Monthly Archives: March 2016

The Evolution Of Shame: Why Shame Is Adaptive

In The Boston Globe, Megan Scudellari reports on recent research by UCSB evolutionary psychologist Daniel Sznycer and his colleagues on shame:

In a new study published in the Proceedings of the National Academy of Sciences, researchers argue that shame evolved as a defense to prevent individuals from damaging important social relationships.

 

“When people find out negative things about you — say, that you steal or are physically weak or sexually unfaithful — this causes them to be less helpful and more exploitative toward you,” says study author Daniel Sznycer, an evolutionary psychologist at the University of California Santa Barbara.

 

That could be a threat to one’s welfare and success in life — especially back in early human hunter-gatherer social groups. It is possible therefore that humans evolved shame as a way to defend themselves by avoiding or concealing things that would make others devalue them.

 

To test this “defense” hypothesis of shame, Sznycer and colleagues recruited over 900 adults across the US, India, and Israel to answer questions about two dozen fictional scenarios. Each scenario depicted traits expected to invoke shame, such as stinginess, infidelity, and physical weakness.

 

They asked one set of participants to report — on a scale of 1 to 7 — how much shame they would feel if they themselves were committing the act in the scenario, such as stealing money from another person. People in a second group were asked to be observers, and to rate how negatively they would view the offending person. How would they feel, for example, about a person they spotted stealing money?

 

In similar experiments, the team gauged individuals’ feelings of sadness and anxiety in response to each scenario.

 

If shame is, in fact, a defense against the judgment of others, the researchers expected the intensity of shame felt in the first group to match up with the intensity of negative perception, or “devaluation,” of the second group. Such a match would suggest shame evolved to deal with the threat of being devalued by one’s peers.

 

That is exactly what they found. “The shame scores in each of the three countries were very highly correlated with the magnitude of devaluation of those in the audience situation,” says Sznycer. Morever, feelings of anxiety and sadness did not match up, supporting the idea that shame evolved as a defense against being devalued.

 

The findings suggest that shame is an innate emotion that evolved across different cultures, and that it is an evolved, rational trait designed to protect the individual.

Supplemental information about the study is here.

More from Daniel Sznycer about his research and thinking on shame (from his UCSB page):

The psychology of shame.

Ancestrally, the degree to which other people valued one’s welfare would have affected one’s access to resources such as food, mates, and support in times of conflict. Becoming less socially valuable would have entailed fitness costs. This adaptive problem is expected to have shaped adaptations for decreasing the likelihood and the costs of being socially devalued. We proposed that one such adaptation is the emotion of shame. Using this basic functional framework, and in collaboration with John Tooby and Leda Cosmides, I developed a theory of shame—the information threat theory of shame (ITTS)—and tested predictions derived from it.

 

Failing to deploy countermeasures against devaluation when one is devalued is a costly mistake. Deploying shame measures when one is not devalued is another type of mistake. Thus, effective shame countermeasures require an understanding of what does and does not elicit devaluation. In fact, we found a strong match between the extent to which a particular situation elicits devaluation on one hand (audience’s perspective) and shame on the other (discredited individual’s perspective).

 

According to the ITTS, what counts as socially valuable differs from domain to domain. For example, in the domain of cooperation, a track record of reciprocating is viewed favorably. In the domain of mating, value is indexed by things such as cues of fertility and pathogen-resistance. Consistent with this, we obtained evidence that both the elicitors and the motivational responses of shame vary across domains.

 

The more a discrediting piece of information becomes widely known, the stronger the shame response is expected to be. Supporting this ITTS prediction, we discovered that the extent of publicity of a discrediting behavior modulates the intensity of shame—but not the intensity of guilt.

 

The ITTS was also instrumental in making functional sense of cultural differences in shame. The cost of being devalued by an existing relationship partner can be attenuated by forming alternative relationships. Therefore, cultures where opportunities to build new relationships are perceived as being scarce are expected to also display higher proneness to shame—and vice versa. In collaboration with Kosuke Takemura, Andy Delton, Kosuke Sato, Tess Robertson, Leda Cosmides, & John Tooby, we found evidence supporting this prediction among American, English, and Japanese subjects.

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.