Box 1: Evolutionary MedicineEvolutionary medicine aims to bridge the gap between evolutionary theory and medicine and to provide insightsinto the origin and persistence of diseases.

• Organisms should be viewed as collections of compromises shaped by natural selection to maximizereproduction. Therefore, organisms consist of tradeoffs and constraints that can result in less than optimal health.

• Cultural change occurs much more rapidly than biological evolution. This mismatch results in various diseases.

• Pathogens evolve much faster than humans.

• Disease phenotypes are influenced by the interactions between multiple genes and other environmental factors.

What Role Could Evo Devo Play in Improving Medicine?Simply put, evolutionary medicine bridges the gap between medicine and evolutionary biology. Proponents arguethat there is a reciprocal relationship between the two fields. Not only can evolutionary insights add somethingnew and useful to medicine, both in the clinic and research laboratory, but disease studies also reveal newquestions and challenges for evolutionary biology. Though, thus far, most of the energy has been focused on theformer.

Much of evolutionary medicine is grounded in population genetics. This approach is used to explain the presenceof deleterious or disease-causing alleles due to pleiotropy, epistasis, or linkage with beneficial alleles but does notapply to many diseases. It also does not easily fit with the study of disease causation in individuals (rather than thepopulation).

The aim of this poster is to suggest that the perspective of evolutionary developmental biology broadens the scopeof evolutionary medicine and helps to understand a wider range of diseases.

Box 1 is a summary of the present day form of evolutionary medicine. Box 2 is a brief description of evolutionarydevelopmental biology. Below Box 1, cancer is used as an example of how evolution and development lead to abetter understanding of the disease. Below and to the right, I use translational medicine to show how evo devo’smethodology, specifically for choosing model organisms, can be beneficial to medicine.

Box 2: Evolutionary Developmental BiologyEvolutionary developmental biology (evo devo) is a broad, pluralistic research field that investigates thecomplex causal relationship between evolution and development. Proponents of this approach seek tounderstand evolutionary dynamics of developmental processes and the generation of phenotypic variation.

Important aspects of evo devo for medicine:

• The study of complex regulatory networks, especially on the genomic level, has led to insights into thegeneration of phenotypic variation, including pathological variation.

•An expanded evo devo framework includes the role of the environmental and epigenetic effects in contributingto phenotypic variation, including disease, without direct genetic change.

The Role of Evo Devo in Translational MedicineKatherine Liu

Center for Biology and Society, School of Life Sciences, Arizona State University

Conceptual Example: CancerDespite the great advances in our understanding of cancer since the passage of the National CancerAct in 1971, cancer is still the second leading cause of death in the United States. Much of currentcancer research focuses on genetic, molecular, and cellular mechanisms and other proximate causes,including environmental exposures. This information has led to successful advances in differentialdiagnosis, screening, and certain treatments. However, questions about vulnerability, or why certainindividuals are more at risk for cancer than others, also require an evolutionary perspective. Inaddition, an evolutionary medicine framework explains the presence and prevalence of canceramong humans. Cancer is a problem of both evolution and development. Evo devo has theconceptual tools needed for a new integrative approach. Here is how cancer is a problem of bothevolution and development:

During normal development, regulation, differentiation, and proliferation are tightly linked. Toomuch or not enough proliferation can lead to deleterious or unhealthy effects. Any breakdowns inregulation due to mutation or epigenetic change can lead to uncontrolled growth and tumorformation. Furthermore, tumors such as teratomas show how tumor development can mimic normaldevelopment (e.g. embryogenesis).

Cancer is also a consequence of evolution. Complex organisms, such as humans, have evolvedmechanisms for valuable characteristics such as epithelial regeneration and adaptive immunity.However the tradeoff for these benefits is the risk of cancer and tumor development. The very samemechanisms that make these characteristics so beneficial for the organism (the ability for tissues tocontinually replicate throughout life and genetic recombination during lymphocyte maturation,respectively) are what make the organisms so vulnerable to cancer.

Methodological Example: Translational MedicineIn the broadest sense, translational medicine involves the transfer of knowledge gained from basicbench top research to the development of bedside applications for human health and disease.However, the process of translation is rarely discussed, raising the question: how does one goabout taking the knowledge gained from working with model organisms in the lab to successfullydeveloping drugs for human diseases? Drugs or therapies that work in the lab on mice or othermodels often do not work with humans. Part of this difficulty in translation is based on thedependence on a small number of model organisms, the insensitivity to the environment thatresults from standardization, or just the natural differences between humans and non-humanorganisms.

The NIH and Science Translational Medicine have argued that translational medicine needs a newapproach including new ways of thinking. Serious concerns have been raised that the continueduse of canonical model organisms (Figure 3) in the lab, which are too standardized and abstractedfrom the real world, is problematic. In this context, evo devo might be helpful. Many diseasesinvolve problems of regulation and are connected to developmental plasticity. Therefore, modelsshould be chosen that can display mis-regulation or express developmental plasticity. Due to thegoal-directedness of translational medicine, a model intended to be representative of a human maybe chosen. Evo devoists have moved outside the canonical set of model organisms to choosemodels that will allow them to answer specific questions or learn about certain phenomena. Evodevoists, for example, choose dung beetles (Figure 4) to serve as a model system fordevelopmental plasticity because many species express different horn phenotypes in differentenvironmental conditions. This broader evo devo perspective, incorporated within the largerframework of evolutionary medicine, represents those new ways of thinking called for by the NIH.

Conclusion and Practical ImplicationsEvolutionary medicine brings new and exciting insights to human disease biology. There are areas, such as antibiotic or antiviral resistance, inwhich the application of evolutionary theory has been well worked out and implemented. There are other areas, such as psychiatry, where suchapplication is still an open possibility. Yet, the current form of evolutionary medicine, with its foundation in population genetics, cannot fullyaccount for many diseases. These are the cases where a developmental or evo devo perspective needs to be implemented.

Cancer is one such example, where an evo devo framework can (1) lead to a better understanding of cancer biology and (2) suggest newdirections for research, such as more emphasis on the constraints on regulatory mechanisms and the role of microenvironments.

An evo devo framework can also contribute to a better understanding of the process of translation of basic research findings into clinicalapplications. Specifically, it suggests that a broader range of model organisms, including those that have not previously been widely used,should be considered. This represents a new and creative way of thinking, such as those called for by the NIH.

In order for any of this discussion to truly make an impact, educational changes need to be made. Randolph Nesse and colleagues have recentlysuggested learning objectives for premedical and medical competencies in evolutionary biology. Moreover, they have suggested topics thatshould be covered in medical school courses on evolutionary biology. Though they acknowledge that extensive courses in developmentalbiology are important for physicians to understand the human body, the importance of a curricular incorporation of evolution and development isalmost completely ignored. The two examples on this poster show why it is useful to also incorporate evo devo topics into the basic medicalcurriculum.

Figures 1 and 2. Clonal Expansion Theory: Through advantageous mutations (represented bydifferent colors), a cell will outcompete its neighbors. This process is repeated through many cycles.As tumors further develop, genetic instability greatly increases, resulting in high mutation rates andgreater genetic heterogeneity. Therefore, tumors are able to develop via numerous paths ofmutations and many networks within the cell can be affected.

SourcesGluckman, Peter, Alan Beedle, and Mark Hanson. 2009. Principles of Evolutionary Medicine. Oxford: Oxford University Press.Gluckman, Peter, and Mark Hanson. 2005. The Fetal Matrix: Evolution, Development and Disease. Cambridge: Cambridge University Press.Greaves, Mel. 2002. Cancer causation: the Darwinian downside of past success? The Lancet Oncology 3: 244-51.Greaves, Mel. 2007. Darwinian medicine: a case for cancer. Nature Reviews Cancer 7: 213-21.Jenner, Ronald A, and Matthew A Wills. 2007. The choice of model organisms in evo-devo. Nature Reviews Genetics 8:311-14.National Institutes of Health. Translational Research - Overview. http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp

Thesis: An evolutionary developmentalmedicine can supplement evolutionary medicine

both methodologically and conceptually.

In addition, cancer can be understood as an evolutionary phenomenon, representing a fundamental conflict between different units of selection, theorganism and the cell that lies at the heart of the evolution of individuality. As soon as the developmental regulatory mechanisms that controldifferentiation break down, those cells that have acquired the potential to divide uncontrolled, will be selected on the cellular level (Figures 1 and 2).

Therefore fully understanding cancer requires incorporating both developmental and evolutionary perspectives.

A framework that incorporates evolutionary and developmental perspectives better represents the complexity of the many factors involved in cancerbiology. As a consequence of such and in order to develop better therapeutic approaches, researchers need to move past genetic or molecularbiomarkers and also incorporate studies of tumor microenvironments and the interactions that occur between tumor cells and thesemicroenvironments. This would be an evo devo based evolutionary medicine.

Nesse, Randolph M., Carl T. Bergstrom, Peter T. Ellison, Jeffery S. Flier, Peter Gluckman, Diddahally R. Govindaraju, Dietrich Niethammer, Gilbert S. Omenn, Robert L. Perlman,Mark D. Schwartz, Mark G. Thomas, Stephen C. Stearns, and David Valle. 2010. Making evolutionary biology a basic science for medicine. PNAS 107(suppl. 1): 1800-07.Perlman, Robert L. 2005. Why disease persists: an evolutionary nosology. Medicine, Health Care and Philosophy 8: 343-50.Pierce, G. Barry, Robert Shikes, Louis M. Fink. 1978. Cancer: a problem of developmental biology. Englewood Cliffs: Prentice-Hall, Inc.Stearns, Stephen C., Randolph M. Nesse, Diddahally R. Govindaraju, and Peter T. Ellison. 2010. Evolutionary perspectives on health and medicine. PNAS 107(suppl. 1): 1691-95.von Eschenbach, Andrew C. 2004. A vision of the National Cancer Program in the United States. Nature Reviews Cancer 4: 820-28.Weinberg, Robert A. 2007. The Biology of Cancer. New York: Garland Science.

AcknowledgementsI thank the faculty and students of the Center for Biology and Society at Arizona State University for their intellectualassistance and moral support. I also thank the School of Life Sciences at ASU and AAAS Section L for travel fund assistanceto this meeting.

Figure 4. Dung beetles express differenthorn phenotypes in different environments

Figure 3. Laboratory mice are used asmodel organisms in much of biomedicalresearch.

http://www.sciencedaily.com/releases/2010/01/100119154719.htm Raff, RA. 2000. Evo-devo: the evolution of a new discipline. Nature Reviews Genetics 1:74-9.

Greaves 2002 Weinberg 2007

Image by Laura Hale (http://www.sdbonline.org/index.php?option=com_content&task=view&id=104)Early cleavage pattern of a sea urchin embryo.