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Interviewer: What makes a genius? Today, we'll talk with the University of Utah Health evolutionary geneticist, Dr. Nels Elde, a 2020 Genius Grant winner. Dr. Elde, congratulations.

Dr. Elde: Thanks, Julie.

Interviewer: How do you feel?

Dr. Elde: I feel pretty good. I have been trying to convince my wife for many years that I am indeed a genius, although the MacArthur Foundation likes to point out that it's a creativity award. So maybe that's a more fair definition.

Interviewer: Well, I'm glad you said that because that is my very first question. The MacArthur Fellowship, or Genius Grant, is known for pinpointing individuals who are not only dedicated to their pursuits but who are also creative and incredibly original, comes up with their own line of thinking, and goes after it. I'm wondering how do those qualities manifest themselves in your work and in yourself?

Dr. Elde: That's a great question. So I have to say I'm just absolutely thrilled for . . . surprised and thrilled for receiving this award. As you know, Julie, in my lab we study the evolution of interactions between infectious microbes and their hosts, and those microbes are mostly viruses.

I'd say the year 2020, for more worse than better in a lot of ways, has been the year of the virus as we're all grappling with the current pandemic. And so to be recognized for a lot of our work on the evolution of viruses and also the evolution of our immune system, how do our immune systems recognize and fight viruses, and putting that into the sort of longer evolutionary context, it's really an incredible honor to be recognized for our work there.

Interviewer: You describe yourself as an evolutionary geneticist. You touched on that a little bit, but how would you explain that term?

Dr. Elde: Well, I grew up actually as a cell biologist. I was really curious about . . . if you just look at our cells or cells of other critters, how they're put together, but more than that, what are the shared features between them in unrelated species, cells from unrelated species?

And this got this idea sort of stuck in my head or this interest that I couldn't sort of put down, which is what does that really mean from a genetic standpoint? The DNA that encodes the genes and the proteins that are doing the work in the cells or even the architecture of the cells, how are all those things related over evolutionary time? And so that's kind of what moved me into this area of evolutionary genetics, and in particular, got really excited about the interactions or collisions between infectious microbes, so things like viruses, bacteria, fungal pathogens, and our immune system or our cells in general. And so that's where we've been doing this work now at Utah for coming up on 10 years.

Interviewer: So you're talking about collisions between viruses and humans or animals. What do you mean by that and what happens when those collisions happen?

Dr. Elde: Yeah, I think this is an idea that's pretty much front and center these days. So we've had a lot of unfortunate collisions with viruses. With the current coronavirus pandemic, SARS-2, if we use that as an example, I think it can illustrate sort of what's going on here.

So we're still obviously sort of trying to frantically learn what's going on, but there is this idea that a virus very closely related, or identical basically, to the pandemic strain was circulating perhaps in bats or another animal, what we would call a reservoir where the virus is replicating but not having maybe a visible or certainly not medical impact. Then somehow there is a physical collision between us and these animals that might be harboring these viruses.

This is, by the way, happening constantly all around us and to us. And most of the time, nothing happens actually. It's sort of a dead-end event. The collision, the virus ricochets off of the host, which could be us or another animal.

But then in these really rare cases, these spillover events, something really consequential could happen. The collision, just like a car accident, might really change your life. And that's what happening to us all now, as we know sometime back last fall or about a year ago, maybe early winter, this virus emerged. So it spilled over somehow from a still somewhat mysterious animal reservoir and it began to replicate in humans and, worse than that, transmit between humans. Now, one collision, one car accident, becomes millions of collisions. And we're still working with the impact of that today.

Interviewer: And so what's the value of learning that information?

Dr. Elde: We've seen that viruses are pretty impactful, and so it's really important, I think, for many reasons. We're actually both practical, so if we can understand how do these viruses change and defeat, for example, our immune defenses, then we might have a better chance of actually countering them.

And so if we can understand what it is that makes these viruses tic, how they replicate better or worse, whether it's in just a few short days or a number of years, then we're starting to learn their secrets, their tricks, for how they become successful and, in many cases, which makes us sick or unsuccessful, and then can we kind of bend the curve? Can we start to intervene?

At the same time, we are interested in maybe a slightly different question as well, a bigger question, which is how does evolution work? So viruses because they replicate so quickly and mutate so fast, it's almost like a little laboratory of evolution that you can see before your eyes.

So half our lab involves setting up evolution in action. This is experimental evolution. We're taking viruses that are weakened strains, so they're not dangerous, and we allow them to continuously replicate just to see if they get better. Can they return to their old state? Not turn into superbugs, but can they just improve a little bit?

And actually, over the course of a few months, watching that process, we're learning about how evolution works. It turns that not only how viruses replicate allows them to be successful, but a lot of the same mechanisms are at play over a longer time course in our own genomes, our own DNA, as we look at all of the diversity in our own species.

And so the viruses are sort of giving these gifts back. We have all these terrible health consequences that we're grappling with around the world today, and yet there is also this sort of positive side where they are actually sort of teaching us both about evolutionary process and even how our cells work in some cases.

Interviewer: So you witness these relentless attacks from viruses and how they can just change on a whim to overcome our defenses. In a way, that's pretty scary. I mean, what gives you hope at the end of the day?

Dr. Elde: It is true. I think we've been focusing on a lot of the negative consequences of viruses these days. The good news is that we have these incredibly complex and amazing immune systems that counter these viruses. And so that's the other half of the work that we're doing in the lab, is to try to understand the evolution of the host. And the host could be us. It could be our close relatives among the primates.

Here, we don't have that luxury of evolution happening as quickly. Our generation times are more like 20 years than 20 minutes. And so what we do is take a very different approach, and that is to compare all of the diversity of modern species, and in particular the slight differences in our immune defenses, and then try to work backwards. What did our ancestors look like, and how has this changed? Maybe not over the course of 3 months but over the course of 30,000 or 300,000 years.

And in doing that, what we're beginning to discover is all of this incredible diversity, these genetic patterns that sort of give some of the clues to how it is that we exist at all.

Our immune systems have been up to the task, and in many cases, in increasing cases, we've actually used our knowledge that we've gained about these interactions to start to bend the curve, whether these are new vaccines that we've seen that have worked in some of the viruses that we've been studying or ones we're dealing with now. There is really great reasons for optimism that now, in addition to all this diversity, we're using our brains as scientists to start to bend the curve and to learn how to have better outcomes.

Interviewer: Yeah, that's really amazing. And just the idea that you can watch evolution in the lab, that you can kind of manipulate that and see how it unfolds, that just sounds amazing.

I love listening to you talk about this and you use words like "fun" and you can hear the excitement in your voice and just the way that you describe things is very imaginative.

I know that training trainees, post-docs and graduate students, is something that's very important to you. Are there ways that you can instill kind of this same creativity that you're known for in them?

Dr. Elde: Yeah, that's certainly the hope. And this has been a challenging few months as we've been dealing with the pandemic, so a lot of our work, of course, is over Zoom meetings or working alone. But it's exactly what you're saying, Julie. That doesn't represent sort of the main energy of the lab, which is working together and kind of teaming up.

And so the scientific process really is to me and I think to the trainees . . . it can obviously be hard and there's a lot of complicated work to understand and put together, a lot of failures along the way, but it really, at the center of it, is fun. These are adventures we're kind of setting out to explore and we don't know what we're going to find.

And so I think just by kind of framing the questions or kind of creating the space to explore and to not be sort of stuck that you need one answer or another or trying to fit one idea into something . . . we try to let the viruses or the microbes tell us what they've learned about our biology, about our evolution. And in some ways, that takes a little of the pressure off. We can sort of allow the experiments to tell us and to kind of follow our noses. I think that naturally makes things a lot more fun.

And then to get to your question, the trainees that have joined on these projects are all bringing their creative energy to the table. And that's not just sort of an added effect. It feels like a multiplying effect where as we're colliding as scientists and bringing our own curiosity, bringing our own creativity, really fun things can happen.

Interviewer: Well, thank you very much for talking today, and congratulations again on the award.

Dr. Elde: Thanks, Julie. Great to talk to you today, and looking forward to the science adventures ahead here at Utah.

Interviewer: Eight percent of human DNA originally came from viruses. A new study published in "Science" reveals how our body is putting these viral remnant to work.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The Science and Research Show is on The Scope.

Interviewer: I'm talking with the University of Utah Geneticists Dr. Cedric Feschotte and Ed Chuong, who've published a study in "Science" together with collaborator Nels Elde. Scientists for a while have known that some of our DNA comes from viruses. So I don't about you, but I actually find it kind of uneasy to think that I'm not just me, I'm part virus.

Dr. Feschotte: Eight percent of our genome is viruses, but then another 40% on top of that is actually other kinds of selfish genetic elements as well. So one might even say you're less human than you think. Definitely, a huge portion of the genome is represented by these kinds of selfish elements that most scientists often dust under the rug, so to speak.

Interviewer: What you've shown is that our body actually uses some of that foreign DNA for a very specific purpose. What did you find?

Ed: Yes, what we found is that some of these pieces of viral DNA being recycled to serve now some set of functions. Important for the defense of cells against pathogens including viruses.

Interviewer: How did the viral DNA get there in the first place?

Ed: There are remnants of past viral infections that have actually plagued our primate ancestors many, many millions of years ago. And they are descendants and they are been assimilated in the genome of the host and now what we are seeing still is that still some of these elements retain some of the properties, ancestral properties, regulatory properties of these viruses.

Interviewer: So tell me again what you think they're doing. How they're interacting with the rest of the defense system?

Dr. Feschotte: Your body has many ways to sense infection by virus or other kinds of microbes. And one of the first things that happen is that when you sense infections, cells will release, the signal, the warning signal called interferon. In the genomes of our cells there are hundreds of genes that are dedicated to fighting infection, fighting micros, fighting virus but they're normally turned off. Then what happens is when you have responses like the interferon response turned on, these cells sort of awaken from dormancy and then turn on and do their business and eventually sort of turn off. And what we found, basically, was that in addition to a lot of human DNA that gets activated by the signal, a lot of viral pieces are activated as well as thousands of viruses seem to be activated by the interferon response.

Interviewer: So these elements, these viral pieces are basically like triggers that help set off the immune weapons that they're sitting next to?

Dr. Feschotte: When we think about the switches, their original evolved function, so to speak, was to drive transcription of that virus. So I think, initially, 50 million years ago, that was the purpose. But clearly over time, some of these elements have been collocated or domesticated, you know there's different words for it by their host, in this case primates to act then exactly as you say, to act as switches that now instead of turning on viral genes, now they turn on genes that are pivotal for our own immune defenses.

Interviewer: Kind of the cool thing is that you're thinking of this as sort of a coordinated system.

Dr. Feschotte: You can imagine, no one protein is going to be enough against the pathogen. Our strategy is essentially the throw in hundreds of genes that together collectively make a very strong and robust defense system. And I mentioned earlier that the regulation of genes in response to interferon is governed by little molecular switches called regulatory elements. And our question was really, know how do these regulatory elements get there. How do they evolve in the first place? And one idea is that these regulatory elements can sort of evolve through mutation, the code necessary to turn on these genes or response interferon. But what we found was this potential mechanism where these endogenous retroviruses are actually providing these switches.

And what makes that mechanism so attractive is that these endogenous retroviruses have this built in ability to copy and paste themselves throughout the genome. And so if we are trying to think about how do you evolve a coordinative response? Well, it's a lot easier to take a pre bill switch provided by these viruses that are so common in the genome rather than to a sort of "rely" on random mutations to build these switches.

Ed: One reason why we think this mechanism of spreading these elements might be a good way to wire these networks and distribute these switches is that, indeed, the switches already existed. And again, they were serving probably viruses to begin with, but you didn't have to reinvent them.

Interviewer: Do you have evidence that this isn't a one-off thing? That this is happening kind of over and over throughout evolution and in different species too, right?

Ed: Yes, well, this was really another surprise that came kind of late into the study. And what we realized is that some of the elements that were similar are not identical. But very similar to the ones we would see in the human genome and in other primate genomes were actually also present in [inaudible] genome. Now a different location in the genome, but they had the same regulatory properties, it seems. That it contained some of these switches to respond to this infection, essentially. We see them present in multiple species and, indeed, we speculate that maybe the same mechanism has also spread some of these switches in other species to wire their own lineage-specific network of these immunity genes.

Interviewer: Do you think these viral DNA pieces might be impacting our health in other ways?

Ed: Yeah, so we think this is something really interesting that we need to follow up on. Because some of the genes that we found to regulated by this viral DNA have been implicated in cancer, autoimmune disease, they are themselves mis-regulating this disease. And we also know that some of this retroviral DNA is often activated in the same conditions. So now we've sort of connected the dots and are thinking that this provided mechanism can explain some of this mis-regulations of these genes in cancer and in autoimmune disease, but have been co-opted for a new regulatory function.

Announcer: Interesting, informative and all in the name of better health. This is The Scope Health Sciences Radio.

Interviewer: There's a war going on around us and most of us don't even know it. Dr. Nels Dr. Elde, assistant professor of human genetics is investigating the evolutionary arms race between viruses and ourselves. Dr. Dr. Elde you describe a so-called arms race between pathogens and humans, what do you mean by that?

Dr. Elde: One of the ways we think about this arms race is actually to do with a literary reference, and this is what's known as the red queen hypothesis. So this comes from Lewis Carroll's book, Through the Looking Glass, and the character the red queen who's talking to Alice. And she says, "It takes all the running you can do to just stay in the same place." We've kind of co-opted that idea for host-pathogen evolution. So the idea of an arms race at the molecular level is that we go in these back and forth counter adaptations where viruses and other bugs are having a negative impact on our health or fitness which leads to whether or not we're able to reproduce, and who is able to reproduce? On the other hand, when our populations are able to defeat a bug, this is another leg of the arms race. You can imagine this as just playing out again and again as evolution unfolds.

Interviewer: Every year we need a new vaccine for the different strains of flu that are circulating among us, is that an example of this race?

Dr. Elde: Yeah Interviewer, that is a great example of the arms race. Every year we come up with a vaccine, that is hopefully beneficial for knocking out influenza. Then what happens is that its only useful for so long because in this arms race scenario the influenza virus return with genetic variation that can defeat that vaccine.

Interviewer: Yeah, so how do they do it? What is there secret?

Dr. Elde: So these vaccines are designed to recognize certain shapes, basically, on the surface of the virus. If we're able to effectively recognize those shapes it'll alert our immune system to come in and destroy the viruses. So what the viruses do is then through mutations and selection of their genes, change their shapes and then they become virtually invisible to our vaccines.

Interviewer: So how do you study these host-pathogen interactions in the lab?

Dr. Elde: In particular, one of the viruses we study is called vaccinio virus. It's the model pox virus. The pox viruses are most famous medically for small pox. One of the ways it was eradicated was through vaccination using a highly related but much more safe virus called vaccinia. And so what we do is take this relatively safe virus into the laboratory, present it with puzzles or challenges. For example, we give it cells if its not good at replicating. And then given all the advances in genome sequences technology, what we can do is sequence the genomes of the viruses before and after we present them with these immunity puzzles. And then ask what's different about the virus at the end...

Interviewer: Oh cool.

Dr. Elde: ...of the experiment.

Interviewer: Yeah.

Dr. Elde: Yeah, its pretty fun experiments. Of course, you have to be careful, we are dealing with viruses.

Interviewer: Yeah.

Dr. Elde: And so, one of the very cool findings from one of our initial studies of the vaccinio virus that really surprised us. Was that virus was adapting not only by, so called point mutation, where you exchange only one letter of DNA, so to speak, but these viruses were becoming, the genomes were becoming larger right in front of us. So even over the course of a few infections, the virus, the genome was increasingly in size up to 10-20%. It's really striking.

Interviewer: What does it mean for a genome to expand.

Dr. Elde: What I mean by this is if we just look at the size of a genome, for example, and for these pox viruses like vaccinia and smallpox there are about 200 kilo bases. This is 200,000 DNA letters in a row. What we found was that they're getting more letters. They were going from 200,000 letters to up to 220,000 letters. It wasn't just that you were adding, a gobbledygook of 20,000 letters, you were adding the same repetitive letters of about 300 in a row of a certain gene.
And it turns out this gene is actually an important inhibitor of one of our immune response genes. What we saw was that for this specific gene, it went from one copy, to as many as 20 copies, very quickly. Having 20 copies meant that the virus was much more able to defeat our immune response versus if it only had one copy. What was really- a second surprise was that once this virus had 20 copies of this gene, it was actually 20 times more likely to come up with a new single letter change or a point mutation, that in of itself could defeat the immune system.

Interviewer: So not only is it defending itself better but it is also driving it's own evolution.

Dr. Elde: Exactly.

Interviewer: That's so cool.

Dr. Elde: It's a two for one. It's cool but its also kind of scary. Right?

Interviewer: Yeah, right.

Dr. Elde: These things can really, and this is again sort of this idea of an arms race.

Interviewer: Yeah.

Dr. Elde: And its sort of any mechanism that can aid the virus in its replication will very quickly be selected for. The imagery we've been using to name this hypothesis is called the accordion model of virus evolution. The idea is that the virus expands as an accordion might, as a musician is playing part of a note, and then in this expanded form, you sample all of these extra copies for changes. If you hit on one that works then the accordion can contract the second part, it's like a musician playing the experiment, right?

Interviewer: Yes

Dr. Elde: But here the virus is playing evolutionary process and changing in ways that benefit its replication.

Interviewer: So, how can we use information like that to help combat these viruses?

Dr. Elde: We always want to look at what we see what we observe in the laboratory and ask, does this apply in the wild? There's this really interesting story with a pox virus that infects rabbits. It was purpose, the virus was called myxoma, it was purposefully released in Australia back in the 1950s as a biological control agent. The idea was that some of the settlers in Australia had brought rabbits from Europe. The rabbits had gone crazy and now billions of rabbits and you have a problem. One of the proposed solutions was to release a virus that could kill the rabbits. So this was myxoma virus.
So, there's this really interesting historical record where people save the virus years after it was released in the rabbits. What we believe, what we done is look at the genomic changes and we see hints of these gene duplication, or almost accordion-like dynamics. We think this could happen in the wild as viruses are exploring new hosts. What we're trying to do with this is trying to understand at a basic level, how these viruses operate, how they adapt, how they evolve. If we're in position to have that information before that happens, we might be in a much better spot to stop them before they get out of control as new epidemics or pandemics.

Announcer: Interesting, informative, and all in the name of better health. This is the Scope Health Sciences Radio.