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Interviewer: You never know where basic science will take you. Today, I'm talking to biochemist Wes Sundquist about a nature inspired system that can deliver molecules to human cells. We'll talk about that next on The Scope.

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

Interviewer: Tell me what it is you've done here. You've made kind of a delivery system that can bring small molecules to other human cells. What is that?

Wes: Right. So what we've been able to do is to design new proteins that normally wouldn't have these activities to act like viruses in the sense that they can assemble into spherical particles. They can drive their own release from cells. And if we have the appropriate signals, they can enter new cells. Those are properties that we normally associate with viruses, but these are proteins that are designed in ovo and so we would envision that they can be more flexible in terms of what we can do with them than the nature viral systems.

Interviewer: Why is that interesting to maybe some of our listeners?

Wes: Right. So a couple of things, one is we've been for a long time interested in how viruses do this. So this is something that viruses are able to do, leave an infected cell and enter a new cell. That's how they spread infection, and we and others have been studying that those processes.

We wanted to know if we really understood them, and designing new proteins that normally don't have those properties but now acquire them is a good test of whether we understand the rules for how proteins assemble, how they bind to membranes, how they, what we call envelope themselves, that is wrap themselves in the membrane and how they bud, pinch the membrane off behind themselves. So this was a good test of whether we understood what's required for that process.

Interviewer: You know, viruses have a reason for wanting to spread themselves to other cells but why would you want to do that intentionally? Why would you want to deliver things to other cells intentionally?

Wes: So molecular genetics has over the last, perhaps five years, made great strides in terms of having the ability to do things like alter genomes with especially what's called the CRISPR/Cas9 system that can edit DNA so that it can correct, for example, genetic mistakes. The bottleneck now has become how do you deliver those very potent activities to new cells? So you could envision gene therapy situations in which you want to deliver potent enzymes that edit the genome and now you have to get them into cells. So that's really, as I said, a bottleneck and something that we and many other groups are working on trying to do efficiently.

Interviewer: And so, how did that feel when you actually saw that what you learned actually works, that you could tell a cell to do what you had thought it does?

Wes: I actually get excited all the time about research and when Jorg Votteler, who's the person who did the work and he deserves credit for that, came in and said, you know, it looks like it's working, and that was really the first time we tried it, which is an unusual situation in our lab. Usually, it doesn't work and then we sit there and try and figure out why not, but this was a case where the first design worked and that's partly a testament to Jorg, but it's also partly a testament to the fact that it just takes a lot of work to understand how things work, but once you do, you have opportunities to do things that you didn't before you understood how they worked.

Interviewer: That's right. I bet you never expected that your research on viruses would take you here.

Wes: Yes, that's right. There's a big field called nanoparticles and also a big field in terms of development of delivery systems, and we don't pretend to know all of it, but I'd follow it, but only from a distance and not envisioned that our lab was part of it, but I think that's the importance of research is that if you do it well, you don't know where you're going to end up, but I think you can be sure that as a field, things will move forward.

Interviewer: What else do you think viruses have to tell you? Or do you even know?

Wes: Yeah. So viruses have quite a history of teaching us really important things. So DNA replication was first reconstituted in mammalian DNA replication using viral systems. Of course, the discovery of the ACCA gene, so, cancer biologists don't often tell you this, but it wasn't cancer biologists, it was virologists who discovered that there were genes that when misregulated would cause cancer. And I think that there's just no doubt that they have more to teach us maybe particularly in the mechanistic area.

So we don't understand still how many of the machines work. They're exquisitely good at replicating things and moving around the cell, but also exquisitely good at reprogramming cellular pathways. So the great example is the ACCA gene but there are many other viruses modulate their environment. And then I think they're also teaching us a huge amount now about the immune system. So, I would say those are the three areas in which viruses continue to make a major conceptual contribution, not to mention, of course, the fact that they're important pathogens.

Announcer: Interesting. Informative. And all in the name of better health. This is The Scope Health Sciences Radio.

Announcer: Examining the latest research and telling you about the latest breakthroughs. The science and research show is on The Scope.
Federal funding for scientific research and development has shrunk by 20% over the last 3 years and biomedical researchers are feeling the strain. My guest and professor of biochemistry, Dr. Sundquist, went to Washington D.C. to advocate on behalf of scientists across the country. Dr. Sundquist, would it be an exaggeration to say that biomedical research is in a crisis situation?

Dr. Sundquist: I think one should use words like crisis carefully, but I think that if you asked our young faculty, they would tell you that they feel that they're in a crisis situation, that we're losing very talented young people who absolutely have the ability to make major contributions to our understanding about how the world works that can be translated into real advances in healthcare or real innovation in communications, and so on and so forth. So, I think they would tell you that we're in a crisis and I think if your young people think you're in a crisis, you are.

Host: Would it be fair to say that most researchers here at the University of Utah and probably most major research universities, a lot of their research is funded from the National Institutes of Health?

Dr. Sundquist: That's correct. Most of the research, for example, at the University of Utah, School of Medicine in particular, comes from the National Institutes of Health, or N.I.H. The other major funder is the National Science Foundation, but it's significantly smaller.

Host: There have been some striking statistics that have come out that shows how funding has changed over the past few years.

Dr. Sundquist: Yes. So, the ASBNB amongst other organizations, has compiled numbers in real N.I.H. spending, and in the last decade, that's decreased by 20%. So, that has real and very detrimental impacts. If you envision your own salary going down 20% over the last 10 years, or you envision your household budget going down 20% over the last 10 years, then you have a picture of what's happening to biomedical research funding.

Host: What does that mean for the research enterprise? How does it change things?

Dr. Sundquist: Of course it has affects on every level. At the global level, it means that our country is less competitive and we are losing some of our best researchers to competitive positions elsewhere. At the more local level, it means that new professors that we hire are struggling to establish their labs because they don't have enough money to do their research, and so instead of spending time coming up with their most creative ideas, they're spending times writing grants and worrying about how they're going to pay salaries to people in their labs.
And then, at the earlier level, I can tell you in my own lab it has an impact on how graduate students and post-docs feel about continuing on in research. They see very good people struggling to get funding and they realize that this is a difficult road right now. These are people that we've invested a lot of money in, they're our sort of best and brightest, but we're also spent a lot of money training them. And so, every time we lose one it's a loss for our system, not just a personal loss.

Host: Are you personally worried about your research?

Dr. Sundquist: Yeah. I have a grant. That's a personal question, but I have a grant right now that got a score, it's the 8th percentile. So, that means that it scored above 92% of the grants. And, I will only find out this month if it gets funded or not. There is a chance that it won't get funded.

Host: Eighth percentile. Wow. And, how does that compare to in the past?

Dr. Sundquist: By and large, right now 90% of grants are getting rejected. So, 10% are getting funded, and that's as bad as it's been for 25 years. In a very real sense, it's worse than it's ever been because the situation 20 years ago, when it was that low, it rebounded quite quickly and N.I.H. was supported strongly through the next decade. But, for this decade, things have been going down for literally 12 years, and they're now down more than 20% than in real purchasing power. And, there's no immediate help on the horizon.

Host: So, you've personally seen kind of a shift in the culture of science? The way scientists think about their work and their place in it?

Dr. Sundquist: There's no question that when you go to a conference now, people spend half of their time talking about the funding climate and how to get funding for their labs, instead of talking about what are their best scientific ideas. And, that has absolutely changed in the 20 years that I've been going to conferences as an independent investigator.

Host: And, what's the fear of what might happen in the future?

Dr. Sundquist: A large number of countries are spending a substantially higher fraction of their GDPs on research, and we currently have an advantage. We still are, I think, the best place to do research in the world, but everybody has talented people. And so, there is a point at which if you don't invest in something, it doesn't matter how talented your people are or how good your system has been in the past, you will start to lose ground. And, I think that's already happening. And we don't want others to do poor science. We want ourselves to do the science we're capable of doing.

Host: Is there anything else you'd like to add to that?

Dr. Sundquist: This is an issue that people should care about across our society. Something of a devaluation of science has occurred that we should care about making decisions in a scientific fashion and scientific literacy, and we should care about our competitive position in the world, and also our ability to innovate in ways that deliver better healthcare or deliver better products to people.

Host: Is there something that other scientists can do or citizens can do if they also care about this problem?

Dr. Sundquist: So, one of the things that was kind of fun about going to the Hill, I don't have any delusions that we took over Capitol Hill, but I do think you get the sense that our system is a representative democracy that's responsive to what people think. And so, there are lots of valuable competing interests, but if people say we care about funding science and we care about the quality of research that our country does, if you tell your Congress person or your Senator that, they will respond. I would say, in my view for scientists, I think that having a coherent policy and sort of impact is best done through scientific societies.

Announcer: Interesting, informative, and all in the name of better health. This is The Scope, health sciences radio.

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

Host: Aids is one of the most significant public health challenges worldwide. My guest, Dr. Sundquist researches how HIV infects the body, with the goal of finding ways to stop it. His outstanding research contributions recently earned him a seat on the prestigious National Academy of Sciences.
You investigate how the human immunodeficiency virus, HIV, the retrovirus that causes AIDS infects people?

Dr. Sundquist: Yes, the thing we're most interested in right now is how the virus interacts with the host cells that it infects. So viruses are fairly simple replicating machines. In the case of HIV they only make 12 proteins and that's as compared to 20,000 proteins that a human cell would make. And so one of the interesting aspects of viruses is that they have to use host cell machineries and pathways to replicate and that's something that interests us.

Interviewer: Why does that interest you? What do you hope to gain by learning that information?

Dr. Sundquist: I guess there are a series of reasons to do it. One is a simple curiosity, I think; understanding the world around us is a valuable goal. But of course we would expect that understanding leads to important spin-offs. And two, areas where one can envision such spin-offs and that have been realized in a number of cases, one is in therapy, so of course HIV is still a very important biomedical research problem. There are literally more than 20 million people who are HIV positive worldwide and so that's a huge health problem, and drug resistance is an increasing problem. And so we need to understand new vulnerabilities of the virus and we can only do that by understanding how the virus replicates.
But maybe a less obvious but still very important aspect of this type of work is that we can learn a lot of cell biology as well. So viruses, because they use host cells pathways, are actually the ultimate cell biologists, and so if we follow them we can learn a lot about cells work. And that's been famously, for example, oncogenes, which are the genes that go awry when people get cancer were discovered by studying retroviruses and understanding how they transform cells. And so this is something that keeps happening again and again is that we study a good model system and make fundamental discoveries that have impacts in other areas that we couldn't have predicted.

Interviewer: So can you talk about one area of your research, what are you focusing on?

Dr. Sundquist: Sure, one of the things we work on fairly intensively is understanding how the virus exits cells. So if a cell is infected in order to spread the infection the virus has to leave that cell. And we're interested in how that happens. And we got interested in that in a collaboration initially with Myriad Genetics where we were able to show that by a tech company here in Salt Lake City. And together we were able to show that the virus uses a host cell pathway called the escort pathway to leave cells. And the interesting spin-off, that was just over a decade ago, the interesting spin-offs are that we now understand that almost all envelope viruses use the same pathway to leave cells, so this has turned out to have quite a global impact on our understanding of viruses in general.
But the other thing that's happened is that this pathway, which of course performs important cellular functions, the cell isn't making these proteins so they can be infected by viruses, but rather to do other things. It turns out that the most important function of this pathway we now think is in the final step of cell division. And so a lot of what we do now is study how cells divide, rather than how viruses leave cells, even though we got into the problem through our interest in viruses.

Interviewer: Okay, so the escort pathway actually is something that occurs in human cells, but the virus needs it to get out of the human cell so it can infect other cells; is that right?

Dr. Sundquist: That's exactly right.

Interviewer: Okay.

Dr. Sundquist: And that's fairly common; as I said HIV and other simple viruses have only a dozen genes and so they have to use host cell pathways and reprogram them in order to do many of the steps of viral replication.

Interviewer: Why do you think this work is so fascinating? I mean, you've been studying HIV biology...

Dr. Sundquist: Why can't we quit?

Interviewer: Exactly. Is it an addiction?

Dr. Sundquist: Yeah, it is a little bit of an addiction. I think that you have on the best days, and they don't happen very often, you have a feeling that you're seeing something you and your students and your post-docs are seeing things that nobody has ever seen before, and understanding things that nobody has ever understood before. And that's sort of an exhilarating feeling, and it doesn't happen so often. Much of what we do is quite routine, but I think the idea that you can discover something that hasn't been known before is quite exhilarating.

Interviewer: What are you most excited about right now, in looking at that...?

Dr. Sundquist: The thing that I'm most excited about right now? There's are a subset of machinery of the escort pathway that we think forms filament strings basically and that those strings act like a noose from inside the neck of a budding virus and pinch the membrane together so the virus can leave. And they seem to do the exact same thing when cells divide. So they sit at the region between the two dividing cells and pull the membranes together. And we have a very talented young faculty member in our department, Adam Frost, and together with Adam Frost our lab and people in our lab have been able to I think make real progress in understanding the structure of those filaments. That's quite recent; we haven't yet published that. And it gives us at least ideas about how the noose might work.

Interviewer: I know Adam Frost has come up with these really cool visualization methods for these machines and cells. Have you been able to see a picture of this noose?

Dr. Sundquist: Yeah, we have at least what we think is the first picture of what it looks like. And I should say that we have a long-time collaboration with another structural biologist, Chris Hill, who is also in the Department of Biochemistry. And between the two of them they've given us a huge number of pictures of how the escort machinery works.

Interviewer: It sounds like cliche, but a picture is worth a thousand words, right?

Dr. Sundquist: It is.

Interviewer: But what can looking at a picture of that structure do for you?

Dr. Sundquist: Yes, I think if you view this in analogy let's say to a car, you have no idea of how an engine works until you look at an engine and see what it's parts look like and how they all fit together. And that still doesn't tell you how it works. But it means that now you have ways of thinking about it in concrete terms, what a piston might do, and so forth. So I'm a big believer in structural biology and other ways of actually seeing what things look like. I think that often gives you clues about how they work.

Interviewer: You seem to not be afraid to collaborate with people who do different types of research than you do. Would say that's a fair assessment?

Dr. Sundquist: I hope that's a fair assessment. I think that one of the really fun aspects of science is that you have interesting bright people who are doing different but complementary kinds of things, and some of the most exciting science gets done when they get together.

Announcer: Interesting, informative, and all in the name of better health.