BEACON Researchers at Work: The Many “Arms-and-Eyes” of Retinoblastoma Family Proteins

This week’s BEACON Researchers at Work blog post is by MSU graduate student Yiliang Wei.

Profile

Hello BEACON members, I’m Yiliang Wei, a graduate student in the Arnosti Lab at Michigan State University (https://arnostilab.natsci.msu.edu). For my first blog at BEACON, I’m going to talk about my study of the functional diversity of the Drosophila Rbf2 protein, a recently evolved Retinoblastoma family member in Drosophila, and its possible role in regulation of ribosome biosynthesis. This study has been recently published on G3 (Genes|Genomes|Genetics) (doi:10.1534/g3.115.019166).

Our lab has been studying Retinoblastoma (Rb) tumor suppressor proteins in Drosophila. Rb proteins function as transcription co-repressors that bind to E2F/DP to control transcription of a diverse set of genes involved in cell cycle regulation. The Rb-E2F pathway plays central roles in cell cycle and development in most eukaryotes. The Drosophila Retinoblastoma family members Rbf1 and Rbf2 are structurally similar to their vertebrate counterparts and possess functionally conserved activities.

A canonical model for Rb-E2F pathway. Rb proteins interact with E2F and DP, and repress target gene expression, such as cell cycle related genes.

A canonical model for Rb-E2F pathway. Rb proteins interact with E2F and DP, and repress target gene expression, such as cell cycle related genes.

Many studies so far have been focused on Rbf1, since it has a dominant role in regulating the cell cycle control and mutants exhibit a lethal phenotype. A few years ago, our lab conducted a genome-wide analysis of the Rbf1 binding profile, and identified a number of non-canonical Rb targets, suggesting diverse functions of Rbf1 besides cell-cycle regulation, such as regulating signaling pathways (Acharya et al. 2012). This aspect of function of Rb appears to be conserved in mammals as well.

On the other hand, the study of Rbf2 has been less intense, mostly due to the mild phenotype and weak transcriptional activity. However, as we turned our eyes to Rbf2, we found some interesting features of this protein. First, the genus Drosophila is different from most arthropods in that it possesses this additional retinoblastoma family member – most arthropod genomes encode a single Rb gene. Second, the Rbf2 protein contains a distinct, derived C-terminus when compared to Rbf1. It is known that the C-terminus of Rb proteins influence regulation and promoter targeting in mammalian systems. These observations led me to consider why the rbf2 gene is strictly evolutionarily retained throughout the Drosophila lineage, despite the modest observed phenotypes; has the Rbf2 protein gained new functions during evolution, and might the unique C-terminus of Rbf2 contribute to differential targeting?

To answer these questions, I carried out parallel ChIP-seq analysis of Rbf1 and Rbf2 in Drosophila embryos. At first, we expected that Rbf2 genome-wide targets might be a subset of Rbf1, based on the canonical Rb-E2F interaction model that Rbf1 binds to both dE2F1 and dE2F2, while Rbf2 binds only to dE2F2. To our surprise, we found that Rbf2 has much more genome-wide targets than Rbf1, and in fact, Rbf1 targets are just a subset of Rbf2. As we noted in our G3 manuscript “this pattern either represents the neofunctionalization of Rbf2 with acquisition of novel gene targets, or alternatively, many of these genes may be bound by the Rbf1 homolog in sister species, with a Rbf2 acquiring some of these interactions through subfunctionalization of Rbf1.” This binding profile of Rbf2 runs contrary to the canonical Rb-E2F model, that Rbf proeins bind to their targets through E2F/DP. Our bioinformatic analysis indicates that Rbf2-only promoters may tend not to have strong E2F-like sites, suggesting that other transcription factors may recruit Rbf2- a property shared with mammalian Rb. In fact, over half of the Rbf2 targets were not associated with E2F binding when compared to another study (Korenjak et al. 2012). It has been noticed that the C-terminal regulatory domains of mammalian Rb proteins partially drive the specificity of these protein interacting with other cofactors. Likewise, the unique C-terminus of Rbf2 may allow it to interact with different types of regulators, other than E2F/DP cofactors.

As we further explored the nature of the bound genes, we found Rbf2 targets have diverse functional groups, similar to what we saw for Rbf1 targets. However, what we didn’t observe in Rbf1 is that the majority of ribosomal protein gene promoters were bound by Rbf2. Unlike the potent Rb activity on cell cycle genes, which are shut down by a small amount of Rb overexpression, the Rbf proteins’ repression activity on ribosomal genes is weaker, but widely spread to the majority of the ribosomal genes. We think that ribosomal protein genes are a different sort of target than cell cycle genes – they typically have less variation in expression levels than developmentally-regulated genes, which can be completely off in many settings. It is possible that the transcriptional regulation of ribosomal protein genes by Rb proteins may be subtle, but we think that it would have pleiotropic consequences. Interestingly, none or very few studies have shown any negative regulatory mechanism for ribosomal protein gene expression, it is rather surprising that this group of genes would be controlled only by positive input. Thus, our study offered an aspect of negative regulatory mechanism of ribosomal protein gene expression.

Intriguingly, one of the few reported phenotypes for rbf2 mutants may tie into the negative regulation ribosomal protein gene expression: rbf2 null flies lay eggs at a considerably higher rate than wild-type ones. This mild phenotype has been neglected, however, the egg laying is in fact tightly coupled to nutritional signals. Though it may sound good, laying too many eggs under certain conditions may have long-range fitness effects, perhaps reducing lifetime fertility. Therefore, Rbf2 may regulate Drosophila reproduction by fine-tuning the biosynthetic components, such as ribosome protein gene family.

An overlooked aspect of previous ChIP sequence data relating to human Rb and related p130 and p107 proteins is their similar enrichment on ribosomal protein promoters (Chicas et al. 2010). Interestingly, the mammalian Rb proteins are known to directly regulate RNA polymerase I and III activity. Together with the ribosomal protein gene regulation, this multi-layer gene regulatory network cover all aspects of ribosome production – what we usually consider as a potent break switch on cell cycle genes may also be regulating by numerous, subtle contributions the biosynthetic capacity of a cell. Clearly an activity relevant to cancer cells! Our findings provide a new view of the impact of Rb proteins in cancer.

Just like the Kuan-yin of a Thousand Arms, with each hand holding a unique power, the Rb family proteins have reached their “arms” to many aspects of the gene regulatory network. (Picture from The Palace Museum, http://www.dpm.org.cn)

Just like the Kuan-yin of a Thousand Arms, with each hand holding a unique power, the Rb family proteins have reached their “arms” to many aspects of the gene regulatory network. (Picture from The Palace Museum, http://www.dpm.org.cn)

As it turns out, 5000 years of Chinese culture provides an apt analogy for the action of the Drosophila Rbf proteins. Like Kuan-yin of a Thousand Arms and Eyes from Chinese Buddhism culture, where each hand holds a unique power, the Rb family proteins have reached their “arms” to many aspects of the gene regulatory network. Our studies of Rbf proteins indicate that there are many more functions of Rb, as well as non-canonical mechanisms that recruit Rb proteins to their targets. The appearance of the novel Rbf2 protein on the genome landscape, just as the more recently derived human Rb protein, indicates that gene duplication and diversification contributes to these central processes.

References:

Acharya, P., N. Negre, J. Johnston, Y. Wei, K. P. White et al., 2012 Evidence for autoregulation and cell signaling pathway regulation from genome-wide binding of the Drosophila retinoblastoma protein. G3 (Bethesda). 2: 1459–1472.

Chicas, A., X. Wang, C. Zhang, M. McCurrach, Z. Zhao et al., 2010 Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 17: 376–87.

Korenjak, M., E. Anderssen, S. Ramaswamy, J. R. Whetstine, and N. J. Dyson, 2012 RBF binding to both canonical E2F targets and noncanonical targets depends on functional dE2F/dDP complexes. Mol. Cell. Biol. 32: 4375–87.

Wei, Y., S. S. Mondal, R. Mouawad, B. Wilczynski, R. W. Henry et al., 2015 Genome-Wide Analysis of Drosophila Rbf2 Protein Highlights Diversity of RB Family Targets and Possible Role in Regulation of Ribosome Biosynthesis. G3 (Bethesda). In press.

For more information about Yiliang’s work, you can contact him at wyliang1987 at gmail dot com.

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BEACON Researchers at Work: Explain it to me like I’m a four-year-old.

This week’s BEACON Researchers at Work blog post is by University of Washington graduate student Sonia Singhal.

Sonia Singhal, Carrie Glenney, and Brian Connelly in front of the activity table at the Pacific Science Center's UW-centric "Paws-On-Science" event.

Sonia Singhal, Carrie Glenney, and Brian Connelly in front of the activity table at the Pacific Science Center’s UW-centric “Paws-On-Science” event.

How do you know that you understand a scientific concept?

When you can explain it to a four-year-old.

While this is not a situation I encounter in my day-to-day work, studying viral evolution in Dr. Ben Kerr’s lab at the University of Washington, I do face it frequently as a Science Communication Fellow with the Pacific Science Center. On a Saturday morning every couple of months, I take the bus down to Seattle Center, and in the bright, airy Ackerly Gallery of the Pacific Science Center, I set up a table with boxes of colored beads and sheaves of colored paper. These items form the backbone of the activities I am developing to teach visitors to the Pacific Science Center about evolution.

I run two activities. The first activity, which demonstrates mutation, is a drawing game. Visitors choose a simple line drawing and copy it as many times as they can in one minute. I then encourage them to tell me how their drawings compare to the original drawing. The second activity demonstrates selection. I set up boxes with colored beads, representing bacteria with different traits. Each box contains beads of predominantly one color, with a few beads of other colors mixed in. Visitors pour out the beads and notice the different colors. They then explore how the different colors – the different traits – are important by choosing colored paper backgrounds (antibiotics) that will “kill” beads with a matching color.

The activities have been designed so that any visitor to the Science Center, regardless of their age or background, could learn from them. However, I find that I get mostly 4- to 11-year-olds visiting my table. Interacting with them is demanding, hectic, frustrating, great fun, and incredibly rewarding, often all at once. Some of the children take their time copying a few pictures; some of them get into the game and make so many copies that they run out of room on the page. Some of them like to color-code their beads after pouring them out. Some of them want to pour out every bead from every box to make a multicolored bead soup. Some of them want to take home the boxes, or the beads, or the colored pieces of paper, or even the plush microbes that I bring in from my advisor’s office as props. But they all love making drawings and playing with the beads. Even when I don’t feel I’m getting my point across, I have fun watching them have fun.

The children teach me as much as – if not more than – I teach them. Working with them forces me to explain my research without jargon, and for a 4-year-old, this includes words like “bacteria” and “reproduce”. It stretches me to think of analogies between my research and the children’s everyday lives. For example, I will explain to them that bacteria copy themselves, and sometimes those copies look a little different from the parent, “just like you look a little different from your mom or your dad.” Most importantly, working with children challenges my assumptions. The media is rife with evolutionary stories involving antibiotic resistance and emerging diseases, so to those of us working in experimental evolution, viruses and bacteria are obvious examples of evolution in action. However, most of the children at the Pacific Science Center do not understand that viruses and bacteria replicate; they view germs as static forces rather than dynamic populations. And it turns out that this single point is a key hinge for explaining evolution. If the microbes are not copying themselves, they have very few avenues for dramatic changes.

The Pacific Science Center believes in giving its visitors freedom to explore. As in a typical museum, there are placards to read, but there are also levers to pull, wheels to spin, pressure pads to jump on, and water nozzles to aim at moving parts. In the same spirit, I let the visitors decide which activity they want to try. Usually they only choose one or the other, but sometimes I can take them through both and watch them fit the two activities together. One young girl decided that she wanted to draw, so we went through the drawing game; then she decided that she wanted to know what was going on with the colored boxes, so I had her choose one and pour out the beads. “Not all of them are pink,” she noticed. I told her, “That’s right. Just like you made copies of that drawing, these germs are making copies of themselves. And just like your copies were all a little different, the germ copies are a little different too.” “Oooohhh,” she said, with the intonation of a “eureka” moment.

The activities are flexible enough that I can layer in additional details. One boy liked the bead activity so much that he played it three times in a row. The fourth time, I asked if he wanted to try something a little different. “This time,” I said, “let’s give this person medicine before he gets sick, rather than after he gets sick.” I had him pour the beads directly onto the colored background, rather than adding the background afterwards. He immediately responded differently to the activity. Where before, he would dump out all the beads at once, now he shook them out a few at a time and stopped every four or five beads to remove the ones that matched the background color. He understood that, since the environment was different, the population of beads that were able to “survive” was also different.

My most interesting interactions, though, occur when the children bring their own questions to me. One girl, who already knew a little bit about disease-causing microbes (“Germs can infect people, or dogs, like parvo,” she told me.), asked a lot of detailed questions about how our bodies fight disease off, and how microbes can hide from immune cells. Another girl and her younger sister wanted to know whether mice were vertebrates or invertebrates. I had to shift gears abruptly to rack my microbe-centered brain for examples of common vertebrates and invertebrates. By the end of our conversation, I was explaining to them the difference between an endoskeleton (an internal skeleton, such as we have) and an exoskeleton (an external skeleton, such as insects have).

Working in an academic research lab requires understanding the minutiae of one’s question, organism, and experiments. At the same time, this fine focus can impede us from communicating the salient points to a non-scientific audience. My work with the Pacific Science Center gives me a way to step back, review the broader context of my research, and decide what is truly necessary for understanding. Although I’m still working out how best to present and explain evolution, I feel that every iteration of my activities brings me a little closer.

For more information about Sonia’s work, you can contact her at singhal at myuw dot net.

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Tortoises, hares, and topography: how fitness landscape structure affects the speed of adaptation

NahumHello fellow BEACONites and interested members of the public, I’m Josh Nahum, a postdoctoral fellow, who was at the University of Washington during the early years of the Beacon Center, but now I’m doing research at Michigan State University (more info found here: http://beacon-center.org/blog/2012/03/29/introducing-beacon-distinguished-postdoctoral-fellow-joshua-nahum/). I do digital and microbial evolutionary experiments, and some of my previous work involved the evolution of prudence in E. coli was covered on this blog is the past (http://beacon-center.org/blog/2011/08/29/beacon-researchers-at-work-survival-of-the-weakest-when-doing-poorly-does-best/). Similar to my previous post, today I’m going to talk about how spatial structure affects evolving populations. 

All living things rely on evolution by natural selection to become better adapted to their environment. The process of adaptation requires mutations (changes in DNA) that improve their reproductive success (called fitness) to be present in order to be selected. However, other research has shown that beneficial mutations can interfere with each other. This interaction (called epistasis) can constrain adaptation and make it more difficult to become well adapted. Studying this effect is important, as understanding (and predicting) evolution affects our ability to anticipate changes in evolving populations. This is useful in planning for the evolution of disease (such as the flu), mitigating the evolution of antibiotic resistance, and predicting how populations will respond to climate change. 

To investigate how evolution is constrained by epistasis (whether a mutation’s effect on fitness is adversely related to the presence of other mutations), we employ a common visual metaphor in evolutionary biology: the fitness landscape. In a fitness landscape, potential genotypes (specific possible DNA sequences) are envisioned as a surface, where genotypes that are just one mutational step from each other are adjacent. The fitness of each genotype is represented by the elevation of that point in the landscape. Thus a genotype with a high elevation is more likely to reproduce. A population consists of a cloud of points on the surface of this landscape, each point being a single organism’s genotype. Mutation adds new genotypes to the population, often causing cloud to spread. Natural selection operates to remove low fitness genotypes (organisms at lower elevation), leading the cloud to increase in average fitness (elevation in the metaphor) over time. If the cloud of genotypes reaches the highest location in the fitness landscape, then the population it represents is optimally adapted to its environment.

Similar to the Aesop's fable of the Tortoise and the Hare, more structured populations begin adapting more slowly, but can ultimately outpace less structured populations in the long run. Image attribution Project Gutenberg.

Similar to the Aesop’s fable of the Tortoise and the Hare, more structured populations begin adapting more slowly, but can ultimately outpace less structured populations in the long run. Image attribution Project Gutenberg.

Our work addresses the fundamental question of whether the fitness landscape is smooth or hilly. If a landscape is hilly, populations that possess genotypes that place them at the top of a hill (a location where all nearby mutations decrease fitness) will be trapped there, because any mutants that go down the hill will be outcompeted by those at the top. This is a problem if there exist taller hills a long way away. The genotypes that the peaks of these hills represent possible individuals that would be better adapted to the environment, but the current population has no way of evolving toward them. This problem doesn’t exist if a landscape is smooth (having just one hill), as all adaption leads to the global optimum (the best adapted genotype).

In nature, populations can be spread across an environment in a variety of patterns. Some of these patterns make it easy to migrate from one part of the population to another, while others make it challenging. Easier migration allows for beneficial mutations to spread through the population, while decreased mutation slows this process.

Interestingly, we can use this property to determine how hilly an adapting species’ fitness landscape is. If the fitness landscape is smooth, populations will evolve to the same optimal genotype, regardless of how easy migration is, although populations with more migration will get there faster. However, in hilly landscapes, populations can become trapped on various different fitness hills. A population with lots of migration is likely to all get trapped on the same hill, because beneficial mutations will sweep across it shortly after they first occur. Populations with limited migration, on the other hand, will likely reach a wider variety of peaks, as different beneficial mutations sweep through different parts of the population. This means that the population will evolve slower, but can better adapt to its environment because some of the explored peaks may be higher in fitness than the peak discovered by a less structured population. We name this effect the Tortoise-Hare Pattern; the population with less migration (Tortoise) initially evolves slower than the population with more migration (Hare). However the Hare can become trapped at a suboptimal fitness peak, allowing the Tortoise to surpass it in fitness and win the “race”.

Adaptation of E. coli populations over time demonstrating the Tortoise-Hare Effect. Along the x-axis is the number of transfers made during the experiment (a.k.a. time). The y-axis is the relative fitness of evolved populations compared to the ancestor (fitness = 1 means the same fitness as ancestor, but fitness > 1 means better adapted than ancestor).  The restricted migration treatment (slow migration, Tortoise) is in green and initially adapted slower than the unrestricted migration treatment (easy migration, Hare) as denoted the asterisks indicated significant differences between populations. But in the later transfers, the restricted treatment out-adapts the unrestricted treatment leading to a Tortoise-Hare Effect and the implication of a rugged landscape. For details see linked paper at the end of this post.

Adaptation of E. coli populations over time demonstrating the Tortoise-Hare Effect. Along the x-axis is the number of transfers made during the experiment (a.k.a. time). The y-axis is the relative fitness of evolved populations compared to the ancestor (fitness = 1 means the same fitness as ancestor, but fitness > 1 means better adapted than ancestor). The restricted migration treatment (slow migration, Tortoise) is in green and initially adapted slower than the unrestricted migration treatment (easy migration, Hare) as denoted the asterisks indicated significant differences between populations. But in the later transfers, the restricted treatment out-adapts the unrestricted treatment leading to a Tortoise-Hare Effect and the implication of a rugged landscape. For details see linked paper at the end of this post.

The presence of a Tortoise-Hare Pattern indicates that the fitness landscape is hilly (as the Hare would always win in a smooth landscape). We first used a digital model to confirm that the Tortoise-Hare Pattern is a litmus test for landscape hilliness. Afterwards we performed experiments with the gut bacteria, Escherichia coli, and found a Tortoise-Hare Pattern when we experimentally manipulated migration rates in a laboratory-based evolution experiment. We divided multiple populations of E. coli each into a grid of 96 subpopulations and had migrations occur between neighboring subpopulations (slow migration) or between any other subpopulation regardless of distance (easy migration). Finding evidence of landscape hilliness in a bacterial system implies that other living things are evolving on hilly fitness landscapes as well. 

Too Long Didn’t Read (TLDR):

We experimentally evolved Escherichia coli populations, divided into smaller sub-groups, to explore whether more spatially restricted migration allows populations to achieve better adaptations. We found that limiting migrations between sub-groups does in fact yield greater fitness improvements, at the cost of slowing evolution. We name this the Tortoise-Hare pattern, as it is the slow-and-steady population with low migration that ultimately wins the fitness race.

For further reading there is a MSU press release concerning the work found here (http://msutoday.msu.edu/news/2015/tortoise-approach-works-best-even-for-evolution/). And, the paper corresponding to this work is recently published in PNAS found here (http://www.pnas.org/content/early/2015/05/06/1410631112.abstract, doi: 10.1073/pnas.1410631112). Unfortunately, the paper is behind a pay wall, but you can see a draft of the manuscript on bioRxiv (http://biorxiv.org/content/early/2014/06/03/005793) or email me at nahumjos@msu.edu.

 

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BEACON Researchers at Work: Perspectives on Evolutionary Medicine and Public Health

MSU LBC Students Attend Inaugural Meeting of the International Society for Evolutionary Medicine and Public Health

Tempe, AZ, March 19-21, 2015

On Thursday March 19, 2015, six MSU Lyman Briggs College students, accompanied by Dr. Jim Smith (LBC Biology), traveled to Tempe, Arizona to attend the inaugural meeting of the International Society for Evolutionary Medicine and Public Health (EMPH). The meeting, held at the Tempe Mission Palms Hotel, brought together nearly 200 research scientists and physicians committed to the idea that evolutionary thinking can help us better understand human health and disease. 

The trip was made possible for our students by generous support from the Lyman Briggs College, the MSU Honors College, and the NSF-funded BEACON Center for the Study of Evolution in Action.

One highlight of the trip was our encounter with LBC alumna Dr. Julie Horvath (Lyman Briggs Zoology, 1996), who is currently Research Associate Professor of Biology at North Carolina Central University and Director of the Genomics & Microbiology Research Laboratory at the North Carolina Museum of Natural Sciences.

As a part of the trip, each student was asked to write a “blog post” in the form of a description of his/her journey from both an intellectual and experiential standpoint. What follows below is what each student wrote.

Our group in front of the Tempe Mission Palms Hotel. From left to right: Ryan Owen, Justin Jabara, Collin Stapleton-Reinhold, Jim Smith, Julie Horvath, Andrew Benner, Lauren Mamaril, and James Conwell.

Our group in front of the Tempe Mission Palms Hotel. From left to right: Ryan Owen, Justin Jabara, Collin Stapleton-Reinhold, Jim Smith, Julie Horvath, Andrew Benner, Lauren Mamaril, and James Conwell.

Andrew Benner

The presentation that moved me the most was by Dr. Erida Gjini’s, entitled “Integrating antimicrobial therapy with host immunity to fight resistant infections: classical vs. adaptive treatment.” Dr. Gjini, a post-doctoral researcher at the Instituto Gulbenkian de Ciencia in Portugal, combined clinical, experimental, genetic, and epidemiological strategies to formulate a mathematical model to analyze and calculate optimum levels of antibiotic treatment. The adaptive treatment model analyzes an array of variables, including symptom threshold, proper dosage, timing, and duration of treatment. The incredible finding was that synergistic clearance by drug and host immunity optimizes treatment outcomes. That means that rather than using a massive amount of antibiotics, a more moderate treatment allows the human body to intertwine its immunological functions with the antibiotic, working together to produce a more successful, unified treatment. Dr. Gjini’s research and mathematical model were eye opening for me with respect to analyzing and predicting the optimal level of antibiotic dosage, treatment timing, and host immune response.

The social aspect of our attendance at the meetings was equally rewarding. Although demanding and extremely dense in scientific jargon, the bits and pieces of understanding proved to be an irreplaceable exposure to evolutionary medicine and professional research in general. An aspect of the trip that I did not anticipate was my interaction with my classmates, as well as the professionals at the conference. I was able to gain insight on the lives of my classmates and the researchers that were present, aside from just an academic understanding. Although we still had conversations about the lectures we were attending and relative coursework/research interests, it was an experience in itself getting to know my peers outside of the confines of the classroom.

James Conwell

While there were a number of fascinating presentations at the Evolutionary Medicine Conference, one really stood out for me. Mr. Casey Roulette, a Ph. D. candidate at Washington State University, gave a presentation on the effect of plant drug use in humans, and its relationship with human parasites. In his research, he was able to follow a group of people in the Central African Republic to test the relationship between the number of gut parasites that they had and their drug use. His research indicated that those that were using tobacco or marijuana had lower amounts of gut parasites compared to those in the population who did not use those drugs. I later spoke with Mr. Roulette about his research, and we discussed drug use in our culture, and the possibility of drug users having allergies, as there may be a link between IgE and drug use. It was a fascinating concept for me to think about, and I am now writing my senior research paper on the relationship between allergies and drug use. 

While the conference itself was fantastic, one of the neater points was having the opportunity to connect with my classmates who attended, as well as meet other professionals in the field, and get to know them personally. The directors of the conference did an excellent job of getting everyone out in the beautiful Arizona sunshine, and encouraging others to meet, and to learn a bit about them. One great opportunity to meet others was how all of the meals at the conference were outside, in a break from the professional setting, and the options for eating were endless. Beyond this, a man named Baba Brinkman rapped about Evolutionary Medicine, and it was a fun way to think about the content of the conference. Everybody laughed, and had a great time at his show.

Justin Jabara

During the Evolutionary Medicine conference there were many interesting presentations but one was of particular interest to me. Dr. Charles Nunn from Duke University gave a presentation on the evolution of sleep that focused on how humans compare to other great apes. One of the conclusions of the study was that of the great apes (humans included) we sleep the least out of any ape. In contrast to this reduced sleep time, we spend more time in REM sleep than any other great ape. This is important because sleep plays such a critical role in health and happiness. For example, when a patient suffering from depression begins pharmaceutical antidepressant therapy, REM sleep greatly decreases. This is because antidepressants target monoamines, which mediate sleep cycles. Applying findings of evolutionary medicine to medical problems such as this one can lead to novel ways of thinking about diseases and could lead to progress in their medical treatments.

We had a blast in Arizona. After the conference was over we found the hotel pool and soaked in the sun. It was awesome having 90°F weather in March. We also made friends with people at the conference. One person we met was Will from Newcastle University, who was in his final year of medical school. We ended up spending quite a bit of time with him and became friends. We even travelled via Uber to an awesome desert botanical garden a few miles north of Tempe. Overall, the trip to Arizona was a smashing experience!

Lauren Mamaril

My experience at the International Society for Evolution, Medicine & Public Health meeting in Tempe, AZ was a first of its kind for me. One of the presentations I found most interesting included an evolutionary standpoint of natural birth and Caesarian section, presented by Dr. Wenda Trevathan from New Mexico State University. Dr. Trevathan examined excessive C-section rates in various countries, and suggested that relationships exist between the rise in C-section and the rise in HIV, obesity, diabetes, and maternal age. Also, with elective C-section, she brought to light that an infant does not receive the same gut microbiome from its mother compared to babies born by vaginal birth. Dr. Trevathan also examined tocophobia (the fear of vaginal delivery) and suggested that the anxiety and pain experienced during childbirth may be evolutionarily advantageous. She implied that providing emotional support through the birth experience may be healthier than elective C-section.

The Mission Palms at Tempe conference center was a beautiful facility featuring a courtyard and numerous orange trees, and only contributed even more positively to the opportunity. I had the unique opportunity to meet with many of the pioneers of this field, including Dr. Randolph Nesse, President of the International Society for Evolutionary Medicine and Public Health. Having this experience with my fellow classmates allowed me to get to know them better compared to just being in a classroom setting. It was cool to see what their interests in medicine are, what makes them click, and which particular presentations struck them the most in comparison to my own interests.

Ryan Owen

One of the more intriguing talks I attended was by Dr. Ruslan Medzhitov, Professor of Immunobiology at Yale University. He described two types of mechanisms that contribute to a healthy state: maintenance mechanisms and curing mechanisms. The former generally operate until they are not needed anymore, and this makes sense. Our lifespan has been defined by extrinsic mortality factors for our entire ancestral history, and therefore these maintenance programs have evolved accordingly. However, modern medicine has allowed humans to live far past ages that our bodies are evolved to, and these mechanisms are not adequately evolved to deal with the health consequences. We have to approach curing disease from an evolutionary perspective, understanding what is causing the disease state: is it a maintenance malfunction or a curing malfunction? Our bodies have evolved natural solutions to curing malfunctions that can be utilized by finding the right “button” and pushing it (statins, beta-blockers, etc.). If the disease does not have a defense that has naturally evolved (i.e., cancer), then we need to stop looking for curing mechanisms and start searching for ways to upregulate our maintenance mechanisms.

 The experiential highlight for me was being able to see Arizona for the first time. The trip was a great balance of academia and leisure, and it allowed for some exploration around a state I had never seen before. The learning went beyond the conference as I was able to take in a lot about the culture and the people through talking to locals, indulging in the cuisine, exploring the Desert Botanical Gardens, and hiking the incredible land formations.

Collin Stapleton-Reinhold

The one presentation that I enjoyed the most was by Dr. Stefan Ruhl from the University at Buffalo. What stood out about his presentation was that he wasn’t your normal researcher. He was a dentist and his team was looking at the different kinds of proteins found in saliva in humans, chimps and gorillas. Even though they found many proteins that were linked in the same way throughout all three species, the interesting thing was they found multiple proteins that were different enough to be looked into further. They also found that human saliva is a lot more watery than chimp or gorilla saliva, which they reasoned might cause those species to be able to eat a more cellulose dense diet. In all, they found many different proteins that were different among all three species, which could indicate that saliva is a hot bed for evolution and that we should do more research in the field to see if those changes can be linked to any other evolutionary changes that we many have with our closest non-human relatives.         

I loved how the directors of the conference had all of our meals outside and the spread was out of this world. You could fill up a plate and still not have gotten everything that they offered. If that wasn’t enough, after everything was over on Friday night, Baba Brinkman rapped about evolutionary medicine. It was spot on. To make things even more enjoyable, he had dancers come up for one of his songs and dance in front of everyone there for his show. After multiple shoves and nagging from my fellow Briggsies, I became one of the dancers and it is a memory I will never forget. 

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BEACON Researchers at Work: Peering into the Cooperative Brain

This week’s BEACON Researchers at Work blog post is by University of Texas at Austin graduate student Chelsea Weitekamp.

With my 2 month old son, the inspiration behind my sleep-deprived musings.

With my 2 month old son, the inspiration behind my sleep-deprived musings.

An unlucky vampire bat returning to roost at night with an empty belly can solicit help from a roost-mate to avoid starvation. A young Florida scrub-jay will forgo years of breeding opportunities to help rear their siblings and defend their parents’ territory. A subordinate lance-tailed manakin will perform an outrageous dance to help his dominant partner secure a female and will get nothing immediately obvious in return.

Decades of work have provided us with a solid understanding of how such cooperative behaviors evolved, but this doesn’t necessarily answer the question of what is going on in their in minds, in their brains. It can help, though. For example, in vampire bats, cooperative food sharing through regurgitation is more likely if the hungry bat had previously shared a meal of her own, and if there has been more allogrooming between the two. This implies the involvement of memory and individual recognition.

The arrow shows an ‘active’ dopamine neuron, a method I use in A. burtoni to investigate the role of the reward system in cooperative behavior.

The arrow shows an ‘active’ dopamine neuron, a method I use in A. burtoni to investigate the role of the reward system in cooperative behavior.

I am interested in what underlies decision-making in these examples of cooperative behavior. Going back to the bats, we can visit the extremes of anthropomorphism, and think, “how sweet, that vampire bat is compassionate, helping out her dearest friend,” or we can call on Descartes, and regard these behaviors as a means by which the machine-bat continues to survive, a reflex, perhaps, but certainly nothing conscious. Fortunately, modern techniques can help to shed some light on the issue. We can start by asking which brain regions are active during the cooperative behavior. So, if regions known to be involved in emotional processing are activated, do we have evidence of “higher cognitive processing”? It’s a step. What if we determine the reward system to be a crucial component in determining whether or not the female bat shares her meal? What if oxytocin, the so-called “love hormone” is released when she shares? Or not? Where does this get us? Closer.

The types of cooperative behavior in which I am interested involve evidence of a cognitive component. While cooperation can often be achieved through simple rules, there are many cases in which behaving cooperatively requires learning, memory, and individual recognition, as in the bats. An interesting question arises – is cooperation really a special phenomenon? Cooperation exists, of course, but it can be defined within very narrow or very wide terms, depending who you ask. So, does a circuit of sorts exist in the brain, common across different types of cooperative behavior and common across species? Is it realistic to expect a similar neural basis for behaviors that are so difficult just to define?

To address these questions, I study fish. Since diving into the world of fishes, I have been amazed by the behavioral complexity of which fish are capable. And they happen to be particularly great models for studying cooperation. For example, groupers sometimes hunt collaboratively with moray eels, using referential gestures to oust hidden prey. Pretty impressive for species considered by some to not even be wildlife.

Cleaning wrasse and their clients, though, may take the cake for impressive behaviors. Cleaner wrasse set up shop along the coral reef and ‘clients’ pay them visits to have ectoparasites and dead tissue removed. Cleaners actually prefer client mucus which is costly to cleaners, and hence, by suppressing their preference, cooperation arises out of conflict. Cleaners still try to get away with stealing mucus when they can. Redouan Bshary and others have showed that cleaners will cooperate more when being observed by by-stander clients. They also tend to be more cooperative with predatory clients, a good choice. We recently started a collaboration with Dr. Bshary to try to get at the neural basis of some of these nuanced behaviors.

A. burtoni males engaging in a border dispute.

A. burtoni males engaging in a border dispute.

Cichlids offer some competition, as far as impressive behaviors go. Of course there isn’t enough room here to discuss all the ways in which cichlids are smarter than some humans, but I’ll start. The Hofmann lab studies an African cichlid, Astatotilapia burtoni. Males of this species are highly perceptive of their social environment, and also respond differently depending who is watching. Neighboring territorial males will also cooperate by forming defense coalitions against invading wanna-be males trying to steal their space. I use these paradigms to try to get at what is going on in the brain when the males are processing these different stimuli and making decisions. I look at what brain regions are involved, and at what gene pathways within those brain regions may be regulating behavior.

Of course, we’ll never really know what these fish are thinking. Thomas Nagel offers some insight on the matter, in considering what it is like to be a bat (yes, more bats): “Our own experience provides the basic material for our imagination, whose range is therefore limited. It will not help to try to imagine that one has webbing on one’s arms, which enables one to fly around at dusk and dawn catching insects in one’s mouth; that one has very poor vision, and perceives the surrounding world by a system of reflected high-frequency sound signals; and that one spends the day hanging upside down by one’s feet in an attic. In so far as I can imagine this (which is not very far), it tells me only what it would be like for me to behave as a bat behaves. But that is not the question. I want to know what it is like for a bat to be a bat.”

 For more information about Chelsea’s work, you can contact her at chelseaweitekamp at gmail dot com.

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