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Thursday, October 12, 2017

What Ants Mice Monkeys can teach us about the impact of stress 10-13

Stress is a common feeling, and it seems we’re dealing with more of it in our lives than ever before. Work, finances, relationships — all have the ability to create chronic stress that can lead to anxiety, depression and other issues. Two Penn Integrates Knowledge (PIK) professors — Michael Platt, a Wharton marketing professor and professor of neuroscience and psychology at Penn, and Shelley Berger, a Penn professor of cell and development biology and director of The Epigenetics Institute, have teamed up in an interdisciplinary approach to learn more about how stress affects individuals.

Platt and Berger recently spoke about their research and its implications on the Knowledge@Wharton show on SiriusXM channel 111. 

Following is an edited transcript of the conversation. 

Knowledge@Wharton: Tell us the background behind this research.

Shelley Berger: It’s something we’ve been interested in for some time. The research I’ve been doing is focused on epigenetics, which has led into this interest in the environment and how it affects behavior. But in recent years, we’ve become very interested in the brain from work we started on the ant system. We actually have an ant lab at the Perelman School of Medicine. We’ve been interested in ants and studying their behavior. They’ve been a great model for behavior. Recently, we became interested in mouse behavior and studying the brain and epigenetics in the brain. Through conversations with Michael, that led to how this whole thing began on crossing species and studying mouse, primate and even human.

Knowledge@Wharton: Give us a better understanding of epigenetics.

Berger: Epigenetics is the study of how the environment affects the way genes are expressed. We commonly think about mutations affecting genes and gene expression. But epigenetics is the study of how the environment can affect the way genes are turned on and off without mutation. Specifically, it’s the effect of how chemicals coming in from the environment through our bodies can sort of decorate the proteins that associate with the DNA and change the way genes are turned on and off. That’s of great interest because many things are coming in from the environment, including stress. We’re talking about psychological effects and stress, and that can lead to changes in the brain. Post-traumatic stress disorder is a great example.
“Burnout is the number-one topic that I hear about from our MBA students, and they want to do how to deal with that…. Stress is everywhere.” –Michael Platt
Knowledge@Wharton: Michael, tell us about your interest in this research?

Michael Platt: We have been interested in behavior for a long time. We got interested in how genes affect the development of the structure and function of the brain and nervous system to ultimately produce behavior. Of course, that equation leaves out the central role of epigenetics that Shelley just described, which is that the same genes in the same body in a different environment can lead to very different outcomes. If you imagine yourself living with lots of family support, for example, you might respond better to the stresses of the environment — to a stock market crash, to problems in the economy, etc. But if you are living alone without any social support, then that stressful event or the long-term stress can be much more impactful on your body and your brain.

Shelley and I met two years ago, when I had just arrived here from Duke University…. As we were talking, we began to realize that we were interested in very similar things, although our expertise is very complementary. We had been working on the neurophysiology of behavior, the neurophysiology of social behavior and how genetics might influence that. But we had really no expertise in epigenetics at all.

Knowledge@Wharton: How will this research lead to a better understanding of the human brain and how it reacts to stress from environmental factors?

Berger: We’ve been studying mouse behavior for the past five years, and you can model stress in mice. There’s a method called “fear conditioning” by which you subject the mouse to stress, and then you can study what happens to the brain. How are learning and memory affected by the stress of fear conditioning?

We had been working with post-mortem human brains from people who had suffered neuro-degeneration from Alzheimer’s Disease, so we’d been developing a lot of methodology to study parts of the brain. Humans are difficult because, of course, they’re not experimental animals. We have to work out all the methods to carry out high-resolution studies of these chemical marks in the brain from human post-mortem samples. Then, starting to get interested in some results we had in mouse, we thought that the crossover between fear conditioning in mouse and PTSD in human could be really interesting. We got in touch with a guy who has a bio-bank of humans who had suffered from PTSD. We can take these methods that we’ve developed in mouse, then fine-tuned in human post-mortem brains through our work on Alzheimer’s, and now we can look at PTSD in humans. Michael filled in the middle part with primate research, which is a great link between the two.

Platt: Right. As useful as a mouse is for understanding a lot of the basic processes that we think are involved in the response of the human brain to stress, sometimes that translation is not perfect. That reflects the fact that mice and humans last shared a common ancestor much longer ago than humans and monkeys. For that reason, the human brain and the monkey brain are much more similar than the human brain and the mouse brain. There are certain aspects of behavior, in terms of behavioral complexity and social complexity, that are shared between humans and monkeys, that are less well-paralleled in the mouse.

The monkey gives us the capability to look at some of these other issues like social support and how that might help with the problems that one encounters with social competition. This is very different from what mice experience. People and monkeys live in groups for a good reason. It allows you to do things that you can’t do alone, like evade predators or chase away other groups and get resources. On the other hand, when you’re living in a group, you have to compete with everybody else. That’s a source of stress that I think we all can easily identify with.

This is a beautiful partnership because it has the potential to lead to understandings that can lead to new treasuries. Also, putting my Wharton hat on, this kind of project can potentially illuminate ways in which we might be able to mitigate stress, say, within the workplace. That’s a huge problem these days. Burnout is the number-one topic that I hear about from our MBA students, and they want to do how to deal with that. You hear the same thing from residents who are training in medicine. Stress is everywhere.

Berger: The beautiful thing about the primates, with respect to humans, is that humans are not an experimental animal — we don’t know exactly what their social situation is in its entirety. But scientists watch [primates] all the time. Michael has scientists working with him, watching these animals in their natural habitat, so they know exactly what sort of place they have in the social spectrum. We can’t know all that about humans. As much as we get metadata about humans — that we can get information about their background — they’re not experimental animals. We can’t control and know.
“We’re not talking about the kinds of stresses our kids go through over smartphones. We’re talking about the kinds of things that really impede your ability to function.” –Shelley Berger
Knowledge@Wharton: That space between mouse and monkey feels like it’s very important because there’s more of a more recent link between monkey and human than human and mouse.

Platt: I think that’s why these studies need to be done. There are very few places where you can really do them and where people will collaborate to try to discover those links and make the connections. I think what Shelley can do in her lab, with really exquisite techniques and technologies that allow you to hone in on the mechanism, we can closely approximate in primates. But it’s not the same kind of thing that we can do.

On the other hand, what we can provide is a much richer understanding of the social environment and all of the other factors that might affect an individual in how they respond to stress and how that ultimately leads to changes in behavior. The particular population of monkeys that we study evolves. This is a population in which individuals are free to fight and to flee and to breed. Some monkeys do better than others. That means that whatever traits those individuals have — traits that allow them to offer stress, to make alliances and connections — can be passed on to the next generation. We can see these kinds of changes in the population over time. That’s almost impossible to see in people.

Knowledge@Wharton: If you find enough links, you’re talking about being able to deal with a lot of prevalent medical issues — burnout, depression, suicide, PTSD.

Platt: It’s really compelling to see the data. There has been a lot of attention paid to a new report that analyzed the incredible increase in depression and anxiety, especially in teenagers, after the introduction of smartphones in the 2000s. There does seem to be, potentially, some link to the kinds of technological environments in which we find ourselves. I think one implication is that it leads to social disconnection, which I think reinforces what we’ve learned both in people and in monkeys that having social support is really critical. If you don’t have it, then things really fall apart.

Knowledge@Wharton: The social support is not as much of a factor when you’re talking about mice. But perhaps it is for ants because of how they live in colonies, correct?

Berger: That’s an astute observation. Ants are a great model for complex social interactions, and there are very few models like that. That’s why the medical school supports us to have an ant lab. They see the great translational aspects of studying ants and their social interactions.

Knowledge@Wharton: How do you think that information could play out when you’re talking about dealing with stress?

Berger: I’ll go back to our mouse research, which we’re translating both ways to the ants and would love to translate it to the monkeys and definitely to humans. We discovered that the machinery to make one of the chemicals that’s placed on the genes to regulate them is associated with the genes. It’s an enzyme that makes this chemical, and that enzyme can be inhibited. We think if we inhibit that enzyme, we can alter learning and memory in mouse. This is the kind of experiment you can do in mouse. We can’t do it in primates because they’re too complicated.

One of the things we’ve been talking about is whether an inhibitor like that could be relevant to humans. We’re not talking about the kinds of stresses our kids go through over smartphones. We’re talking about the kinds of things that really impede your ability to function.

Knowledge@Wharton: Going back to the business aspect, if these discoveries lead to treatments down the road, that could chip away at some pieces of the health care problem in this county.
Platt: Sure, and hopefully down the road is not so far down the road. The enzyme that Shelley’s talked about, it’s quite clear that one could imagine developing a drug to target that specific mechanism. If you had a combat veteran who was exposed to a blast or something else incredibly stressful, you could potentially deliver that drug at the right place and the right time and block the formation of bad memories. That would be an incredible opportunity.
“If you had a combat veteran who was exposed to a blast or something else incredibly stressful, you could potentially deliver [a] drug at the right place and the right time and block the formation of bad memories.” –Michael Platt
The other extension of this are ways of trying to mitigate stress before it leads to something. We’re talking about chronic stress rather than acute stress. Are there ways that we can prevent it? There are a lot of options that people are exploring, such as improving your social connections, mindfulness and meditation, exercise. We know those things are all really good. We just don’t know how they work.

Knowledge@Wharton: Is there a difference between people who handle stress really well and those who don’t?

Platt: This is a really tricky and interesting and important question. Is it something you’re born with or something you can teach? There is fabulous work from Penn professor Angela Duckworth on grit, which is this resilience. It seems like some people have a great reservoir of grit, while it’s harder for others to demonstrate it. That leads to the question of whether you can develop it. Can you train it? Can you educate people to display that grit more often? If so, then that’s another approach to dealing with life stress.

Berger: It seems to me that the monkeys are the place to study that because Michael’s group sees which monkeys are accepted.

Platt: One thing that’s really fascinating about the monkeys that we study is that they have personalities, just like people do. The big five personality instruments that you would apply to a person, you could do the same with a monkey. We’ve done that, and their personalities are consistent over time. A monkey who’s very timid and anxious when he’s 6 months old is going to be similarly timid and anxious when he’s an adolescent. A monkey who is very bold or very aggressive, you’ll see those patterns continue. It’s not 100%. It’s not like it’s genetically determined. I think that’s where the fascinating thing is. Maybe 25% or 50% is purely genetic, and the rest is environment in how they respond to it. That’s why this is so important.

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