The National Institutes of Health has awarded a University of Arkansas professor $2 million to study how organisms respond to stressful environments. Jeff Lewis is an associate professor of biological sciences at the University of Arkansas. He says his research will focus on things like how cells respond to stress, what causes some to be more resilient and what makes others more sensitive. His organism of choice for his research.
Lewis: Brewer’s yeast. And so this grant will allow us to look at sort of unexplored aspects, things that have been sort of underdeveloped in terms of stress biology and how it’s regulated and why individuals vary.
Moore: Why stress?
Lewis: I think stress is one of those things that all of us relates to, and it’s why we think of it, as organisms with brains, as sort of psychological stress. But our cells also experience stress at all different times. So we’re responding to sort of different environments.
And it turns out that as long as life has existed, there’s been stress. There’s been fluctuations in temperature and there’s been feast and famine. When microbes and plants started oxygenating the Earth, that became a major source of stress that cells had to deal with.
So the way that cells deal with this happens to be ancient, because over billions of years, stress has existed and we have coevolved to deal with it. And so we can learn a lot about just resiliency in general in any organism by studying stress in one organism. And we can also learn sort of themes and how evolution has decided to solve a problem in different ways.
Moore: As you said, we often think of stress as an emotion. We think of it as something we mentally experience. But through your work, it seems clear that there are physical manifestations of stress. So can you talk a little bit about, maybe, is there a distinction between the stress we feel in our head or emotional stress as opposed to physical stress?
Lewis: Yeah. So I think in organisms such as ourselves that have a lot of different cells and organ systems and things that are interacting with each other, there’s definitely a brain-body connection. And there’s definitely stress hormones and things that are associated with stress that lead to inflammation. For example, if you’re stressed, you more easily get sick. There’s those types of things and it permeates into a cell on a cellular level.
And our cells are experiencing stress. They’re having to deal with an oxygenated environment as one example. But the basic truth of cellular stress existing and our cells in our body having to deal with it without our brains telling them how to deal with it still happens.
So that’s a long way to say that I think looking at simple microbes can tell us a lot about how our cells have to deal with stress as well.
Moore: Which I imagine is why you chose yeast.
Lewis: Yes. So yeast is a really easy genetic model. If you can imagine a genetic manipulation, you can do it. And that’s not something obviously that you can do with humans. And even with human cells, it can be challenging to do some of the genetic experiments. So even if you pull cells out of a body and try to manipulate them, yeast is a much easier organism to work with.
So the big part of this, though, is that even though yeast seem very different from human cells structurally and at the molecular level, there’s a lot of similarities, that we’re both eukaryotes. We both have a nucleus. We both have the same basic cellular organization.
And about half of the essential genes in yeast, you can take the human version, put them in yeast. If they wouldn’t work, the yeast cell would die, and about half of them work perfectly fine. So even though there have been millions and millions of years of evolutionary divergence, it’s still a really good model for just understanding how a basic eukaryotic cell like ours works.
Moore: Talk to me more about resilience. As you look at humans and resilience to stress, and you look at other organisms and their resilience to stress, is there some common ground? Is there some similarities in that?
Lewis: Yeah, definitely. So taking maybe a smaller step, we can look at resilience in yeast. And we have different yeast strains, wild strains with different genetic makeups. And some of these wild strains are super good at withstanding, say, heat stress. Some of them are really bad at it. Probably reflects the environment that they grew up in and evolved to withstand. So things perhaps in warmer environments have evolved to tolerate high temperatures.
But anyways, there’s variation in these. We see that in other animals. So we see variation in, say, fruit flies, which is another really good genetic model. And we have fruit flies. Some of them are much more heat tolerant.
So once you sort of go up in complexity, it becomes less ethical to do these types of experiments. But we do know that there are human populations that have, for example, evolved to do better at micro oxygen, like in Nepal, for example. So we have examples of sort of microevolution for resiliency in populations, just based on sort of their unique environments. And so in principle, these things can tell us about resiliency in that way.
We also know, though, that there are some people that are more susceptible to disease. And so we can think of disease as sort of related to stress. And the principles of understanding stress resiliency often apply to disease biology as well.
So we know that some people have a higher propensity, for example, to get Alzheimer’s disease or Parkinson’s, neurodegenerative disease. Some of those seem like they might be related to stress response pathways. And the genetics of trying to untangle that is very, very complicated in humans, with hundreds of genes involved whenever folks have looked at it. And it’s really hard to test individual effects.
But we can do these types of experiments in yeast really easily and figure out if the rules that govern stress resiliency in yeast also apply to humans. And we can at least test things in human cells, for example.
Moore: I could think of a lot of ways to stress out a human. How do you stress out a yeast cell?
Lewis: Yeah. So we try to think about this in terms of where do you find yeast in nature and what kind of stresses would this type of microbe encounter.
So a little bit of history of the life cycle of yeast. So we know it as an organism that is used to make beer or it’s used to make bread. And one of the reasons that’s really good at that is that it takes sugar from the environment and it ferments. It produces alcohol, which, when we make bread, that burns off. But what doesn’t is the CO2, so the bubbles. So we’re either carbonating our beer or we’re causing bread to rise. And that’s the reason that we’ve domesticated yeast and use it for all of these food-type things.
In nature, it’s finding sugar generally in fruit or in sap from trees. And it really loves sugar. So it’s in the environment. Fermentation can cause heat, and also just being in the environment, you’re going to be exposed to varying temperatures.
Once you ferment, you produce ethanol. And that’s actually a harmful compound. It seems that yeast is very tolerant to ethanol, unlike a lot of microbes. So it could actually be a form of sort of chemical warfare or competition as well, that less ethanol-tolerant competitors might get killed off.
And then the yeast take up that ethanol. And then instead of fermenting, they respire. And cellular respiration produces reactive oxygen. So at that point they’d be exposed to oxidative stress.
They’re exposed to potentially high-sugar stress at times when they’re inside of certain types of fruit, like grapes that have really high sugar concentrations. You can imagine, like jelly, things don’t grow well in jelly. It’s sort of a natural preservative because it has so much sugar. Well, yeast sort of are at the border of where things can survive in sort of high-sugar environments. So that’s a stress that they encounter.
And then in nature, feast and famine all the time. So they might find a grape, use all of the resources in the grape, and then they’re stuck until they find another one, until generally a fruit fly or something transports them to another grape. But they might be facing starvation or they might be dormant in the soil, forming spores for long periods of time. So they might be faced with starvation for long periods of time.
Moore: So the feast-or-famine thing is the thing that sticks out to me, is essentially two very simple ways of thinking about providing stress to yeast is to either give it way too much of something or to really withdraw it from a lot of things, too. And both of those are ways to put a yeast cell in stress.
Lewis: Oh, absolutely. So that’s one of the classic ways to do it, is you can put them in water and now they don’t have any nutrients, and that’s extreme starvation. Or you can give them really high amounts of sugar. And they’re pretty happy with the nutrient part, but they’re not necessarily happy with sort of the shock of having all of that sugar around.
Moore: The work that you get to do here through this grant, does it offer students an opportunity to take part in your research and to play a role in that too?
Lewis: Oh, absolutely. So when you get a grant, in this case, it’s about $275,000 a year. And the vast majority of that goes to salaries for graduate students. So their salaries and their tuition and their benefits, staff scientists.
And so generally, I have around four graduate students in the lab at any given time. Many of them happen to be native Arkansans. And then we always have several undergrads in the lab at any given time. So actual UofA students that are participating in the research and often doing this for their honors projects. And gives them a good opportunity to decide whether research is something that they want to continue with.
So some of them have been interested in going on to graduate school after not really knowing that that was an option. But either way, we’re really keen on integrating both graduate and undergraduate students into these funded projects.
Moore: Was that an experience that you got to have?
Lewis: Oh, absolutely. So I was a junior in college and I took a microbial genetics class. And that’s sort of how I got into this. And I love the class. I was a first-gen college student, so I didn’t really know anything about anything, but I knew that there were people working in labs.
And so after class, this was back when email wasn’t as much of a thing, so I actually went up and talked to the guy and asked, “Hey, I don’t know anything about anything. I’d like to work in the lab. Is that something I can do?” He’s like, “Oh, you’re doing really well in here. Yeah.”
And so I was just sort of thrown in. I was playing with the E. coli and doing microbiology and I had no idea what I was doing, but it was fun.
And then I was told that I think about this stuff pretty well, and have I considered graduate school? I was like, “Oh, OK.” And so I was sort of then directed at microbiology graduate programs.
So I definitely wouldn’t be where I am now without being given that opportunity as an undergrad. So that’s a huge motivating factor for sort of how I run my lab.
Moore: Well, and as a first-generation college student, I’m sure you probably see elements of yourself in those students, too, who you’re working with. Regardless of whether or not they’re a first-generation student, you’re seeing that sort of curiosity they maybe haven’t had a chance to explore yet, because it sounds like that was what you had.
Lewis: Oh, yeah. Yeah. And it definitely impacts how I mentor people. There’s lots of things that I sort of wish I knew going into it, things that I sort of learned the hard way. And so part of it is, yeah, I was like, “Oh, I didn’t know you’re supposed to do this and that,” and all sort of the little things for navigating the academy. So I definitely teach those types of things.
Jeff Lewis is an associate professor of biological sciences at the University of Arkansas. He joined me last week in the Bruce and Ann Applegate News Studio Two.
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