”

In 1977, I joined the laboratory of Peter C. Doherty to pursue a Ph.D. in immunology.  Dr. Doherty was an Australian immunologist who along with his Swiss collaborator at the Australian National University in Canberra, Rolf Zinkernagel, discovered, in 1974 (Nature), “Major Histocompatibility Complex (MHC) restriction” of virus-specific cytotoxic T cells, the name for a phenomenon that distinguished how T lymphocytes recognized antigen from how B lymphocytes recognized antigen.  In 1996, The Nobel Prize Committee for Physiology or Medicine acknowledged the seminal importance of the results obtained by Doherty (a holder of veterinary and graduate degrees) and Zinkernagel (a holder of medical and, ultimately, graduate degrees) (http://www.nobelprize.org/nobel_prizes/medicine/laureates/1996/).  Specifically, these two investigators found that T cells could only recognize a viral antigen if it was associated, in some sense, with a self-MHC molecule.  We now know that the antigen-specific receptors, composed of alpha chain-beta chain heterodimers, of so-called conventional T cells recognize peptide fragments from foreign (e.g. viral or bacterial) proteins that have been noncovalently associated with either class I or class II MHC molecules.

Doherty and Zinkernagel rose rapidly to prominence in the international immunology and virology communities due in part to their novel insights into how T cells recognize antigen but also because of an evolutionary argument that they made.  Specifically, they suggested that MHC restriction might provide a basis for explaining the extensive genetic polymorphism (i.e. allelic diversity) at most MHC class I and class II loci through heterozygote advantage.  Given the centrality of antigen-specific immune responses by T cells to a vast array of medical conditions, it would be perverse to deny that the advances associated with Doherty and Zinkernagel are highlights of evolutionary medicine.

My thesis research in the Doherty laboratory addressed an aspect of the interaction between humoral and cell-mediated immune responses to influenza A viruses.  By the 1970s and early 1980’s, it was clear that influenza A viruses provided powerful exemplars of rapid pathogen evolution in response to host immune responses, as exemplified by many studies such as one by Schild et al., (1974).  Of necessity, I had to learn about antigenic drift and antigenic shift that respectively correspond to gradual small changes in the amino acid sequences and antigenic properties of the virion surface protein spikes, hemagglutinin and neuraminidase, due primarily to point mutations, and to more dramatic changes in the amino acid sequences and antigenic properties of the virion surface proteins due primarily to recombination events.  Clearly, influenza virus drift and shift, the former being associated with the need for annually updated vaccines and the latter being connected causally to influenza pandemics, represent evolutionary processes of direct relevance to clinical medicine.

Another critical aspect of my experience as a graduate student was that my closest friend in the program, Jonathan Yewdell (now at NIAID, NIH), did his thesis research on antigenic drift in influenza A viruses.  His very first publication from his thesis project (Nature, 1979) used monoclonal antibodies to define the rate of occurrence of antigenic variants in hemagglutinin molecules from cloned influenza viruses and to characterize the antigenic sites, or epitopes, of these molecules.  The first two sentences of the abstract demonstrate the unambiguous relevance to evolutionary medicine.

“Although vaccines have been developed against many human viral pathogens, vaccination against influenza type A viruses has not been wholly successful. This is mainly due to the fact that the viral surface proteins, haemagglutinin and neuraminidase, are subject to antigenic evolution1.”

Other examples of evolutionary phenomena of clear relevance to medicine came to my attention via my interests in genetics and evolution beginning in my undergraduate years.  For example, when I learned about sickle cell disease and other hemoglobinopathies in college and medical school, I was already primed to appreciate the relevance of evolution to understanding the geographic variations in prevalences of these conditions in relation to the distribution of malaria due to Plasmodium falciparum (Allison, 1954).

None of the preceding denies that many physicians not focused on immunology, microbiology, infectious diseases, hematology, oncology, genetics, or molecular biology were largely oblivious to evolution before or even after 1991.  However, within the just named medical or biomedical fields, many clinical practitioners and researchers were quite aware of the relevance of evolutionary concepts and principles to understanding various aspects of disease prevalence, pathophysiology, and treatment.

Furthermore, going back decades, any researcher working with cell lines in tissue culture or amplifying microbes in vitro confronted the occurrence of mutation and selection (i.e., evolution) whether wanted or unwanted.  Those trying to genetically modify cells routinely employed mutation and selection, artificial selection, in performing experiments.  In fact, attenuation of viral pathogens for the purpose of creating “live virus” vaccines represents a highly practical and obviously medical application of evolution.  In my view, all of these phenomena are deserving of being included in the domain of evolutionary medicine.

So, I agree that the 1991 article in the Quarterly Review of Biology by Williams and Nesse was an important milestone in the development of the field of evolutionary medicine.  Their article has played a valuable role in systematizing thinking and galvanizing interest in the field over the past 25 years.  Nevertheless, it did not initiate the recognition that evolution is relevant to medicine or the active application of evolutionary notions to medicine or biomedical research for many of the people active between 1945 and 1990 in immunology, microbiology, infectious diseases, hematology, oncology, genetics, and molecular biology.

In summary, I salute Randy Nesse and others, such as Steve Stearns, who have devoted enormous time, effort, and expertise to creating a cohesive field of evolutionary medicine.  Prior to 1991, and even for some time after 1991, evolutionary medicine did not exist as a distinct discipline.  Even now one can raise questions about the boundaries of the field, and we still confront challenges in clearly defining its boundaries.

Looking to the future, I have argued in both public and private that the long-term viability of evolutionary medicine as a distinct discipline will depend to some degree on the investigators active in the many other medical or biomedical fields that involve evolutionary concepts, principles, and methods becoming aware of and gaining respect for the individuals who constitute ISEMPH.  The members of ISEMPH will not foster such awareness and respect by ignoring a vast body of experimental, conceptual, and theoretical work that can easily be related to the interests, methods, and goals of investigators active in ISEMPH.  Building connections to these other and much larger research communities seems to me to be a critical aspect of guaranteeing a vibrant future for ISEMPH.

References

Nesse R. Evolutionary Medicine: The Top Ten Questions. June 21, 2016 http://evmed.asu.edu/blog/evolutionary-medicine-top-ten-questions.

Bentley, GR. Applying evolutionary thinking in medicine: an introduction. In: Evolutionary Thinking in Medicine: from Research to Policy and Practice, Edited by A. Alvergne, C. Jenkinson, and C Faurie. Springer, Switzerland, 2016, pp. 1-16.

Williams GC, Nesse RM. The dawn of Darwinian medicine. Q Rev Biol. 1991 Mar;66(1):1-22.

Judson, HF. The Eighth Day of Creation: Makers of the Revolution in Biology. Simon and Schuster, New York, 1979.

Burnet FM A modification of Jerne’s theory of antibody production using the concept of clonal selection. Aust. J. Sci. 1957;20: 67–69.

Burnet, F. M. The Clonal Selection Theory of Acquired Immunity (Cambridge Univ. Press, Cambridge, 1959).

Talmage DW. Allergy and immunology. Annu Rev Med. 1957;8:239-56.

Talmage DW. Immunological specificity, unique combinations of selected natural globulins provide an alternative to the classical concept. Science. 1959 Jun 19;129(3364):1643-8.

Nowell P.C., Hungerford D.A. Chromosome studies in human leukemia. II. Chronic granulocytic leukemia. J. Natl. Cancer Inst. 1961;27:1013–1035.

Nowell PC. The clonal evolution of tumor cell populations. Science. 1976 Oct 1;194(4260):23-8.

The Nobel Prize in Physiology or Medicine for 1996. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1996/.

Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature. 1974 Apr 19;248(5450):701-2.

Doherty PC, Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet. 1975 Jun 28;1(7922):1406-9.

Schild GC, Oxford JS, Dowdle WR, Coleman M, Pereira MS, Chakraverty P. Antigenic variation in current influenza A viruses: evidence for a high frequency of antigenic ‘drift’ for the Hong Kong virus. Bull World Health Organ. 1974;51(1):1-11. PubMed PMID: 4218138; PubMed Central PMCID: PMC2366252.

JW Yewdell, RG Webster, WU Gerhard. Antigenic variation in three distinct determinants of an influenza type A haemagglutinin molecule.Nature, 1979;279:246-248.

Allison AC. Protection afforded by sickle-cell trait against subtertian malareal infection. Br Med J. 1954 Feb 6;1(4857):290-4.