Category Archives: Evolutionary Medicine

Evolutionary Psychiatry Group Started

It’s the Evolutionary Psychiatry Special Interest Group (EPSIG) at the Royal College of Psychiatrists in the UK.

They list their objectives:

  1. Raise awareness of the value of understanding the contribution of evolutionary theory to psychiatry.

  2. Encourage research into the evolutionary psychiatry.

  3. Provide a forum for psychiatrists and others to discuss evolutionary models, research ideas and data with fellow evolutionists.

  4. Facilitate networking with academic institutions and evolutionary scientists, biologists, psychotherapists, psychologists and other disciplines such as philosophy.

  5. Keep members and supporters of the SIG informed via a webpage and newsletter.

  6. Organise workshops, symposia and conferences on Evolutionary Psychiatry and related subjects.

  7. Organise sessions at the WPA and the RCPsych’s International Congress as well as with other college Faculties and Divisions.

Via psychiatrist and researcher @RandyNesse, whose own work applying evolutionary theory to psychiatry and medicine can be seen here.

How Understanding Evolution Can Help Us Treat Cancer

Evolutionary scientists Athena Aktipis, Randolph Nesse, and their colleagues and grad students are doing fascinating and important research in evolutionary medicine, and — the topic of this post — they have been applying an evolutionary framework to cancer, in order to think about it and treat it more effectively.

Athena’s post-doctoral fellows, Amy Boddy and Helen Wasielewski, pulled together these exciting examples just below of the work they’re all doing in this area (and are surely researchers to keep an eye on for more exciting work to come).

 

How Understanding Evolution Can Help Us Treat Cancer 
This is a foundational paper in the field of cancer evolution and explains how cancer progression is an evolutionary process and how understanding this evolutionary process can change how we think about and treat cancer.

Aktipis, C.A., Nesse, R. (2013). Evolutionary foundations for cancer biology. Evolutionary Applications. 6(1) 144-159. DOI: 10.1111/eva.12034 Open access.

Abstract: New applications of evolutionary biology are transforming our understanding of cancer. The articles in this special issue provide many specific examples, such as microorganisms inducing cancers, the significance of within-tumor heterogeneity, and the possibility that lower dose chemotherapy may sometimes promote longer survival. Underlying these specific advances is a large-scale transformation, as cancer research incorporates evolutionary methods into its toolkit, and asks new evolutionary questions about why we are vulnerable to cancer. Evolution explains why cancer exists at all, how neoplasms grow, why cancer is remarkably rare, and why it occurs despite powerful cancer suppression mechanisms. Cancer exists because of somatic selection; mutations in somatic cells result in some dividing faster than others, in some cases generating neoplasms. Neoplasms grow, or do not, in complex cellular ecosystems. Cancer is relatively rare because of natural selection; our genomes were derived disproportionally from individuals with effective mechanisms for suppressing cancer. Cancer occurs nonetheless for the same six evolutionary reasons that explain why we remain vulnerable to other diseases. These four principles—cancers evolve by somatic selection, neoplasms grow in complex ecosystems, natural selection has shaped powerful cancer defenses, and the limitations of those defenses have evolutionary explanations—provide a foundation for understanding, preventing, and treating cancer.

 

Applying Life History Theory At The Cancer Cell Level
This paper applies evolutionary life history theory at the cancer cell level and describes the likely tradeoffs between cell proliferation and cell survival and how these tradeoffs may affect the tumor’s response to different treatment strategies.

Aktipis, C. A., Boddy, A., Brown, J., Gatenby, R, Maley C. C. (2013). Life history tradeoffs in cancer evolution. Nature Reviews Cancer, 13, 883-892. DOI: 10.1038/nrc3606

Abstract: Somatic evolution during cancer progression and therapy results in tumour cells that show a wide range of phenotypes, which include rapid proliferation and quiescence. Evolutionary life history theory may help us to understand the diversity of these phenotypes. Fast life history organisms reproduce rapidly, whereas those with slow life histories show less fecundity and invest more resources in survival. Life history theory also provides an evolutionary framework for phenotypic plasticity, which has potential implications for understanding ‘cancer stem cells’. Life history theory suggests that different therapy dosing schedules might select for fast or slow life history cell phenotypes, with important clinical consequences.

 

Treating Cancer Like an Infectious Disease
Chemotherapy resistance is a major problem in cancer biology, yet we have no strategies to target resistance. Similar to resistance to antibiotics in infectious diseases, this paper describes costs and benefits of controlling a tumor population instead of attempting to kill all the cancer cells.

Jansen, G., Gatenby, B., Aktipis, C.A. (2015). Control vs. eradication: Adopting strategies from infectious disease treatment to cancer. Proceedings of the National Academy of Sciences of the United States of America 112.4 937. DOI: 10.1073/pnas.1420297111

Abstract: Clinical treatment for metastatic cancer has traditionally entailed administering the highest possible dose in the shortest period, a strategy known as high-dose density therapy. The implicit goal is complete eradication. Unfortunately, a systemic cure for most metastatic cancers remains elusive, and the role of chemotherapy has been reduced to prolonging life and ameliorating symptoms.

 

Cancer is Common to Multicellular Life
This paper is a review of cancer in species across the tree of life. It shows cancer or cancer-like phenomena are found in almost all multicellular organisms.

Aktipis, C. A., Boddy, A., Jansen, G., Hochberg, M., Maley, C., Hibner, U., Wilkinson, G. (2015). Cancer across life: Cooperation and cheating in multicellularity. Philosophical Transactions of the Royal Society B. Published online June 8 DOI: 10.1098/rstb.2014.0219 Open access.

Abstract: Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times. We review the existing literature on cancer and cancer-like phenomena across life, not only focusing on complex multicellularity but also reviewing cancer-like phenomena across the tree of life more broadly. We find that cancer is characterized by a breakdown of the central features of cooperation that characterize multicellularity, including cheating in proliferation inhibition, cell death, division of labour, resource allocation and extracellular environment maintenance (which we term the five foundations of multicellularity). Cheating on division of labour, exhibited by a lack of differentiation and disorganized cell masses, has been observed in all forms of multicellularity. This suggests that deregulation of differentiation is a fundamental and universal aspect of carcinogenesis that may be underappreciated in cancer biology. Understanding cancer as a breakdown of multicellular cooperation provides novel insights into cancer hallmarks and suggests a set of assays and biomarkers that can be applied across species and characterize the fundamental requirements for generating a cancer.

 

Reproducing versus Maintaining the Body is Important to Cancer Risk
All species vary in the investment of cancer defense mechanisms. Why certain species are more susceptible to cancer, while others are cancer resistant is an open question. This paper explore whether reproductive tradeoffs cancer influence an organism’s risk for getting cancer.

Boddy, A., Kokko, H., Breden, F., Wilkinson, G. Aktipis, C. A., (2015). Cancer susceptibility and reproductive tradeoffs: A model of the evolution of cancer defenses. Philosophical Transactions of the Royal Society B. Published online June 8 Open access. DOI: 10.1098/rstb.2014.0220

Abstract: The factors influencing cancer susceptibility and why it varies across species are major open questions in the field of cancer biology. One underexplored source of variation in cancer susceptibility may arise from trade-offs between reproductive competitiveness (e.g. sexually selected traits, earlier reproduction and higher fertility) and cancer defence. We build a model that contrasts the probabilistic onset of cancer with other, extrinsic causes of mortality and use it to predict that intense reproductive competition will lower cancer defences and increase cancer incidence. We explore the trade-off between cancer defences and intraspecific competition across different extrinsic mortality conditions and different levels of trade-off intensity, and find the largest effect of competition on cancer in species where low extrinsic mortality combines with strong trade-offs. In such species, selection to delay cancer and selection to outcompete conspecifics are both strong, and the latter conflicts with the former. We discuss evidence for the assumed trade-off between reproductive competitiveness and cancer susceptibility. Sexually selected traits such as ornaments or large body size require high levels of cell proliferation and appear to be associated with greater cancer susceptibility. Similar associations exist for female traits such as continuous egg-laying in domestic hens and earlier reproductive maturity. Trade-offs between reproduction and cancer defences may be instantiated by a variety of mechanisms, including higher levels of growth factors and hormones, less efficient cell-cycle control and less DNA repair, or simply a larger number of cell divisions (relevant when reproductive success requires large body size or rapid reproductive cycles). These mechanisms can affect intra- and interspecific variation in cancer susceptibility arising from rapid cell proliferation during reproductive maturation, intrasexual competition and reproduction.

 

Cancer as an Evolutionary Process
Cancer is an evolutionary process, yet this concept is overlooked in cancer research.

Aktipis, C. A., Kwan, V.S.Y., Johnson, K. A., Neuberg, S.L., Maley, C.C. (2011) Overlooking evolution: A systematic analysis of cancer relapse and therapeutic resistance research. PLoS ONE 6(11): e26100. doi:10.1371/journal.pone.0026100 Open access.

Abstract: Cancer therapy selects for cancer cells resistant to treatment, a process that is fundamentally evolutionary. To what extent, however, is the evolutionary perspective employed in research on therapeutic resistance and relapse? We analyzed 6,228 papers on therapeutic resistance and/or relapse in cancers and found that the use of evolution terms in abstracts has remained at about 1% since the 1980s. However, detailed coding of 22 recent papers revealed a higher proportion of papers using evolutionary methods or evolutionary theory, although this number is still less than 10%. Despite the fact that relapse and therapeutic resistance is essentially an evolutionary process, it appears that this framework has not permeated research. This represents an unrealized opportunity for advances in research on therapeutic resistance.

 

How Do Elephants Avoid Cancer?
Larger, long-lived species have more cells and more time to accumulate mutations. This should make them more cancer prone than small, short lived species. However, larger, long-lived species typically get much less cancer than expected (known as Peto’s Paradox). This paper explore the elephant genome and finds that elephants have an extra 19 copies of P53, an important tumor suppressor gene.

Abegglen, Lisa M., et al. Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA 314.17 (2015): 1850-1860. DOI: 10.1001/jama.2015.13134

Abstract: Importance Evolutionary medicine may provide insights into human physiology and pathophysiology, including tumor biology.

Objective: To identify mechanisms for cancer resistance in elephants and compare cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome (LFS).

Design, Setting, and Participants: A comprehensive survey of necropsy data was performed across 36 mammalian species to validate cancer resistance in large and long-lived organisms, including elephants (n = 644). The African and Asian elephant genomes were analyzed for potential mechanisms of cancer resistance. Peripheral blood lymphocytes from elephants, healthy human controls, and patients with LFS were tested in vitro in the laboratory for DNA damage response. The study included African and Asian elephants (n = 8), patients with LFS (n = 10), and age-matched human controls (n = 11). Human samples were collected at the University of Utah between June 2014 and July 2015.

Exposures: Ionizing radiation and doxorubicin.

Main Outcomes and Measures: Cancer mortality across species was calculated and compared by body size and life span. The elephant genome was investigated for alterations in cancer-related genes. DNA repair and apoptosis were compared in elephant vs human peripheral blood lymphocytes.

Results: Across mammals, cancer mortality did not increase with body size and/or maximum life span (eg, for rock hyrax, 1% [95% CI, 0%-5%]; African wild dog, 8% [95% CI, 0%-16%]; lion, 2% [95% CI, 0%-7%]). Despite their large body size and long life span, elephants remain cancer resistant, with an estimated cancer mortality of 4.81% (95% CI, 3.14%-6.49%), compared with humans, who have 11% to 25% cancer mortality. While humans have 1 copy (2 alleles) of TP53, African elephants have at least 20 copies (40 alleles), including 19 retrogenes (38 alleles) with evidence of transcriptional activity measured by reverse transcription polymerase chain reaction. In response to DNA damage, elephant lymphocytes underwent p53-mediated apoptosis at higher rates than human lymphocytes proportional to TP53 status (ionizing radiation exposure: patients with LFS, 2.71% [95% CI, 1.93%-3.48%] vs human controls, 7.17% [95% CI, 5.91%-8.44%] vs elephants, 14.64% [95% CI, 10.91%-18.37%]; P < .001; doxorubicin exposure: human controls, 8.10% [95% CI, 6.55%-9.66%] vs elephants, 24.77% [95% CI, 23.0%-26.53%]; P < .001).

Conclusions and Relevance: Compared with other mammalian species, elephants appeared to have a lower-than-expected rate of cancer, potentially related to multiple copies of TP53. Compared with human cells, elephant cells demonstrated increased apoptotic response following DNA damage. These findings, if replicated, could represent an evolutionary-based approach for understanding mechanisms related to cancer suppression.

 

Making Cancer Go Extinct
One goal of cancer therapies is to drive tumors to extinction. What can we learn from species extinction in the paleontological record that can help us improve cancer therapy and prognosis?

Walther, V., Hiley, C.T., Shibata, D., Swanton, C., Turner, P.E., and Maley C.C.: Can oncology recapitulate paleontology? Lessons from species extinctions. Nature Reviews Clinical Oncology, Published online: 17 February 2015 | doi:10.1038/nrclinonc.2015.12

Abstract: Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that inhibit oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. Indeed, driving a tumour to extinction is difficult. Geographically dispersed species of organisms are perhaps equally resistant to extinction, but >99.9% of species that have ever existed on this planet have become extinct. By contrast, we are nowhere near that level of success in cancer therapy. The phenomena are broadly analogous—in both cases, a genetically diverse population mutates and evolves through natural selection. The goal of cancer therapy is to cause cancer cell population extinction, or at least to limit any further increase in population size, to prevent the tumour burden from overwhelming the patient. However, despite available treatments, complete responses are rare, and partial responses are limited in duration. Many patients eventually relapse with tumours that evolve from cells that survive therapy. Similarly, species are remarkably resilient to environmental change. Paleontology can show us the conditions that lead to extinction and the characteristics of species that make them resistant to extinction. These lessons could be translated to improve cancer therapy and prognosis.

 

The Use of Common Pain Medications Could Slow Cancer Growth
This paper explores the potential for slowing down the evolution of cancer cells through the use of NSAIDS.

Kostadinov, R.L., Kuhner, M.K., Li, X., Sanchez, C.A., Galipeau, P.C., Paulson, T.G., Sather, C.L., Srivastava, A., Odze, R.D., Blount, P.L., Vaughan, T.L., Reid, B.J., Maley, C.C.: NSAIDs modulate clonal evolution in Barrett’s esophagus. PLOS Genetics, 9:e1003553, 2013. DOI: 10.1371/journal.pgen.1003553 Open access

Abstract: Cancer is considered an outcome of decades-long clonal evolution fueled by acquisition of somatic genomic abnormalities (SGAs). Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce cancer risk, including risk of progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA). However, the cancer chemopreventive mechanisms of NSAIDs are not fully understood. We hypothesized that NSAIDs modulate clonal evolution by reducing SGA acquisition rate. We evaluated thirteen individuals with BE. Eleven had not used NSAIDs for 6.2±3.5 (mean±standard deviation) years and then began using NSAIDs for 5.6±2.7 years, whereas two had used NSAIDs for 3.3±1.4 years and then discontinued use for 7.9±0.7 years. 161 BE biopsies, collected at 5–8 time points over 6.4–19 years, were analyzed using 1Million-SNP arrays to detect SGAs. Even in the earliest biopsies there were many SGAs (284±246 in 10/13 and 1442±560 in 3/13 individuals) and in most individuals the number of SGAs changed little over time, with both increases and decreases in SGAs detected. The estimated SGA rate was 7.8 per genome per year (95% support interval [SI], 7.1–8.6) off-NSAIDs and 0.6 (95% SI 0.3–1.5) on-NSAIDs. Twelve individuals did not progress to EA. In ten we detected 279±86 SGAs affecting 53±30 Mb of the genome per biopsy per time point and in two we detected 1,463±375 SGAs affecting 180±100 Mb. In one individual who progressed to EA we detected a clone having 2,291±78 SGAs affecting 588±18 Mb of the genome at three time points in the last three of 11.4 years of follow-up. NSAIDs were associated with reduced rate of acquisition of SGAs in eleven of thirteen individuals. Barrett’s cells maintained relative equilibrium level of SGAs over time with occasional punctuations by expansion of clones having massive amount of SGAs.

 

Cancer Evolves, Yet Treatment Often Doesn’t
Another foundational paper that describes the Darwinian nature of cancer and discussing the reason for this therapeutic failure. Greaves, M. & Maley, C.C.: Clonal evolution in cancer. Nature. 481:306-313, 2012. PMCID: PMC3367003. DOI: 10.1038/nature10762 Open access

Abstract: Cancers evolve by a reiterative process of clonal expansion, genetic diversification and clonal selection within the adaptive landscapes of tissue ecosystems. The dynamics are complex, with highly variable patterns of genetic diversity and resulting clonal architecture. Therapeutic intervention may destroy cancer clones and erode their habitats, but it can also inadvertently provide a potent selective pressure for the expansion of resistant variants. The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control.

 

Human Microbiome Papers

Microbes are Tiny Yet Powerful: Can They Change Human Behavior?
Explores novel possibilities for microbial manipulation of host behavior in humans.

Alcock, J., Maley, C.C., Aktipis, C.A. (2014). Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. BioEssays 36(10). DOI:10.1002/bies.201400071 Open access

Abstract: Microbes in the gastrointestinal tract are under selective pressure to manipulate host eating behavior to increase their fitness, sometimes at the expense of host fitness. Microbes may do this through two potential strategies: (i) generating cravings for foods that they specialize on or foods that suppress their competitors, or (ii) inducing dysphoria until we eat foods that enhance their fitness. We review several potential mechanisms for microbial control over eating behavior including microbial influence on reward and satiety pathways, production of toxins that alter mood, changes to receptors including taste receptors, and hijacking of the vagus nerve, the neural axis between the gut and the brain. We also review the evidence for alternative explanations for cravings and unhealthy eating behavior. Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating.

 

What We Eat Affects Whether Our Body’s Microbes Help or Harm Us
Considers diet as a fundamental source of cooperation or conflict between the gut microbiome and its human host, with important implications for health and disease.

Alcock, J., Wasielewski, H., Aktipis, C.A. (accepted pending revision). Conflict and cooperation between host and gut microbiota: Implications for nutrition and human health. Annals of the New York Academy of Sciences.

No link yet available. Not yet published.

 

For More in Evolutionary Medicine: Tweets and other references to the Evolutionary Medicine Symposium at the AAAS, The American Association for the Advancement of Science conference, February, 2016.

Follow: @RandyNesse, @AthenaAktipis@amy_boddy— and check out their papers posted on their sites linked at the top of this post.

The Evolutionary Ecology Of Cancer

Theoretical evolutionary biologist Athena Aktipis, a co-founder of the Center for Evolution and Cancer at UCSF, talks to David Sloan Wilson about how cancer is evolution that’s taking place inside an organism, but a perversely adaptive form of it, since it ends in the death of both the organism and the cancer.

Aktipis explains the selection pressures on cancer cells:

Let’s say that a tumor has evolved and grown so much that the interior is totally absent of nutrients, like you see in some cities, where the slums are totally absent of resources and filled with garbage. There is intense selection for cells to survive better in those conditions, which we call hypoxic conditions. These cells become pre-adapted to live in regions that are far away from blood vessels, so when you give chemotherapy, they are able to hide out, a phenomenon called “refugia” in cancer treatment. There are some really important aspects of the environment, ecology, and diversity of ecological niches that get created in the course of cancer progression and changed during treatment that haven’t been fully considered from an evolutionary perspective. There’s a lot of opportunities.

A particular cancer therapy can make sense — that is, until it’s viewed from an evolutionary perspective. Aktipis gives the example of the medical bias toward going with the most aggressive treatment possible:

For a long time it was almost a moral imperative to use the highest dose and most aggressive treatment possible, but now that’s being reexamined and many top cancer treatment hospitals in the country and the world are backing off from that. Not all of them are backing off because of an explicitly evolutionary framework, but some of the work that has been done over the last decade has helped to show why an overly aggressive approach can be problematic. As for drug-resistant infectious agents and resistance to pesticides in agriculture, high doses in cancer treatment imposes the highest selective-pressure on a population of cancer cells. If you have a small population that’s not very diverse, then using a high dose can make sense. But if you have a large and diverse population of cancer cells then the higher the dose, then the greater the selection pressure for resistant cells. That’s one of the really important insights that comes from taking an evolutionary approach to treatment. We shouldn’t just think about killing cells; we should be more strategic about what we want to select for and against.

Dr. Aktipis is also the author of the forthcoming book from Princeton University Press, “Evolution in the flesh: Cancer and the transformation of life.”

Genuine Disorders or Environmental Discrepancies? Review of an Evolutionary Psychology Explanation of Female Sexual ‘Dysfunction’

Like many other nonhuman primates, men and women engage in sexual intercourse for a myriad of reasons: to satisfy their own sexual desires, to satisfy the desires of their partners, to gain access to resources, and every once in a while, to procreate. A woman’s ability pass her genes on to healthy offspring contributes to her genetic fitness, and this ability is closely tied to the timing and frequency of sexual intercourse. From an evolutionary perspective, there should then be selection pressure for alleles that are associated with high sexual arousal and desire in women.

Epidemiological data, however, indicate that is not the case—recent estimates have suggested that up to 50% of women experience sexual dysfunction, characterized by dampened sexual arousal or desire, or inability to reliably experience orgasm during intercourse. But if natural selection favors alleles related to high sexual desire and arousal (and subsequently, the creation of offspring), why does the prevalence of sexual dysfunction in women remain so high?

A recent article in Adaptive Human Behavior and Physiology by anthropologist Menelaos Apostolou suggests that these clinical concepts we’ve labeled as ‘dysfunctions’ did not represent genuine dysfunctions in the pre-industrial environments where the majority of human evolution has taken place. In such pre-industrial environments, women’s sexuality was strictly regulated by parental and societal forces. Women were required by their parents to refrain from intercourse outside of the context of marriage, and were often married off to partners chosen by the parents. Once in that marriage, it was not illegal for husbands to force intercourse upon their wives. In this sort of environment, what we today would consider ‘sexual dysfunctions’ were not dysfunctions at all, as they did not contribute to a woman’s reproductive fitness—having high sexual arousal or desire would not significantly modulate a woman’s frequency and timing of sexual activity. In fact, low sexual desire and arousal may have even been a good thing, as such women would not be motivated to seek intercourse before marriage or with partners other than one’s husband.

Fast forward to the post-industrial society we live in currently, and the regulation of women’s sexuality in many parts of the world has changed considerably. Rather than being potentially maladaptive as they were during much of human evolution, high sexual desire and arousal are traits that now actually increase a woman’s reproductive fitness. In a society where women freely choose their mates and regulate their own sexual behavior, those with greater arousal and desire may engage in intercourse more often, and thus be more likely to pass on their genes.

This concept, of traits being disadvantageous currently when they were advantageous in ancestral societies, is called ancestral neutrality. The argument that Apostolou makes is that we have not lived in post-industrial societies with unregulated female sexuality long enough for evolution to catch up and ‘weed out’ alleles for low sexual desire and arousal, which explains the high prevalence of sexual ‘dysfunctions’ reported. However, depending on the extent to which low sexual arousal and desire decrease a woman’s reproductive fitness in this post-industrial context, it is likely that the alleles for these traits will become increasingly rare over time.

Apostolou’s paper highlights the important point that our conceptualizations of ideas such as health and illness are strongly time and culture-dependent. Low sexual arousal and desire have transformed from being advantageous traits in pre-industrial societies to being natural variants in female sexuality in the late 20th century, to then being dysfunctions warranting DSM-V categorizations and development of drugs to ‘cure’ them. (Sidenote: women’s sexual function has not been the only arena in which societal views modulate what we view as normal or abnormal. Rather than being labeled as having a mental illness, individuals with what the DSM-V would categorize as schizophrenia in ancestral societies were often regarded as shamans with significant spiritual and healing powers.) It will be interesting to keep tracking how societies define health and illness as they relate to female sexuality as our conceptualizations of sexuality continually develop.