COVID Webinar Series: Transcript of session with Nevan Krogan, PhD

Nevan Krogan, PhD, Director, Quantitative Biosciences Institute at University of California, San Francisco; Senior Director, Gladstone Institute; Adjunct faculty, Buck Institute
Recorded Wednesday, May 6th
His session is available for viewing online.  This is a transcript of the Q & A:

KRIS REBILLOT: You’re not so focused on the virus, you’re focused on us.  What is the advantage of that approach?

NEVAN KROGAN: Yeah, hi. Thank you, Kris. It’s a pleasure to be here. Thanks for the invitation.

So as you rightly state, our focus is on the host. This is actually something that we’ve been pushing for some time now, in terms of a strategy to help fight infectious disease. So there’s a lot of groups out there that are trying to target the virus, viral proteins, themselves, which is, obviously, a great strategy. You know, our approach is different. We’re trying to identify the human proteins that the virus needs to infect us and then let’s pharmacologically target those human proteins. And there’s advantages to that strategy.

One, you know, we don’t mutate as fast as viruses. So one of the issues about having drugs that target viruses is that you get mutations, and then you get resistance, and, if you remember, the big breakthrough for HIV was actually a cocktail of three drugs that targeted three different viral proteins, and, therefore, that cocktail of three drugs was what actually overcame the resistance issue. Okay, so that’s one plus, I would say, for host-directed therapy.

Secondarily, we and others have shown that viruses, even very distinct viruses, are targeting similar human proteins. They’re hijacking and rewiring them during the course of infection. So the logic would be if you could actually have a host-directed therapy for COVID-19, it would be more easily brought to bear for COVID-22, COVID-24, or even other viruses that we’re trying to combat, as well.

Obviously, there’s downsides for host-directed therapy, and one of those is toxicity. However, in our approach we’re initially focusing on FDA-approved drugs, and a lot of compounds in clinical trials that have already passed toxicity issues. 

All right so that’s our approach. And going forward, just like you saw with HIV, there may be a cocktail approach that’s most successful, maybe an antiviral like Remdesivir, combined with, you know, a host-directed drug or compound will, ultimately, be a great therapy in the future, of course, more work is required to determine if that’s the case.

KRIS: There’s some indications that the virus might be mutating and that there could be a more virulent form of the virus out there. Can you comment on that?

NEVAN:  Yeah. I mean, is… this information has been available, I guess, now, for a couple of months. I think it’s a paper describing a mutation in one of the coronavirus proteins in spike. And, you know, the question is, is that correlated with higher virulence? If there was an antibody against the original spike protein, would that antibody then also work on this mutated spike protein? The paper in question is actually getting a lot of press. However, to my understanding, it’s a primarily computational paper, and it’s just… there’s a number of hypotheses, very interesting hypotheses, but I think more data, much more data is needed to determine if this mutation is causing more problems, and if people have antibodies against the original spike, would it work on this mutated spike? So it’s an interesting set of hypotheses, but more data is required to really test those hypotheses properly.

KRIS:  So there’s no need for anybody to freak-out about this.

NEVAN:  Well, I guess everyone is freaking out already, so I would say, you know, let’s not get… let’s not freak-out even more. I think this is an example of maybe the press latching onto something and maybe pushing it further than it should be pushed. But that’s not to say these hypotheses, they could be real, but, again, more data is required to actually prove it.

KRIS:  What are protein translation inhibitors, and how might a cancer drug work in this case?

NEVAN:  Well, so there are a number of anticancer drugs that are out there that target the translational machinery. This is proteins in our cells that are needed to make other proteins, and this is, obviously, a set of proteins that the virus heavily relies on in order to make its own proteins. And in our map, we actually had identified a couple of key translational… or set of translational proteins that we thought the virus could potentially need, and we identified a couple of drugs and compounds that target those specific proteins.

One of them we actually found a connection with this one translational factor that interacts with another one that there is a compound that’s targeting it. This is called Zotatifin and it was from the company, eFFECTOR. This is cofounded by a couple of UCSF scientists, Davide Ruggero and Kevan Shokat. And we showed that it does, actually… and this is in a laboratory setting, has a potent antiviral activity. This is a drug that’s now being used in a clinical trial for multiple myeloma. So we’re very excited about that. The company, eFFECTOR, is now looking to get this quickly into a clinical trial for COVID-19.

And another protein, or… it was a translational protein that had… was known to... a drug or compound to target it was worked on from Jack Taunton. Tinactin 4 is a compound that he had synthesized and it targets the one protein eIF1A, and there’s known that there’s an FDA-approved drug structurally distinct from Tinactin 4 that targets the same protein. And this is from a Spanish company, it’s called Plitidepsin and they’re actually have already started a clinical trial using this particular drug for COVID-19.

So these are very potent molecules targeting key proteins in our cells. Toxicity is a concern, but for both of these, they’ve actually both past toxicity tests and we’re very excited to see if they have any effect on COVID-19.

KRIS:  When our cells are infected with COVID-19 what happens inside the cells?

NEVAN:  So the virus, itself, is comprised of protein in RNA, okay? And it injects its RNA into our cells during the course of infection, and it forces our machinery to make about 30 different proteins. You know, there’s only 30 proteins, or probably less, associated with the virus, and there’s over 20,000 potential proteins in each one of our cells. So the virus cannot exist by itself. It can’t live. It needs our cells, our genes, our proteins, in order to live and replicate and infect our cells. So the way it does that is it hijacks and rewires our machinery, our proteins.

So this was really the focus of the study, is, ‘Well, let’s try to systematically understand all the human proteins that the viral protein needs in order to make more proteins and replicate so that it can infect other cells.’ And during this process, as you alluded to earlier, we identified over 300 human proteins that we think are highly enriched for the virus needing in order to infect our cells. And then we looked at those to try to find drugs or compounds that would target those human proteins in a repurposing effort to see if they would have any antiviral activity.

KRIS:  And the cancer drugs, they act on the actual replication of the virus? I mean, they might block that replication that’s happening?

NEVAN:  It’s not blocking the entry. So it’s blocking the ability of the virus to make its own proteins.

KRIS:  Got it.

NEVAN:  You can think of that as the replication process, if you will.

KRIS:  The other category of drugs that your team identified are drugs that modulate proteins inside the cell, known as Sigma 1 and Sigma 2. Talk about some of the drugs that look promising in that category.

NEVAN:  So… right. So we’re very excited about this second category, and, as you say, we’re looking at two receptors, Sigma R1 and Sigma R2, both of which came out of the protein-protein interaction map, as well. One interacted with Nsp6, one of the coronavirus proteins, and another one interacted with another coronavirus protein, Orf9c. They’re actually two sequenced-distinct proteins, but pharmacologically they’re actually similar because similar sets of drugs and compounds are known to bind to and target both of these protein.

So we uncovered these and working closely with Brian Shoichet, who is an expert on receptor biology, and he does a lot of chemo informatics and makes predictions about drugs and compounds that bind to proteins, in particular, receptors, so he’s a perfect collaborator in this regard, and he identified a number of drugs and compounds that were known or thought to bind to Sigma R1 and/or Sigma R2. And when we first looked at this… and, you know, we had reported 69 drugs and compounds, four of which we thought would target Sigma R1 and R2, including… actually, hydroxychloroquine was one, haloperidol, an antipsychotic, and then two other preclinical compounds, and all of them had antiviral effects, which was exciting, and then that allowed Brian to augment the search. Then we included a clemastine, for example, there’s antihistamines, other antipsychotics, which we’re very excited about, also cough suppressants, and the female hormone, progesterone, as well.

So we’ve identified actually a set of drugs or compounds that are related but not at the chemical structure level. If you just look chemically at these, you would say this is not the same set of drugs. But if you know what the target is, and we think we do, and that being Sigma R1 and R2, that’s how you make the connection. And, to me, this is why it’s so exciting to start with the biology, then you go to the chemistry or the pharmacology, and then if you have something you can go back to the biology. And that way you’re so many steps forward than if you’re just randomly screening large libraries of drugs or compounds.

KRIS:  I’m assuming you’re not suggesting that anybody run out and start taking these drugs?

NEVAN:  No, no, absolutely not. I mean, for us, it’s kind of like a confirmation that these are receptors that are important. And, you know, keep in mind, obviously, this is just… they’re just in laboratory setting, in cells, in monkey cells, African green monkey cells, so a lot more work is required. A lot more data needs to be collected to see if any of these drugs or these compounds would have any effect in humans. But I think we’re on a particular area that shows a lot of promise, and Brian and the team are working very hard to identify new drugs that we’re testing and essentially getting data every day on.

KRIS:  I talked to John Newman on Monday. He asked me when I talked to you to just emphasize that antipsychotics and antihistamines are not good for older adults.

NEVAN:  Well, what I say is that they’re not good for anybody at high doses, anyway. So, I mean there’s problems across the board with that.

KRIS:  Talk about the cough suppressant that you looked at that looks like it could boost infection.

NEVAN:  So the drugs and compounds I alluded to with respect to binding Sigma R1 and R2 are, for the most part, classified as antagonists, in that they’re binding to these receptors and turning down their functions. And so Brian, one morning, told me, ‘All right, you know, if this… if these are the right receptors if we add an agonist, which turns up the function, we should see an increase of infection.’ And so that was a prediction he had made. And there was an agonist here for these receptors, dextromethorphan, and, sure enough, in the laboratory setting, it did increase infection. So for us it was really exciting from a scientific and biological point of view because it’s really helped us narrow in on we really think these are some key receptors for the virus.

But, of course, there’s other implications here with dextromethorphan. This is a compound of pretty much every cough suppressant that’s out there in the market right now. And, obviously, that’s very ironic because, you know, coughing is one of the major symptoms for COVID-19. But, again, just like we talked about before with these other drugs, you know, we’re not saying that this drug is going to increase infection in people, however, we just wanted to responsibly report this information and… with a strong caveat that, look, we’re just seeing this in a laboratory setting, obviously, and more data needs to be collected, not just in the laboratory setting, but in people, in humans, as well. But we felt the need to try to, as responsibly as possible, report this, I think, very interesting connection to the public.

KRIS:  Hydroxychloroquine got a lot of attention in the media. What’s the status with that drug?

NEVAN:  Well, we didn’t want to look at it. The data told us to look at it. So this is really data-driven drug discovery. So, you know, as I said, we generated this map of 300 human proteins, narrowed… and unbiasedly made predictions about drugs and compounds, narrowed it down to 69, and, sure enough, one of the 69 was hydroxychloroquine, which... again, we weren’t looking for that. That’s what the data told us to look at. As I said, it predicted to bind to Sigma R1 and R2. And, sure enough, it actually has fairly good antiviral activity in the laboratory setting. But it’s a very dirty drug, in that it hits multiple receptors, and in the collaboration with Brian Roth at the University of North Carolina, who is one of at the best business that studying these receptors, he did some very interesting in vitro analysis for us comparing the affinity of hydroxychloroquine, its binding to Sigma R1 and R2, compared to hERG, the receptor for the heart. If you remember, there’s a lot of hydroxychloroquine clinical trials ongoing, including one that was in Brazil, which was a very big one. It was stopped, because mostly for cardiac toxicity issues, problems with the heart. Well, the data that Brian generated for us nicely showed, again, in an in vitro setting that hydroxychloroquine binds much more tightly to the hERG receptor that’s associated with the heart cells than with Sigma R1, compared to a lot of the other drugs and compounds that we have uncovered.

Okay, so our prediction, at least in the laboratory setting, is that some of these other drugs and compounds would not have that same cardiotoxicity issues if it was introduced into the people.  There may be other issues, there may be other toxicity issues we’re just not aware of, but at least with respect to the cardiotoxicity, we don’t think we would see an issue there. So we’ve generated some molecular data that, I think, helps support why hydroxychloroquine would may not be the best drug for COVID-19.

KRIS:  You found another drug that looks much more potent than that drug, right?

NEVAN:  We found… it’s actually a compound, it’s a preclinical compound called PB28. It was originally synthesized and studied in the 90s. I think it was going to be… it was being looked at as a potential antipsychotic compound. And in the laboratory setting, it’s actually 20 times more potent than hydroxychloroquine, with respect to its antiviral activity. And as I said before, it’s not binding as tightly to the hERG receptor associated with the heart. It has a much higher affinity for Sigma R1 and Sigma R2 compared to hERG. However, this is not an FDA-approved drug. We’re actually looking now to get this into mammalian models to look at its antiviral effects and potential toxicity. But it’s super exciting, because we’ve identified classic compounds and it’s their proposed targets, so now people like Brian can look at this and can start to identify many more compounds and drugs. We’ve actually got several new FDA-approved drugs in this category that we’ve been testing, and they look even potentially stronger than this one preclinical compound with respect to having antiviral activity. So we’re really excited that we’ve identified this set of drugs and compounds. And although this one will take a long time to get into people, there will be… there’s some other ones that are already in people that we think will be just as good as this preclinical compound, and we’re very excited about that.

KRIS:  What is the state of the research?

NEVAN:  Well, we have, you know, obviously, generated this map looking at, you know, SARS 2 in one cell type. We’ve made predictions about drugs and compounds. We’ve been collaborating with scientists in two different continents, two fantastic virological institutes, the Department of Microbiology at Mount Sinai, in New York, and the Institute Pasteur, in Paris. There’s some great work going on now in San Francisco to get the virus up and going, including, you know, Melanie Ott at the Gladstone Institute, who is also an adjunct faculty at the Buck Institute. I think she’s got this up and running. We’re going to be working with her to test some of these. But out of the 69 drugs, we actually only really look closely at 47, only two-thirds of them. So we’re continuing to screen the other third and when we get hits, then we can open up chemical space to look at other drugs and compounds, like I had talked about before. There’s a lot of effort now to get some of these... especially, obviously, the FDA-approved drugs into clinical trials or these compounds that are already in clinical trials for cancer, like multiple myeloma, like these translation inhibitors that I talked about previously. So we’re focusing on how best to get these into people to see if they actually have anti-COVID-19 activity.

But then, I should say the map, itself, is spurning out a lot of hypothesis-driven research. We’ve actually started up this… it’s called QCRG, a QBI COVID-19 research group at UCSF. And, actually… and, also, at the Buck Institute it harbors Eric Verdin, as well, the President of the Buck Institute. And it started with 22 different labs and now it’s expanded to over 40 labs, essentially, encompassing hundreds of different scientists in each one if you look at the accumulation of all the people in the lab, and it’s gotten so big, we’ve got these different subgroups. We’ve got 10 different subgroups, focused on different technologies, like structural biology, or bioinformatics, and then specific biological areas, too, like translation and ubiquitination, and so forth.

So there’s a lot of work ongoing, you know, characterizing these interactions in a more deep fashion, trying to really mechanistically understand a lot of these potential connections that were uncovering. And, for me, this is a really unprecedented collaboration. I’ve never seen this many scientists come together and work together so closely on one particular problem. So, for me, that’s really exciting.

But then, also, to say, you know, we’re in the process of generating more maps. So we looked at SARS 2, we got SARS 1 genes cloned out, we want to do a comparison there.  We’re going to do MERS. We’re going to do another coronavirus that’s not as virulent, like OC43. We looked in one cell type. We want to look across other cell types, and then, also, in that cells, as well.

So there’s a lot of discovery research that still needs to be done, so that’s really exciting to me.

We got a lot of chemical biology approaches that need to be done in terms of trying to find best-of-class compounds in these different classes. And then there’s a lot of work trying to figure out how to translate these findings and more into the clinical world. All right? So there’s so much more work to do, so we’re going to, obviously, be kept busy for a long period of time.

KRIS:  What is the timeline for a drug being available?

NEVAN:  Yeah. So, obviously, these clinical trials take several months. I mean, I think we’ll see… I mean, the epidemiologists are predicting that we’re going to see a lull in infections in the summer, and then a spike in the fall. And this is what we saw with the 1918 flu epidemic, and I think there’s no reason to believe that that won’t happen in this case, as well. So, I mean, maybe best case scenario, six, seven months with some of these drugs. If the trials could get done, maybe they could be brought to bear to help in the fall, when the second wave of this pandemic hits.

So, you know, we’re trying to raise money to help push these things through. So there’s a lot of things connected here. Obviously, a lot of people have helped us. I got to mention one person, Ron Conway. He’s been a… I think he’s called the Father of the Silicon Valley. He’s been helping us raise funding, and he’s been a hero here helping us. So we have people helping us raise money to push the science forward. But there’s still a lot of work to do, and probably the best case scenario is if one of these could be brought to bear maybe by the end of the year.

KRIS:  Could your work eventually validate or not validate the compounds that folks are told to take to boost their immune function?

NEVAN:  Well, I think, obviously, the stronger your immune system is, right, the more effective you will be at fighting off not just COVID-19, but other infectious agents. But my guess would be a lot of those would be, in that case, indirect effects of you fighting off infection. And what we’re trying to do is to get, using mechanistic approaches, data-driven approaches, trying to get right to the heart of the infection. And this is why we’re looking specifically at a human proteins, directly touching these viral proteins, and trying to then pharmacologically target those human proteins that are presumably much more direct than maybe some of these other connections.

So that’s the way we’re looking at it. We’re trying to get as mechanistic as possible, using biology, mechanistic biology to help drive our experiments. But, of course, there’s a lot of other approaches out there, and, you know, my gut feeling is probably some common corollary approach will be brought to bear on this, just like with HIV. You know, the cocktail of three different drugs at the end of the day. That was the big breakthrough. So one could envision maybe one host factor. And as we said, Remdesivir, combining that, or a couple of drugs targeting the virus, or a couple of drugs targeting host proteins, or some combination of that. So I’m hopeful that approach, which has worked in the past on other viruses, could be brought to bear here.

KRIS:  Do you have folks who are actually working on designing new drugs based on some of the findings that you’ve got?

NEVAN:  Absolutely. So, you know, Kevan Shokat is probably the best in the world at this, and he’s… you know, Brian Shoichet is getting involved, and we have other people at UCSF, like Matt Jacobson and Jack Taunton, and, you know, other people around the world, obviously. So once you have this chemical matter, and you know what the target is, that’s important, as well, you can be so much more powerful in terms of tinkering around with these drugs, studying how they interact with their specific targets. And then, in a reiterative way, you can design something that’s much more… that has a higher affinity, and, hopefully, is much more potent.

So that’s really the power, in my opinion, of the approach we’re taking, is it’s really data-driven and leveraging such great expertise that exists in the Bay area around chemical biology. We’ve got the best in the world and they’re all working together in a really exciting way, in my opinion.

KRIS:  Scientists are collaborating, they’re cooperating, they’re not competing, international boundaries don’t matter. How often are you on Zoom meetings with people from all over the place?

NEVAN:  Well, so one thing I’ll comment on, initially, is your point of collaboration, which I think… just like you, I think it’s been absolutely fantastic. And, you know, one of the problems in my mind with science is that it’s very siloed and very competitive, unnecessarily competitive, in my opinion. And it’s competitive because the structure is set up to really reward the individual. The one person gets the award, one person gets the grant, one person gets tenure. And this structure often discourages collaboration, especially for young scientists who have the best ideas or are the most enthusiastic. They become more protective because of the way their system is set up. But here what we’ve seen is these silos have really been broken down. And I think as a scientific community, not just with us but around the world, we see how fast science can actually move and, you know, breaking down silos across different laboratories, across different institutions. And then also between academia and pharmaceutical companies. We’ve seen this as well with us and with other groups. And, for me, this has been really the most exciting part of this.

And if you just think about it, you know, this is a virus we didn’t even know about really at Christmas and now here we are at the beginning of May, four months later saying, ‘All right, we cloned it, generated a map, made predictions about drugs and compounds. We got the virological assays up and running, we’ve tested these, we’ve got some chemical matter that we’re trying to get into humans now, in the matter of less than four months.’ And, to me, that’s unbelievable. And the question is why can’t we be doing this more often? And the challenge now is to sustain this infrastructure that’s in place by changing it, you know, changing the rules of the game, in many ways, hopefully, so that we’re in a much better position when COVID-22 or COVID-24 hits, or we just want to study another virus, or just study any other disease like breast cancer or Parkinson’s. Why aren’t we doing this, you know, studying all diseases?

So. for me, this has been a real silver lining here, is really seeing how fast science can move. And I would say that the Quantitative Biosciences Institute, this is really what we’ve been about the last four years, is trying to break down these silos on so many levels. So. in that regard, I would argue we were in a perfect position to respond to this pandemic. We’ve been seeding these collaborations both in the Bay area and around the world, and with pharmaceutical companies. So we were in a really great position to act on this particular pandemic.

And to your… last part of your question about Zoom, yeah, I mean, it’s… you know, there’s been some meetings where we’ve had several hundred people on Zoom. That just becomes unwieldy. It’s kind of cool to see with respect to this QCRG, but now we’ve got these 10 different subgroups, so that now they each have like 50 or, you know, 60 scientists associated with each subgroup. And, you know, the question is when the dust settles on COVID-19, are we going… how much more are we going to be doing Zoom? You know, I did a thesis exam two days ago in San Diego. I was the external examiner and it, you know, took an hour and a half and then I was done, and that basically saved me a day and a half of travel. So the question is how much Zoom are we going to be doing in the future? Probably a lot more than we’ve been doing in the past.

KRIS:  What happens metabolically during an infection?

NEVAN:  Well, one of the subgroups associated with QCRG is this aging metabolism group, like you say, and that’s being run by Eric and also Natalia Jura at UCSF. And, you know, obviously, metabolism is a key process that’s being perturbed in the context of infection and is also… I think the virus is more actively hijacking it, as well, for its own benefit. And that’s, I think, nicely reflected in the protein-protein interaction map that we had generated. There’s several metabolism enzymes in there that look incredibly exciting, many of which are connecting to aging. There’s a lot of things, obviously, connected to aging. And there’s some enzymes in there that Eric has worked on… I think he’s discovered some of these, you know, many, many years ago. He doesn’t look that old, but he’s been around a long time, and he’s discovered a lot of these enzymes, and he’s in the perfect position to characterize these. And it’s been a great pleasure interacting with Eric and a number of scientists at the Buck Institute. And, again, it’s a testament to, you know, the collaborative relationships that have been formed, you know, in the Bay area around this. And the challenge now is to keep the momentum going, not just on COVID-19 but other diseases, as well.

KRIS:  Would your approach be useful in the future for looking at antibodies to infections?

NEVAN:  Well, there is a lot of efforts to get antibodies, not just for testing, but for treatment. And in the context of the QCRG, there’s a lot of effort around that, a lot of work being done by Jim Wells and Charlie Craik and others trying to get at these antibodies, as I said, for diagnostic purposes and hopefully longer-term treatment purposes. But if…  again, back to this idea of understanding… the more you understand about the biology of the virus, the more powerful you are with respect to treatments, therapeutics, and diagnostics. So if there’s a potential viral protein associated with the human protein, having an antibody that would recognize both in the future could be much more powerful. So, again, it’s this idea of the more biology you know, the more powerful you are going forward. And that’s really the message of, you know, all discovery research, in my opinion, and how you can translate it into something therapeutic.

KRIS:  Were you surprised at the hits that you got? Cancer drugs, antihistamines, progesterone, it’s like they’re all over the map.

NEVAN:  So we’ve generated a number of maps in the past targeting many other viruses, including HIV, and dengue, and Ebola, and Zika, hepatitis C, influenza, and it’s really cool to look at the biology that comes out of these maps, in general, right? Because these viruses, you know, they rely on our machinery, as we talked about before, and they’re going to be targeting key nodes, and key proteins, and key complexes, and, essentially, a lot of major biological processes in our cell. It’s this virus, this SARS 2, in terms of the richness of the map, I haven’t seen anything like it. And, to me, it’s actually quite exciting. It’s really getting its fingers in a lot of different areas of biology of our cell in a way that I’ve never seen before as we looked across, you know, I don’t know, 20 other viruses using this particular approach. So in that regard, you know, it’s not such a big surprise that we’re… you know, since it’s across many different areas of biology, we’re getting a lot of different drugs and compounds encompassing that wide breadth of biology.

But what I’d also just say, too, and we’ve reported on this in the past, is you see these commonalities as you go across different viruses. You see the same proteins being hijacked and rewired as you go across, you know, RNA viruses, DNA viruses, lentiviruses. But if you take a bigger step back, you know, we’re also using these approaches on a variety of other diseases, like cancer, and neurodegenerative disease, and heart disease. You actually see amazing commonality there, as well. It’s the same genes being hijacked by HIV that are being mutated in cancer. It’s the same genes being mutated in Parkinson’s that are being hijacked by Zika. And, to me, that makes sense. You got these Achilles heels of the cell. They become mutated and they result in disease X, Y or Z, or a virus has evolved to attack these, and that, ultimately, results in disease. And why don’t we see this, it’s comes back to this problem of science, is that we’re too siloed, is that people just focus on their one disease and they can’t recognize these commonalities. Well, our approach allows us to scan across these diseases and find these commonalities. So then it’s not such a big surprise in my mind, well, an anticancer drug would actually could be used to fight a virus or vice versa. Maybe there’s an antiviral out there that could be helped to fight cancer. So if you just think about it from a biological point of view and you start to collect this data across these disease areas, to me, it actually makes sense how one drug or treatment for one disease could be brought to bear for another or vice versa.

KRIS:  Is your team looking at viral load, or is that going to be something for clinical trials?

NEVAN:  Well, we always try to get to the molecular mechanisms behind these phenomena, right? So, to me, it is really fascinating as you’re talking about why certain groups of individuals are seemingly very susceptible to this virus and others, there’s no symptoms of all, they’re completely asymptomatic. And probably the vast majority of people are going to fall in that latter category. So the questions are, well, what separates out these individuals? Clearly, there’s other health issues that contribute, but there’s a lot of just seemingly very healthy people, younger people that fall in other one or the other, and the question is why? Well, there’s a lot of genomic analysis being carried out right now, you know, sequencing analysis that’s being generated, and their signal that’s being looked at in the DNA. So people are looking for rare variants like mutations, if you will, in one group versus the other and identifying genes that could be contributing to the susceptibility of his resistance. And that’s the kind of information that we would love to have because that map would help us interpret that genomic data. You know, so if there’s a mutation in one of these host genes that the virus needs, we can then study it in a very detailed way biochemically, biophysically, and structurally, and really try to understand the underlying biology behind some of these molecular connections and what these particular variants are doing. And, in fact, this is what we’ve been doing in other infectious diseases like HIV. We generated this map with like HIV. Then we’ve looked for these people that are resistant to HIV, these highly false CR [?] negatives. This is a collaboration with a group in Chicago. They’ve identified several genes and variants in these individuals that then we go and study at the molecular level. So, really, the goal, in my mind, at least from our work, is to try to connect our data with the genomic information from people that are either being very resistant or very susceptible to the virus to get a better understanding of the underlying biology, which then, hopefully, would point in novel therapeutic directions in the future.

KRIS:  Personally, are you a germophobe or how do you approach everything that’s going on, on a personal basis?

NEVAN:  Well, yeah, I mean, as you point out, that isn’t my area of expertise. And, actually, as a… in the scientific community, we’re trying to learn about this virus. It’s like every day we learn something new. Me, personally, I mean, I have started to go back to work. There’s not a lot of people at work. There’s still a shutdown at UCSF, and only those that are focused on COVID-19 research are allowed in, and there’s a lot of social distancing rules in place, as they should be. But, you know, what concerns me the most is… you know, I hear people talk about this, even some of my friends that aren’t scientists, saying, ‘Well, I don’t know, maybe we can start to, you know, start up life again.’ And, to me, that kind of talk is very scary,  and that type of behavior will, ultimately, lead to a spike, and that spike could be even worse than what we’ve seen so far, at the end of the day. So, you know, I just… my gut feeling is, and there’s, obviously, better people to speak on this area, but my gut feeling is we need to be very vigilant here in the social distancing rules that are put into place, and I think we should still be hunkering down for a lot longer than some of these people are talking about.

KRIS:  It seems like testing is crucial to how we move through this thing.

NEVAN:  Yeah, I completely agree. We don’t have the testing capability to kind of reengage society, That’s what we need. And testing not just to say who have been infected, but then serological tests to say who has potentially been infected and who have recovered, right? So until we have that wider range of testing capabilities, I think it’s even more reason to stay shelter in place, at least in the short-term.

KRIS:  Are you working with biotech companies, big pharma? Can you talk about the positive fallout from what you’re doing and how other companies and organizations are picking up the work and carrying it forward?

NEVAN:  Sure. That’s been another really exciting aspect of what’s gone on over the last few months, not just with our work, but we see this with other people’s work around the world. And I alluded to some of these connections. So, for example, the company eFFECTOR, which has made this one anti-translation drug, which seemingly has strong antiviral activity in the laboratory, now they’re starting to push that compound into a clinical trial. It’s been great to interface with them.

The Spanish company which has Plitidepsin, which targets another translational factor, that’s going forward, and it’s great to be interfacing with them, as well. Also, with the pharmaceutical company Roche, we had actually been working with them over the last couple of years on a couple of other respiratory viruses, and we’re interfacing with them right now. They’re providing some funding for us to do work around this idea of coming up with host-directed therapies, and now we’re in close talks with them to see if they can help us translate some of our findings into the clinical setting.

And, also, I’d just like to say, you know, other companies, smaller companies, a lot of them in the Bay Area have approached us and have offered to generate reagents for us, to give us reagents free to see how they can help out. And there’s been really a lot of generous behavior from, you know, small-, medium-sized companies, you know, not just in the Bay Area but around the world, trying to help us out and help other academic groups out, as well. And, as I said before, the goal is to keep these bridges strong across the academia and companies, large and small, not just for the foreseeable future to fight COVID-19, but, hopefully, these are bridges that’ll stay in place as we tackle other diseases in the future. Because it’s… both sides have so much to bring to the table, and if you can put this together, we’re so much better off, I would argue.

KRIS:  Future pandemics? Do we need to get to the source of what’s causing these viruses to show up in humans anyway?

NEVAN:  Yeah, I completely agree. And it’s, actually, if you think about it, it’s not that big of a surprise we’re dealing with COVID-19. If you look at SARS 1, that was back in, what, 2002, 2003, you know, that had a higher mortality rate, but it wasn’t as infectious, and that got under control, which was, obviously, great. And then there was MERS, another coronavirus, that was in 2012, again, even a higher mortality rate than SARS 1, but, again, not as infectious as SARS 2, and that was contained. And that… the idea there was it went from a bat to a camel and to humans. And now, you know, a few years later, we’re dealing with another coronavirus, and I think the logic there was a bat to human or a bat to a pangolin to a human.

So I couldn’t agree more. You know, studying what could be the next pandemic, going to these different animals to study them. You know, one of the best in the world at studying zoonosis at a molecular level, at least, is Harmit Malik at the Hutch in Seattle, and we’re working very closely with him. He’s making some predictions about viruses that are presently in bats and pointing us in that direction in terms of generating some, you know, molecular maps based on those viruses.

But that also has to come from funding agencies. You know, so I think the most… one of the most powerful ways to study viruses is to study them in an evolutionary way. And, you know, we’ve worked on HIV for years and we… in humans, obviously, but we really wanted to extend that to SIV in primates, and then, you know, there’s FIV, feline, there’s MMV in sheep. We tried to get money from that from NIH. They said, ‘No, you should only study HIV in humans. There’s no point in studying these other virus in other species,’ which I couldn’t believe they said this. So I think that the funding agencies have to have more of an open mind to provide funding for us to study in these other species because this is how these viruses are coming to us through these other species. So let’s try to understand at the molecular level what’s happening with these viruses in these other species, and then that will give us a better idea of when something is going to jump, and then, hopefully, it will point to more powerful ways for… to come up with therapeutics or diagnostics. So I couldn’t agree more. We need more funding to study these viruses and be more predictive of when the next one is going to jump to us.

KRIS:  Do you think it will be a combination of vaccine and treatments?  What do you think this is going to look like once we get a handle on what to do with this virus?

NEVAN:  Well, on one hand, like I pray there’s a vaccine as soon as possible. And then you think, well, there’s a lot of viruses out there where a lot of people have spent effort trying to get vaccines and they haven’t for, you know, viruses that have been around for decades. But then, on the other hand, you’ve… you know, I don’t think you’ve ever seen a situation where so many scientists and great minds are really solely focused on trying to solve this problem, especially in the context of a vaccine. So I just don’t know. I really hope something… you know, something does come up with respect to a vaccine, but you just don’t know.

That’s why you got to be pushing on all fronts, right? So, therapeutically, obviously, we’re focused more on drugs and the pharmacological approach. There’s also a lot of work with respect to identifying antibodies that could be used therapeutically. So I think we need to push as hard as we can on all fronts, and, you know, as you said, and as I talked about previous, at the end of the day, it’s probably going to be a mixture of approaches that will be brought to bear to help out here. So… and it could be, you know, with respect to therapeutic approaches, maybe a drug and an antibody or something, or, as you say, maybe there will be a vaccine for a certain subgroup and there’ll be a therapeutic for another subgroup of individuals that may be… that are older or don’t respond to the vaccine. So that’s why it’s so important to keep pushing on the research on all fronts, because you don’t know what’s going to break out and be the most useful.

KRIS:  Is your research going explain the other effects, like thrombosis, blood clotting, impact the central nervous system?

NEVAN:  Yeah, absolutely, that’s the vision here. And, as you point out, this is a virus, the likes of which we’ve never seen before. And I was actually just talking this morning to Adolfo Garcia-Sastre, one of the best virologists in the world, in New York, and he was just lamenting the fact that this manifests itself in so many different ways, in ways we probably don’t even understand yet, you know, as we do some of these retrospective analyses. So I think it’s going to be so important to study at a molecular level what this virus is doing, from different tissues from different organs, and, you know, why… and then combine that with genomic data from the individuals. You know, why with some people are they going to have certain symptoms and other people will have other symptoms, looking the same age, and similarly….. similar health situation. So I think the more molecular data we can collect around these issues, the better understanding we’ll have, and then the more predictive we’ll be going forward.

KRIS:  Is there anything that I haven’t asked you that you think it’s important for people to know?

NEVAN:  Well, let’s see, we kind of touched upon this with respect to funding. You know, we’re always struggling to find funding, either through federal means or through philanthropic avenues, and it’s just… it’s so important, especially in times like this to have flexible funding, because none of us have grants on COVID-19 because it takes, you know, months, if not years, to get grants in. And we’ve all shifted our focus, or a lot of us have shifted our focus to study COVID-19. So we need to increase funding across the board in every way possible for discovery research. So that’s one thing… so we’re in a better position in the future to tackle the next pandemic.

And then, as we talked about before, I think it’s, you know, very near and dear to my heart, is how do we keep this collaborative infrastructure in place so that science can move this fast in the future? And it really, again, comes down to breaking down these silos, making these connections, maybe reconfiguring the reward system that we’re all dealing with on multiple different levels, so that we can, you know, have this new way of doing science, this new paradigm, set up more effectively in the future. And that’s connected to funding, as well, obviously, so it’s all connected. But I’ve just been so really delighted to see how people have been working together, and the challenge now is to keep that excitement and that level of collaboration going forward for the next several decades.

KRIS:  Thank you for being with us.

NEVAN:  Thank you very much, Kris, for the discussion. It was a pleasure to be here.