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Dr. Lynn Inquist, a renowned virologist and professor emeritus of molecular biology at Princeton University, discusses her journey and interest in virology. She initially had a broad interest in understanding how life processes work, but became fascinated by infectious diseases after being exposed to them through her mother, a nurse. She talks about her educational journey, including challenges and rewarding moments, and emphasizes the importance of fundamentals in science. She also encourages students to focus on what they enjoy and find exciting in the long run. Hello, my name is Tonya Zaku and hi everyone. My name is Lucas Goldstein and we are here today with Dr. Lynn Inquist professor emeritus of molecular biology at Princeton University and a well-renowned Virologist who particularly studied neurobiology and the herpes virus. Dr. Inquist, thank you so much for being here with us today. It's my pleasure and Just to kind of get started if you could tell us like a little bit about yourself Because from our understanding you were born in Denver and you moved around and you were really interested in science and technology And you have some very supportive parents who kind of helped foster that creativity So like what sparked your interest for the study of virology and pursuing research and academia in general? Well, I guess the first thing you should realize is that I didn't get interested in virology until after my PhD in microbiology I had No real interest in viruses specific I had a major interest in trying to understand how life processes work and I Was exposed I suppose that's not the right word But I was exposed to the idea of infectious diseases when my mom who was a nurse in this very very small town in South Dakota would let me come into the hospital and Just sit in with the technicians while they showed me things through the microscope and whatever and I just All of a sudden got to realize it Nobody knew what these little guys were doing in fact They were very difficult to see even under the best microscope and yet some of them made people very sick Others of them didn't seem to do anything. They made cheese they made you know the sewage system to work and everything like that and I just realized that they were everywhere and Even my biology teacher we only had one biology course in high school No AP biology nothing like that and he told me that that that they were going to be the next stage of understanding what was going on in biology and Yeah, remember I started in high school in 1959 and so That was just about six or seven years after the discovery of the structure of DNA It was just when people were starting to get interested in what was a gene. How were they turned on? How are they turned off? What did that mean? You know and I was very interested more in engineering how things work than I was in The fundamentals of biology, but I always kept that in the back of my mind and when I went to college I Decided that I wanted to be an engineer it was the time of Sputnik and Atomic energy and everything like that, but my first courses in Engineering didn't interest me at all. Yeah, I went to my advisor who was a very famous old Bacteriologist Who convinced me that I should switch my major to bacteriology not microbiology, but bacteriology and he showed me how you can work with with bacteria And I just got very interested in that at that time now We didn't have any courses at South Dakota State University in molecular biology We had courses that were more I guess now you would call ecology To finding bacteria out in the in nature and in you know in soil and how they fix nitrogen and things like that and so I got really quite interested in Molecular biology on my own. I just started reading papers and Realizing I didn't have a clue as to what was going on I just I just found it fascinating how people could actually do these experiments in Bacteria and so When I went to graduate school the University of Minnesota, I started working on streptomyces which are soil bacteria that make antibiotics and I got the idea that I wanted to study The DNA of these guys I wanted to isolate it and I wanted to compare DNA from one kind of streptomyces to another one to see if you could Discern whether they were related or not. This is really early days. Nobody knew how to do any of this stuff. And so That's what kind of got me going But there at the University of Minnesota in a in graduate school my first course in molecular biology and hardcore molecular biology Really got me turned on to the idea that E.coli which was the workhorse bacteria and A couple of small viruses that infected E.coli Could tell us how genes were what genes were how they were turning on how they were turning off And I got so excited by that That I decided that I wanted to do more. And so after I got my PhD, I wanted to Go study E.coli genetics and As I wrote I went to the Roche Institute of Molecular Biology, which is in just in New Jersey and it was a brand-new Institute that just focused on molecular biology and There was a a guy there that my PhD advisor told me about who studied Potassium metabolism in E.coli. And so I went to interview with him, but he didn't have a position But down the hall, there was a young lady that just finished her postdoc with Alfred Hershey who just won the Nobel Prize and discovering a lot of basics of molecular biology. Her name was Ann Skelka and she took me and Convinced me to work on bacteriophage lambda, which is a little virus that infected E.coli and Everything in molecular biology was really focused on lambda at that time, at least in my opinion isolating things like repressors and activators and Understanding how the particles were assembled and how the DNA was replicated and whatever. And so that was really my start in virology and I started that So my first postdoc was in 1978. And so that was really my start in biology in 1971. And so that's when I really started focusing on viruses. Wow, that's super interesting. Honestly, I'm really intrigued by how the teachers had such an influence on your spark into virology and honestly moving into biology. Honestly, that's how A lot of teachers have influence on their people and students nowadays, especially for me. And to talk more about your educational journey, was there any any challenges or anything that was particularly rewarding moments during your training? Sure, there are plenty of them. I think all of a sudden realizing that, you know, the courses that I took in algebra and preliminary calculus and whatever actually had some value. And when you were studying, you know, kinetics of bacteriophage growth or whatever, you had to make plots and the plots had slopes and the plots had optimums and minimums and you could figure out a lot of things. And that it was just sort of eye opening to realize that all of this stuff that I had been soaking my head in actually had meaning. And it showed me that if you wanted to make progress in science, you had to be good at fundamentals. You just couldn't jump in and say, oh, I want to study herpesviruses. You had to you had to show how you could do these things to people that were training you and they would recommend you to other people and whatever. And so it was the realization that the basics of study was essentially all about the fundamentals of chemistry, fundamentals of calculus, the fundamentals of statistics. And all of these things, you know, all of a sudden were eye opening to me. I just couldn't get enough of this stuff. And and my teachers, my high school teachers in civics and in biology and chemistry were amazing. They they said, you know, you're going to learn that there's more out there than what we're teaching you. And you better study hard, figure out what was going on. And their motivation, I wasn't motivated by grades. I was motivated in learning something and learning meant that I had to read and I had to explain things and whatever. And so and in college, my major professor was a bacteriology guy. And, you know, he convinced me to go to graduate school and said, you know, there are many things you can do as a bacteriologist. You can go into food microbiology, dairy microbiology and whatever. But if you really want to know what's going on, you're going to have to study some more. And there's just a lot of exciting things that were happening. And he just convinced me that I could do it. It wasn't so much that I didn't want to do it. I had a lot of friends that I wasn't from South Dakota. Nobody knew where that was. And I didn't know anybody in the business who from molecular biology who was from South Dakota. So it took me a little while to get my courage up to be able to go and deal with these very famous people. Well, clearly you could do it. I mean, based on your career, I mean, I'm so impressed. And I really resonated with, sorry, with what you said about, like, learning the fundamentals and, like, actually learning, like, why you're learning something, I suppose, is kind of what motivates me to actually learn. Because if I don't know why I'm learning it or I don't, like, put things in my head, I'm like, what's the point? I'm kind of just, like, sitting there. But once I realized how all these things connect, I think I just, it just motivates me more to pursue something greater to, like, how my curiosity drives my knowledge, in a sense. At Princeton, I was advising many, many undergrads. I taught over 700 kids in biology. And I was a career advisor for quite a few of them. And they would come to me, you know, and what can I do? What should I do next? You know, and whatever. And I told them that you guys worry so much about what's going to happen in the next year or the next two years. Honestly, you should be looking for the, in the long run, what's the most exciting thing that's going on right now that you're looking at? So for me, my big change in my direction was studying viruses that infected the nervous system. But I had, I never had a course in neurobiology. I never had anything. And I turned my whole lab over to that and got students who were interested in helping me learn at that time. So it's always finding out what you don't know and then trying to figure out how you can know it. And it's more or less deciding very early on, what do you like to do? Not so much what your passion is. I mean, I'm passionate about fishing. But I mean, what I like to do is I like to study science. I like to teach. I like to be around students. I like to write. And all of those things you can do. But sooner or later, you've got to focus. You just can't be all over the place. You've got to start focusing. But don't worry about it so early in your career. Work on the fundamentals. Discover what you really like. Like you said, all of a sudden figuring out how something works. You know, it was when I took a course in differential equations as an undergraduate and it was just sort of mind boggingly numb. I, I couldn't see the practicality of that. And all of a sudden, one day I was in the lab working on my undergraduate thesis and I was making some plots. And all of a sudden I realized that, you know, first order kinetics, actually there were equations that described them. And I was like the lightbulb going, you know, that, you know, math has value. It's not just memorizing things and doing proofs and whatever. And that, those kinds of experiences for me were great. Like in chemistry, when all of a sudden I realized that I understood how ATP could actually be a high energy molecule. I memorized that, but I didn't know what that meant until we were doing experiments in organic chemistry and we could show that these kinds of bonds, these phosphates established a structure that made it easy for groups to leave and groups to bind to and whatever. All of a sudden all of that started to make sense. And I, all I knew was that I had to take organic chemistry as a requirement and all of a sudden it was something that I really enjoyed. And I went to talk to the professor who taught the course and he told me all kinds of interesting things about how all biology is chemistry and it's organic chemistry and inorganic chemistry and physical chemistry. All of these courses that I was taking that were just courses that were just requirements. They didn't have any meaning until all of a sudden I started realizing that if I was going to be a top notch scientist, I was going to have to learn how to do all of these things. And I had to know, like you said, how they worked. Why, why are you saying I have to take this course? And all of a sudden it wasn't why I have to take it, it's I want more. I want, I want to figure out more. What do I have to do? Wow, okay. I really, honestly that was so beautifully said about how you really have to find the value of something, especially as a student. We're always in the classroom and we're getting stuff thrown at us and we sometimes don't really fully acknowledge what is being said except for the things that we're truly interested in. And so I really like the fact that you brought up having to value stuff. But something really did intrigue me in what you said. As a high school student, I'm always thinking about what's happening in the next month or two months or the next year, especially with college coming up. But you also said something about how you should be focusing on the long run. Is that something that a high school student should have, like should work towards having a mentality for? I think that's difficult to decide how you're going to do that. What I really meant by that was as you began to study and began to find things that you, that you like, you should be thinking about what's the next big problem? Where in the world is science going? So neurobiology, cell biology, artificial intelligence, you know, all of these things. And that's what I meant by beginning to focus a little bit. So you got an interest in math, you got an interest in chemistry and whatever, and you're just loading up with facts. But you've got to say, you know, I think I want to know how the brain works. I think I want to know. And what does that mean? You want to do it from a computational point of view? Do you want to do it from a biology point of view? Do you want to understand how neurons work or do you want to understand how circuits work? And as you start thinking about that in the long run, you probably aren't going to be able to answer that, you know, locally and in the next year or so. But you need to sort of say, OK, that's how I'm going to decide where I want to go to college. I want to go to a place that focuses or has at least some really good neuroscience or some really good developmental biology. And, you know, choosing the school that you go to is less important than choosing in your head what you want to do with that school. And, you know, I went to South Dakota State University because my parents didn't have any money and it was the only place I could go to college. And I didn't even know what college was all about. All I knew was I just wanted to learn more. And my biology teacher told me that South Dakota State had a really good bacteriology department. So that was that was it. They're not the best in the world, but they were very, very conscious about teaching and good teaching for an undergraduate school. And you've got to just sort of keep this idea up that you want to do what you're interested in, but you also want to have a long term goal in mind. You know, my whole career, people talk about going to work and whatever, and I never considered anything they did was work. It was all fun. I remember in Princeton, we lived about a mile from campus. I would walk in the morning and I would think about what was going on. I would think about could hardly wait to get in the lab and see what the students had done. And that was more exciting than, you know, going to an office and open up my briefcase and filling out forms or whatever it was. If you pick this right, you do this right, you're going to have a great life. That's for sure. And I think worrying too much about what's going to where I'm going to school, you know, is occupies a lot of energy that you probably should be doing other days. Thank you so much, Dr. Inquis. I feel like a lot of the concerns that you just addressed are, like, really relevant to people like us, like high schoolers, college students, people, like, pursuing their careers. Like, obviously, that's kind of, like, at the forefront of our minds, but I guess what you're saying is, like, just take a step back. And so I just realized it's not exactly right now, but just in the long term, find what makes you happy and how you can pursue, like, certain things that actually you like are interesting. If that makes sense, I hope I. Yeah, no, that's right. And don't worry so much. My my grandson right now is just starting college and he's starting to think about majors. And he hasn't even started yet. I told him, God, you know, are you interested in science? Are you interested in math? Are you interested in computers? And then try to figure out. But I think the schools are trying to force people to get majors too early. I changed my major from engineering to bacteriology because I had to go there and I had to think, yeah, I know I don't want to be an engineer. That's not what's exciting. Bacteriology seems to be very exciting. So, yeah, it's it's making this worrying about making decisions is worse than anything. Making decisions is hard enough, but worrying about, am I going to make the right one? Have I got the right idea? It's life is too short to worry too much. Thank you. And also just to pivot a little bit and focus a little bit more on your like research, from my understanding, you used a virus called the pseudorabias virus. And if I'm not mistaken, you're actually the first in the world to sequence its genome. And there seem to be some benefits to using this virus in research. Can you tell us more about what the pseudorabias virus is and about your work using its research infectious properties of viruses, tracing the path of infection and the peripheral to central nervous system, etc.? Like, can you tell us more about that whole kind of topic? Well, so first of all, pseudorabias virus is a very curious virus. It's a herpes virus. It's related to chickenpox virus and related to herpes simplex virus. But it even though it can infect human cells, it doesn't really do a good job of infecting humans. And the other thing that it does is it grows very fast, relatively speaking. So you can get an experiment done in a day or so with this virus where it would take a week with other viruses and for some herpes viruses even longer than that. So I got interested in this virus after my postdoc at the NIH. I was at the NIH for like nine years and I got an opportunity to go to a little biotech company. There was only four of them in the United States at that time. And this one was in Minnesota was called Molecular Genetics. And they were working on viruses that caused disease in agricultural animals, cows and pigs and whatever. And I grew up in South Dakota. I grew up on my grandparents' farms. I knew all about animal diseases and how bad they were and how they caused economic disasters. And so Pseudorhabes virus is a herpes virus. Like I said, it's very closely related to human viruses. But its natural host tends to be swine, pigs. But it can infect dogs and cats and cows and in fact just about every other animal and just about every other animal that it infects, it kills. The only animal that it infects and doesn't do much is swine, is pigs. And it was causing great disaster in terms of economics of pig production in the United States in the early 1980s when I started working on a vaccine against Pseudorhabes virus. Now I should just tell you it got this name Pseudorhabes virus by vets in Europe in the 1800s. Dogs and cows were getting really sick and the disease looked like it was like rabies, which causes nervous system infections and whatever. But it wasn't like rabies. And so they called it Pseudorhabes. And it's a terrible name, unfortunately. But it's better than Pseudorhabes virus 1, I guess, which is what its taxonomic name is. And you noted that I was the first one to sequence its genome. That wasn't really so. We were the first ones to clone genes from this virus and clone some of the very first genes that were ever cloned from viruses. And that's what we did. And we pulled the genes out for the surface proteins that if you made antibodies to them, they blocked the virus from replicating. So that's what we did. And as I started studying this virus, I realized there were so many interesting things about it. Like, why did it not infect people, but it could infect human cells? Why did it infect dogs and cows and kill them as opposed to its natural host, pig, where it essentially gets into the animal and goes into the nervous system and shuts off? And I just wanted to know why. How could that be? Because all herpesviruses cause what's known as a latent infection. You get infected usually as a young person, babies, young kids, and you might get a rash, you might get some cold sores or whatever, and then it goes into your nervous system and it stays with you for the rest of your life. And I thought at first that that was a crazy strategy for a virus to get into its host and then shut off. And then I realized that its major, major biological solution was that it didn't shut off permanently. Anytime the host got stressed, the virus would reactivate, wake up, make particles, and you could spread to adjacent hosts. We call it the rats leaving the sinking ship model. The virus goes in, shuts off, doesn't do anything to the host. The host gets sunburned, gets stressed, gets put into a truck driving down the road, breathing exhaust, and virus comes out and infects other animals. And so that whole process got me started on the rest of my career, which was to try to understand the pathogenesis of this virus. Why is it almost non-pathogenic in adult animals and really pathogenic in newborn animals? Why is it really modestly pathogenic in pigs and seriously, fatally pathogenic in cows and dogs and whatever? Why is that? It's the same virus. It's the same biology. What's going on? And that is the next stage of my career in which I got involved in understanding how these viruses can infect different cells and how different cells give different outcomes. Wow, that's really interesting. And now that we're on viruses, I know that we've just recently recovered from COVID and a lot of public perception of viruses can sometimes be driven by fear, as we've seen. And how do you think scientists can improve communication with the public about viruses and the important role they play in our world? So this has been a very active area for me because I was president of the American Society for Virology. I was the editor-in-chief of the Journal of Virology, one of the major virology journals, and now editor-in-chief of the Annual Reviews of Virology. And the whole purpose of this is how scientists communicate with each other. But we have to do a much better job of communicating with others. Usually, you know, when I'm on a plane and somebody is next to me and they say, oh, where are you from? I say, oh, I'm from Princeton. They say, oh, what do you teach? I say, virology. Oh, God, you know, that's horrible. Or they say, what kind of viruses? I say, herpesvirus. They say, oh, jeez. You know, I've got a friend who's got fever blisters or genital herpes or whatever. I say, right. Well, I'm not a medical doctor. I can't advise you on what to do. But I can tell you that viruses are everywhere. Every living thing is infected with virus. And the more we study them, the more we realize that they do good things and bad things. And you just are focusing on the bad things. You know, it takes a little while to understand. This is not something that you can get in a couple of sound bites or a TikTok video. Biology is really a fascinating area, subset of biology, where these little guys have are intracellular parasites. They can only replicate inside a living cell. The particles that come out are dead. They're not alive. They don't do anything except injecting genetic information into the next cell and make more particles. But I said that in my mind, I keep thinking that somehow we have to stop, you know, with the worry and concerns about what goes on and deal with the fact that you have to be educated to understand some of this stuff. Vaccines are very important, but some people just, you know, I'm not going to inject anything into this body. Bill Gates is injecting microchips into us, you know. And so this whole business right now of people not accepting that there's quite a bit to be learned by studying viruses as opposed to just making antiviral drugs or making vaccines or whatever. So I think that we have a major job in front of us to try to educate. And education has to start very early. It has to start at the grade school, high school. And you have to deal with the facts and not deal with the, you know, the worrisome aspects of things like that. I wish I could tell you that I have a solution for that. I don't. But I can tell you that when you sit down and you talk to somebody, you discover that they're most people are very interested in viruses or bacteria or, you know, and they don't know. They just know they're interested. They just don't know what to do. And when I start talking about molecular biology, they glaze over. They barely can spell DNA and understanding how genes work and what genes are and whatever. It requires a lot of education. It's like, oh, you pick your favorite field. You know, you can like Shakespeare, but just understanding, you know, the structure of verse and understanding, you know, theater, understanding that a lot of people aren't interested in that, but yet it's a very important aspect of life. Thank you so much, Dr. Inquis. Viruses are super interesting, especially to me. But I also want to move on to your accomplishments. And that's such a well-accomplished research with various publications, accomplishments and awards as you look back on your career. What are you most proud of accomplishing? I think I got the president's award for teaching at Princeton. That was that was really exciting. Princeton's a very small school that really prides itself in top notch education. It's mainly an undergraduate school. There's a graduate program, of course. But there are very famous people that have taught courses there. And the fact that I was one of four teachers that the students selected as being their favorite teacher of that year, that was really great. I enjoyed it. They said I thought like a virus. That is crazy to me, though, the president's award. That's like, wow. I mean, congratulations. Congratulations. And then just to kind of like end off today, you've given like you've already given so much advice and so much insight to us. But if you had to like condense all that you've learned throughout your career, what advice would I know that's difficult, but what advice would you give to young people who are interested in pursuing a career in science or health fields or anything like that? Let me see. I think so. I was just trying to read something that I know that I have written before. No words. Recognize what interests you, even if it's vague at first. Just early on, you know what you like and you know what you don't like. And just recognize that and then foster a vector to make this interest a purpose. You can't do everything that you like. You have to figure out there's something. And I don't mean, you know, watching videos and playing computer games. I mean, you know, something that you like about a possible career. And don't fret about making specific long term plans. Things are always changing. You know, five years ago, I knew about machine learning, but I didn't understand artificial intelligence. And now all of a sudden we're realizing that with artificial intelligence is changing the way that we do research and take advantage of change. Don't worry about change. Explore. Don't be afraid to try new things. You've got to take chances. You've got to. When I left the NIH to go to this little biotech company, all of my colleagues said, you know, I was killing my career. I was essentially giving up a tenured position at the best institution in the country and going to a little place in Minnesota to try to discover new vaccines. And that essentially that choice for me opened up a whole door of working in industry, working at DuPont, working with neuroscientists, working with computational guys. Had I not done that, I would have been stuck at the NIH. That wouldn't have been bad, but it didn't give me the degrees of freedom to try new things. And then I think the last thing is it's not all about you or all about me in this case. It's you've got to leave a wake of influence. You've got to influence people. You've got to pay it forward in your profession. You've got to be a good teacher. You've got to write textbooks. You've got to become involved in different organizations and whatever. A career is more than just doing a few things. A career is a wide breadth of things that somehow is still focused on what you want to do and making a difference, not just publishing papers, but making a difference in other people's lives. Well, thank you so much, Dr. Inquis. I hope that we and all the people watching here at least to some degree follow in your footsteps and follow your example of just taking those risks and pursuing change and pursuing our curiosities and what interests us. And just thank you so much for being here with us today. Your insights were so helpful to us, and we really appreciated talking to you, so thank you. I appreciate what you guys are doing. Thank you, Dr. Inquis. Thank you again for joining us. I found everything that you said, all the advice and all of your research very valuable, and I truly will carry this onto me in my future endeavors. Yeah, I might not be a virologist, but I'm definitely going to follow your advice. Who knows where virology is going? Yeah, we'll see, maybe. You don't know. You never know. Thank you so much. Thank you. It was an honor. Thank you.