Transcript of Episode 40: Nicholas Heaton

Grace: [00:00:00] Welcome to The Bioinformatics CRO podcast. My name is Grace Ratley. And today I’m joined by Nicholas Heaton, who is Assistant Professor of Molecular Genetics and Microbiology at Duke University. Welcome, Nick.

Nick: [00:00:11] Thanks, Grace. Great to be talking today.

Grace: [00:00:14] Yeah. So let’s start off with talking a little bit about what you study at Duke, and that is the influenza virus and other things occasionally. Can you tell us a little bit about that?

Nick: [00:00:26] Yeah, absolutely. So our lab, you know at the highest level is kind of broadly interested in understanding how these viruses make you sick. We basically modify the virus itself so that that virus will act as a tool that we can then use to ask whatever kind of scientific questions that we’re interested in.

Grace: [00:00:45] What kinds of things in particular do you study? Are you looking more at the genetics aspects of influenza viruses or at the structure or how they infect cells?

Nick: [00:00:55] Yeah. So a lot of the things that we’ve been working on, we kind of think about them as falling into the margins or like the gray space of what happens during a viral infection. So for the most part, when a cell is infected by a virus, scientists think of like a program being initiated. And the same thing essentially happens over and over and over. And what we found and others have appreciated as well, is that it’s more complex than that. The different cell types can respond different ways, and that happens at various frequencies. So that’s what we’ve been studying. The more rare outcomes of infections and trying to understand the nuances of how the virus can interact with its host can really then go on to dictate high level phenomena like disease severity or transmission or something like this.

Grace: [00:01:44] And could you tell our audience a little bit about influenza viruses? I mean, most people have heard of flu season and things like that, but what are some basic virology things that people may not have heard about?

Nick: [00:01:56] Yeah. So these viruses, they fall into a family they are called Orthomyxoviridae. And it’s a huge family of viruses. A lot of them are insect viruses, actually. But the ones that fall into the influenza virus family are influenza A, B, C and D. And when we talk about flu, like clinically people getting the flu or mostly talking about influenza A and influenza B. In a given flu year, it’ll be about two thirds influenza A and a third influenza B. Sometimes those ratios can flip. Influenza C’s can infect children sometimes, but they have animal reservoirs. And influenza D’s are rarely, if ever, detected in people. But these viruses, they have genetic material that’s encoded in RNA.

[00:02:31] So influenza viruses are called RNA viruses. And they’re envelope, which just means they take essentially part of the cell membrane with it when they leave. And that’s how they essentially incorporate it into an actual physical particle that can be sneezed on somebody or breathed in. And these are respiratory viruses like coronaviruses or other viruses.

Grace: [00:03:01] Awesome. So where do they originate? Influenza is a zoonotic virus, if I’m not mistaken. So what’s their normal reservoir?

Nick: [00:03:10] Yeah. So the answer is that it’s complicated. The family of influenza virus especially, so influenza A’s, which, you know are kind of the predominant flu strain. It’s really a bird virus. So there’s lots and lots of different subtypes of influenza that are all found in birds. Migratory waterfowl is where you find these things. And that’s probably almost certainly in the initial kind of introduction of those viruses into people or into mammals. But now we just have human strains of flu that just spread from person to person. It’s not like it goes from person to bird, back to person to bird. Now, we have human strains, and our human strains of flu are to a large extent still related to those bird viruses. But yeah, now they just circulate in people. And the subtypes I mean, the letters and numbers that you hear are like H1N1, that refers to the subtype of the virus. And so H1N1 and H3N2’s are what actively circulate in people right now.

Grace: [00:04:08] And for our listeners, the H’s and the N’s refer to the proteins that are found on the envelope of the virus, is that correct?

Nick: [00:04:15] Yes. On the very outside of the virus there’s two kind of dominant proteins:  H is the hemagglutinin protein and N the neuraminidase protein. And that’s where the H and the N come from. And basically there’s dozens of different types of hemagglutinin and different types of neuraminidase’s. So H1N1 that I referred to, that’s a subtype one hemagglutinin and subtype one neuraminidase. And again, these are just the proteins that are on the outside of virus that actually help the virus get into the cell. And because that’s what the immune response is mostly directed against, people have characterized them in these groups based on reactivity of antibodies, is essentially how the subtypes are defined.

Grace: [00:04:56] Yeah. So talking a little bit about how we prevent influenza infection every year, you know, we have our seasonal flu vaccine. But there’s a lot of, I don’t want to say controversy, but I feel like a lot of people are really reluctant to get those vaccines. And I feel like a lot of that has to do with people questioning the effectiveness of the vaccine. So can you tell us a little bit about what it means to produce a vaccine for influenza?

Nick: [00:05:23] Yeah. So we’ve been making vaccines against influenza viruses for a long time. So there’s different kinds of vaccines now. The majority of them are what we call split vaccines, which are viruses that are grown and then purified and then treated with a detergent so that they fall apart. So you just have all the pieces of the virus, but there’s no infectious particles there, and that’s what’s injected into your shoulder. Like I said, the vast majority of people get vaccines, get those. There are also some purified protein vaccines where just the virus is never involved. You just express different proteins from the virus that can be injected. There are some live attenuated vaccines, those are the ones that get squirted in your nose.

[00:06:03] And that’s essentially a version of flu that can’t replicate enough to make you sick, but enough that your immune system can react. And those are basically the three kind of flavors of FDA approved vaccines for flu. The flu vaccine, the efficacy is actually pretty good against matched strains. But therein lies the issue, right. So we know flu season is going to happen. We know when it’s going to happen, right. It’s in the late fall or early winter. And because it takes a long time to produce the vaccines and formulate them and get them distributed to hospitals and physicians and companies like Walgreens and things where people get their flu shot. We basically have to start making those vaccines early, like well before flu season starts.

[00:06:50] And so essentially what people at the World Health Organization do is look at the viruses that are circulating and they predict which ones are going to then circulate when the next flu season comes along. So part of the reason that the flu vaccines don’t always fully protect people is that sometimes a different virus that we weren’t predicting circulates. So you get vaccinated with something that’s kind of close to the virus that you’re going to be exposed to, but not close enough to give you 100 percent protection. The other thing that can happen is sometimes, even if we picked correctly the viruses that we want to turn into vaccines, they don’t grow particularly well under vaccine production conditions. And so in those cases, we essentially select for viruses that grow better. So it’s feasible to produce these vaccines.

[00:07:42] And the viruses that grow that are slightly mutated relative to the viruses that are circulating in people. Any time you are vaccinated with something that’s not exactly what you’re being exposed to, the vaccine doesn’t work as well. But I will say that the vaccines, even if they’re not super efficacious in preventing infection, they still do a really great job of keeping you out of the hospital. So, I think that flu vaccines get a bad rap because it’s true: sometimes you can get your flu vaccine and then you can still get sick with the flu. The chances of that happening are decreased dramatically, but it can still happen. But basically, it almost always keeps you out of the hospital which is important as well.

Grace: [00:08:24] Yeah. And then talking more about these prevention efforts. So what we’ve seen this past year is that there was a really large decrease in flu cases during the pandemic. Can you talk a little bit about what may have caused that?

Nick: [00:08:38] Yeah, absolutely. So there’s a ton of surveillance. We call it surveillance for flu. Places all over the world are testing people when they come in and they’re sick or even just testing people off the street. We test them and we look for viruses. So we have a pretty good understanding of when flu is infecting people, what kinds of flu are infecting people. Over the last year, the last flu season, there was very little flu and nobody knows for sure, but almost certainly the answer is that wearing masks and social distancing helps prevent the spread of respiratory viruses. And flu is a respiratory virus, which transmits in the same way as SARS-CoV-2. So when you take into account that people already have immune responses to flu, everybody is exposed to a virus either by vaccination or infection. Essentially when they’re born, within the first couple of years, they have antibodies against flu.

Even if they haven’t been exposed to the exact strain, their immune system has seen something that’s similar. So, when you take people’s exposure histories, combined with getting flu vaccines, along with social distancing and mask wearing, essentially flu can’t circulate the human population. SARS-CoV-2 has also been controlled efficiently with behavioral practices, right. But the lack of pre-existing immunity is what flu benefits from. And SARS-CoV-2 has benefitted from that at least until recently, now that we have vaccines against it.

Grace: [00:10:08] And so do you think that these measures will be implemented every year for seasonal flu, or do you hope that they will or do you think we’ll probably just go back to getting the flu, getting sick and all that?

Nick: [00:10:20] Yeah. I mean, it’s an interesting debate. You know, it’s kind of been an experiment, right. We’ve never made everybody in the country wear masks and stay away from other people before. And now we know if we do that, we can stop transmission of these and other viruses, right.  The question is where’s the line? Right. Like we could say nobody’s going to be around anybody and everybody’s going to wear a bubble and keep them away. And for sure, that would stop the spread of infectious disease. I think that we’ve done a reasonably good job of controlling flu with vaccination. And the other thing that we have for flu that is really limited for SARS-CoV-2 are antivirals. These are pharmaceutical drugs that you can get when you go to the doctor and you’re sick with flu.

[00:11:05] So if you’re vaccinated and you have an exposure history, you’re already reasonably safe from flu. But if you still got sick and went to the hospital, we could give you drugs that will stop the virus. So we have a lot of tools in our arsenal to combat flu, which we didn’t have when the SARS-CoV-2 pandemic started. So this is the big difference. And that was the concern. That was really the impetus for the public health measures. Like if you get this thing, you’re on your own, right. There’s no medical interventions which are proven to be efficacious to stop you from dying from this disease. But now the vaccines against SARS-CoV-2 are amazing. And there are antivirals which are approved and tons that are in development. So I imagine that in the not too distant future, we’ll have more ways to fight this virus, which I think will help, so that we don’t need to wear masks for forever. But essentially at the end of the day, everybody will make that decision for themselves. But it is interesting to know kind of the magnitude of how much can be accomplished if you implemented those measures.

Grace: [00:12:07] Yeah. I don’t mind mask wearing. I had really bad allergies when I was growing up. And one of the things that they said you could do was wear a mask to prevent pollen from getting in your nose and mouth. And I was like, oh, but if I did that, everyone would think I was weird, you know, like really sick and avoid me. So for my own personal reasons, I hope that mask wearing is a little more accepted, at least in allergy season.

Nick: [00:12:34] Yeah. And it’s worth pointing out. We’re obviously talking about kind of a US centric look at these practices. But in other parts of the world and other cultures mask wearing is much more normal. That could be an outcome of this, right. It could be normalized in the United States and more of a culturally accepted practice. It’ll be interesting to see. Again, it’s kind of a big sociology experiment, how are people’s behaviors and actions being changed by a biological phenomenon like this.

Grace: [00:13:02] Yeah, certainly. So kind of moving into a discussion more about the SARS-CoV-2 pandemic. I really loved your lab’s bio on Twitter, which for our listeners was “we study influenza viruses that cause disease except for when we get interested in something else…” And I can only assume that that’s something else is SARS-CoV-2, given that you’ve recently been publishing a little bit in that space.

Nick: [00:13:27] Yeah, absolutely. So, the SARS-CoV-2 pandemic happened and at least for us, we’re working on these viruses that are kind of similar. Maybe we would have some insight, some things to add to the field. But more than that, the university shut down. Everybody went home. And the exception to that was if you were working on coronavirus. And so that helped increase our motivation to take on this new challenge because it was that or it was sit on the couch. There’s amazing groups who’ve been working on coronaviruses for a long time, and they’ve really led the effort, and a lot of this work. The viruses are different than influenza viruses, obviously, but they still use the same cell. They still use the same host, right.

[00:14:14] And one of the things that we had been working on with influenza was trying to understand what do they need to take over? What do they need to co-opt from the cell they’re infecting in order to replicate? We had been studying those questions for flu and we thought maybe that’s an area that we could work on to try and understand what the coronavirus would need to take from the cell such that it could efficiently replicate. I think people appreciate this, but there really is a dramatic difference in the genetic potential of a virus and its host. Even a big RNA virus, like coronavirus is a pretty big RNA virus, encodes less than 50 proteins, maybe on the order of 30 or so. Influenza viruses encode anywhere between 12 and, I don’t know, 20 proteins or something like this.

[00:14:58] And human cells encode genes is probably about 20,000. And if you take into account splice variants and these types of things it can be hundreds of thousands of different kinds of proteins that all have different jobs. So when you think the virus is going to be able to replicate itself, it’s come up with 20. It’s going to gather some from the host. And that’s an area of interest. A lot of groups, including ours. What does the virus need? Because it opens up kind of a practical option for not just stopping virus proteins, not just inhibiting virus proteins, but if you can inhibit either the interaction between a virus and a host factor that it needs or inhibit the factor that the viruses use. These are new possibilities for kind of antiviral treatments.

Grace: [00:15:38] Yeah. I mean, there was a lot of movement when the coronavirus pandemic started from different fields into virology. So I imagine you had a bit of a head start on that moving in from one field of virology into another compared to someone who moved from engineering, I don’t know something like that.

Nick: [00:15:56] Yeah. It was interesting, you know, science is always better with diverse perspectives. And I think the field has benefited from somebody who thinks about a totally different question or usually thinks about different questions and now says based on how I think about things, what do I think is going on? It has moved the field forward rapidly. And, we know a lot more about these viruses than we did a year ago. I mean, that’s been the good side of the spirit of scientific collaboration and discovery that’s been all focused in this area.

Grace: [00:16:29] How do you think that the pandemic has changed the way that the general public thinks about virology?

Nick: [00:16:36] Yeah. I mean, that’s an interesting question. I think people think about viruses now. For some people the level of resolution is germs. And there are things that make you sick. There’s all kinds of things, right. There’s bacteria, there’s viruses, there’s protests and all kinds of things. The idea of a virus has certainly come to the forefront in people’s mind. I mean, which is cool, right. These are things that we think about all the time. But not everybody does. So it’s kind of cool to have more universal recognition of the types of questions and things that we’re interested in. I think there’s also been an interesting kind of realization and attention paid to the scientific process in general, which I think is really going to be a helpful thing to come out of the pandemic because it costs money, right.

[00:17:24] A lot of the biomedical research in the US is funded by taxpayers. I mean, the lion’s share for sure, is people’s taxes, right. And the question is, what are we studying and how is it helpful? What’s the return on this? Right. And, you know, I would say that the coronavirus pandemic has demonstrated what this return is. You know, it sometimes frustrates people that we don’t have all the answers right at the beginning. But when there’s a question, we can activate this biomedical research machine. We can understand things like how transmissible are these viruses? How long do they stay in the air? Can you transmit them by touching? These are all experiments that are done that answer those questions.

[00:18:03] And I mean, the most dramatic one is the development of these vaccines. I mean, the development of vaccines takes decades. And the fact that collaborative teams were able to come together, pharmaceutical companies and industry and academic institutions for testing and development of all these things, and have a vaccine essentially a year that is highly efficacious. I mean, this is what that money is going to. Discoveries that enable this type of stuff. This is the payoff for supporting that kind of endeavor.

Grace: [00:18:31] Do you think that sort of interest will continue beyond the pandemic or do you think people will as soon as it’s over, be like, oh, forget biology, let’s go back to normal life?

Nick: [00:18:43] Yeah. I mean, I think that’s a natural tendency that will occur to some extent. But, hopefully this will remain fresh enough in people’s minds that I mean, you see these things in congressional hearings, right. Where they’re discussing the budget on science. Why do we need to give this much money to research? At least for the short term and hopefully for longer we’ll be able to say this is why. God forbid, there’s another pandemic. But if there is, we need these people working on these kinds of questions and developing these things. We can’t be caught flat footed.

Grace: [00:19:11] And would you care to make any predictions about what you think the next pandemic might be? Do you think it’ll be pandemic flu or another coronavirus or Ebola? What do you think?

Nick: [00:19:22] Yeah, historically, at least from 1900 on, there’s been a series of pandemics and they’ve all been flu pandemics. There’s been coronavirus outbreaks and they’ve been epidemics. This is like SARS and MERS, the viruses that are very similar to SARS-CoV-2, but they were regionally contained. So just numbers wise, starting again with the 1918 Spanish influenza epidemic or pandemic. We’ve had a number of these flu. Most recently in 2009, the H1N1 swine flu pandemic. They’ve all been flu. So I think if you were betting, you would bet on it being a flu pandemic, the next one. But you know, who knows? And as the environment changes and people are living more places in more proximity to kind of reservoirs of animals. I mean, we’re just increasing the contact between people and things they weren’t exposed to before, including viruses.

[00:20:18] You know, I think one thing that will come out of it is the flu field has been engaged in the surveillance that I was talking about earlier in the development of interventions or countermeasures for pandemics. With the idea that another one is going to happen at some point, we need to be prepared. There is much, much less emphasis on coronaviruses because we hadn’t had a coronavirus pandemic at least since the molecular age. And we could really identify what these viruses were that were causing disease. But obviously, now it’s clear that they can. So I think the same type of effort and in terms of surveillance and predicting these things will be applied to coronavirus. And if it should happen again, I think that we will be much better prepared.

Grace: [00:20:56] Yeah. And I know there’s been some talk in the science community that the frequency of pandemics might be increasing. Can you speak a little bit on that and why you think that may be?

Nick: [00:21:08] Right. So it’s impossible to predict. But if you look at the things that affect transmission of disease, which is required for a pandemic, people move across the world at an unprecedented rate compared to what we used to do. That I can be anywhere in the world and can be anywhere else in the world within 36 or 48 hours is a bad thing in terms of transmitting pathogens around. So that’s a big part of it. The second thing is that we have more people, right. More people closer together. The cities are bigger and it’s much easier for pathogens to transmit when there’s just more people that are infectable around. So that’s a factor. And then, of course, this is what I was referring to before: a lot of viruses are transmitted by vectors, mosquitoes, for example, right. And as climate changes, animals and insects change their distribution as well. So populations come into contact with these viruses or the animals or the insects that carry viruses, which then facilitates these spillover events, which probably happened with SARS-CoV-2 at some point.

Grace: [00:22:13] Do you think there’s anything that we can do to reduce the rate of these pandemics happen?

Nick: [00:22:18] I mean, these are hard questions, right. Because people will have to live and work and travel where they travel and these types of things. Obviously dramatic things like that. I don’t think that’s likely to happen. I think that what’s much more likely in terms of being able to prevent pandemics or to contain them as epidemics and prevent them from becoming pandemics is just surveillance and countermeasures, right. If we know when these things start, we can detect them right away and quarantine people or if we can rapidly make countermeasures, right. If we could have made these vaccines within a month of detecting the virus, that would have presumably made a big impact on how far the virus was able to spread. So I think that’s probably where most of the effort is going to be focused. Understanding where these things are coming from. Understand quickly when they’re in the human population, and then being able to respond rapidly is probably the direction to go.

Grace: [00:23:15] So moving into more of a discussion about you as a person and as a scientist, I’d love to hear a little bit about how you came to virology and influenza and how you made it your way to Duke? Yeah. So start from whenever you first got interested in science at all.

Nick: [00:23:34] Yeah, it’s been a while. So I guess it started in high school. When I was in high school, I took all of the science classes that were offered and there was nothing else to take. And then I ended up going to the university. It was in my town, Utah State University, for credit to work in a research lab. And then when I went to college, when I was doing my undergraduate studies, I had this experience now like I was qualified or at least more qualified to work in a laboratory. And so I got a job working in a lab to pay the bills. I was in a great lab, they gave me some opportunities to develop some of my scientific skills. And then basically I became good at it. You know, I thought this is something that I like doing and something that I think I can do well.

[00:24:19] And from there, I went to graduate school based on that interest. My undergraduate degree is actually in bacteriology. And I went to graduate school to work on bacteria. And then in this kind of fortuitous event, the guy that I ended up doing my thesis work with, we were in the elevator. He was asking me how graduate school is going. We start graduate school. You do rotations where you essentially work in a few different labs and kind of figure out what’s a good fit for you. He asked how my rotations were going, and I said I didn’t know which lab I was going to rotate in next. He said, well, we just got this grant to work on a virus called dengue virus.

[00:24:52] I don’t know anything about dengue virus, but it sounded kind of exotic and cool. And so he said, come rotate if you want. And I ended up working on that virus. It’s one of those mosquito transmitted viruses that’s prevalent in the tropics. And then I was good at virus research. That’s what I was qualified to do. So I kind of kept doing it. I did my postdoc on influenza, then I’ve been working on flu and the respiratory viruses ever since.

Grace: [00:25:18] I always love hearing about the serendipity of people’s journey. I think that’s really awesome. What exactly was your thesis research on?

Nick: [00:25:28] Yeah. So we were working on dengue virus. And one of the questions that we were really interested in was the interactions between the virus and the hosts. And the reason that we were interested in that question in particular was the virus replicates in mosquitoes, right. It lives in mosquitoes. And that’s how you get it. A mosquito bites you. And so this virus has to exist in mosquito cells and in human cells. And those are really different environments, right. A mosquito is very different from human. And so, anyway, those were some of the questions that we were interested in. We ended up doing a series of experiments looking at the role of cholesterol and fatty acids, which make up membranes and how the virus essentially reprogrammed the host cell to make the membranes that it needs for its replication and its assembly.

[00:26:13] That’s what my thesis was on. We published a couple papers on that. Towards the end of it. So we had looked at the host side, and what we really wanted to then do was look at the virus side of things. But the genetic tools for dengue virus at that time were not particularly developed. It’s really hard to make a mutant virus. We were trying to make a virus that couldn’t reprogram the host cell to move these membranes around and see what would really happen. So anyway, this was something we were interested in but were unable to do at the time. And then I was thinking about what I wanted to work on next and this is one of the reasons that I picked flu, because flu had a really good genetic system and there were a lot of things you could do with the virus. And that’s kind of what I was interested in getting trained to learn how to do.

Grace: [00:26:54] So when you aren’t busy being a scientist, what do you do? What do you do for fun? Who’s Nick the nonscientist?

Nick: [00:27:03] Well as you know the process of science takes a lot of time. My wife works in the lab with me, so it’s kind of a family business. And we have two young sons. So between the two of us working and then taking care of the kids, that’s essentially the full schedule of events for us.

Grace: [00:27:20] That’s the life. That’s awesome. What’s it like to work with your spouse?

Nick: [00:27:24] Yeah. As you can imagine there’s pros and cons. There’s way more pros. I think in our particular case, we met in graduate school. And so we’ve always kind of interacted doing science and talking about science and troubleshooting experiments. And so it’s just kind of been a natural evolution. And now it’s really great because, you know, she gets it right. Like when there’s an experiment that has to be done or a time point that’s really late or something spills into the weekend or something like that, it doesn’t take explanation. It’s just as things go and she knows the details, she gets it and we figure out how to make it work. That’s been a huge benefit.

Grace: [00:27:59] It’s better than someone who has no experience in science, because it really does take a lot of work and odd hours and that’s pretty cool. And you always have a carpool, buddy.

Nick: [00:28:09] Yeah, that’s right. Reduce our carbon footprint.

Grace: [00:28:13] Yeah. So as we wrap up the episode. What sorts of advice would you give to people who might be entering the field of virology today?

Nick: [00:28:24] I guess I would have two pieces of advice. The first is that you really need to become good. And what I mean by that is there are metrics in science, right. If you publish papers or you get fellowships or you get grants or these kinds of things. And I think a lot of people focus on hitting tangible metrics so you can put a line on your resume. I got this or I published this or whatever. And I think sometimes there’s less of an emphasis on really becoming an expert in the process of doing science. How do you set up the best experiment so you can make the clearest conclusion from it? And so that’s what I would tell people to start with. All the rest of that stuff comes if you’re doing good, thorough, reproducible science.

[00:29:09] You get all the rest of that, but at the beginning, that’s really what the focus should be on. And it’s satisfying. You know, sometimes from a CV building point of view because there’s nothing you can see, right. You’re thinking about questions better and more precisely. That’s really important. The other thing I would say is that there’s lots of reasons why people go into different fields or pick different topics to study. And I think that science is an endeavor where it’s really important to be excited about the specific thing that you’re working on. And it means different things for different people, even within the context of like working on one virus. There’s all kinds of different directions that you can approach it from. And figuring out what excites you, which little nuance of the questions are you most excited about?

[00:29:55] That’s no small part of being able to be successful and invest what’s required and when an experiment doesn’t work, something like that. I think it’s that that gets you out of bed the next morning. You know, you really care about it and you’re really working on the right question, helps you get through the lows, which always happen.

Grace: [00:30:11] Two excellent pieces of advice. And I hope our listeners can take those away with them after this episode. Thank you so much for joining me, Nick. It was really awesome talking to you and hearing your perspective about viruses and the pandemics and advice for life.

Nick: [00:30:27] Thank you. It’s been a pleasure.