Davey Smith of the University of California San Diego: The Future of Clinical Medicine

Startups get the party. Startups get the party started. Startups get the party. Startups get the party started. You want tech and tacos? Tacos and tech you know we got tacos and tech is on smash border green guacamole keeper captains counting beans Contador quentan frijoles found us trying to raise some queso la vida San Diego school of rappy rapping fire tortillas round jalapenos in these modern times a crappy and coffee my coding yoga posse fold the body origami we be surfing coronado eating tacos el gordo the tacos standing puesto lucha libre and sombrero Got a shout out to cost angels by the ocean watch the sunset la Jolla shores Entrepreneurs trying to get funded When San Diego Startup Week is popping in the summer Oceanside, the Tijuana estee be full of hustlers from couch surfing to penthouses right on the beach Tech leaders believe stars are within reach we interview and founders who be shooting for the moon SD Tecos with your host, Neil Bloom. Startups get the party. Startups get the party started. Startups get the party. Startups get the party started.

Welcome to the Tacos and Tech Podcast. I'm your host, Neil Bloom, and I'm thrilled to have you here. On the Tacos and Tech Podcast, we interview builders of technologies, of companies, of communities, and we do it weekly, so thanks for tuning in. Every Tuesday, a new interview, and on Fridays, we talk about what's new in the San Diego tech ecosystem from a news perspective. So make sure you join us there as well, too. We also have a tech newsletter that comes out every other week@freshbroodtech.com you can subscribe to listen to it without further ado. Enjoy this episode and welcome back to the Tacos and Tech Podcast. I'm your host, Neal Bloom, and today I am joined by Dr. Davey Smith, the head of infectious diseases at UC San Diego. Hey, Dr. Smith, thanks for joining us.

Hey, thanks for having me.

It's a real pleasure. I'm really glad we got connected through Daniel. I'd love to hear a little bit, you know, quick little overview of what your focus is right now.

Yeah, so I'm an infectious disease doctor and researcher and work here at UC San Diego. And during the time of COVID which was horrible for all of us, I was really trying to figure out how to find new therapies, and that's how I got connected with model medicines.

Awesome. Well, we've known the model team maybe since the beginning. Daniel's been on the podcast in a prior role as purely investor. And so it's been really cool to see, you know, him step into an entre, a new entrepreneurial role as well as obviously to see just San Diego being one of the centers of obviously this kind of research, especially infectious disease. So really excited to talk about, I mean, excited in, in a way to talk about how crazy your life was over the last three years. As. As excited as we can be because. But obviously that, that pointed you forward towards some new solutions with modular medicine and few others. But where did it all start? Because obviously we didn't know about COVID 19 way back in the day. We knew about some other Covid, but how did you end up down this path towards infectious diseases?

Yeah, so I always liked infectious diseases, but growing up as a gay man in the 1990s and then going to medical school and seeing just the devastation that happened with hiv, I was like, ah, I think I can make an impact there. So that's what drew me to it. And then when a new pandemic hit at the end of 2019, I was already doing research in viruses and I was tapped by Operation Warp Speed to help try to find therapies for people who were not yet hospitalized. So that's how I got involved.

Oh, interesting. So was there taking it back a little bit more, you know, was Operation Warp Speed, was that a model of some of another. Something else that's been used to attack prior diseases? Was there anything like that for HIV or prior infectious diseases of that effort?

Yeah, that's a good question. Sort of the reason that I got tapped was because I was working in a group called AIDS Clinical Trial Group actg and that is a group of researchers all across the world actually that do clinical trials try to find new therapies and cures for hiv. So we already had this infrastructure up and ready. And then when Covid hit, I approached them and said, hey, we need to jump into this pandemic. We already have the infrastructure and we know how to deal with people who have infections and we know how to make therapies, et cetera. So let's just do that. And that's how I got started.

Got it. Interesting. And does UC San Diego have a history of just having a center of excellence for infectious diseases? Is that how you ended up at ucsd?

Yeah, that's one of our shticks. Super proud of UCSD around this area. But in particular we were the very first AIDS clinical trial group site. We have tested every single HIV drug that has Ever been used, and that is currently being used has found its way through testing at ucsd.

Wow, I had no idea. Other infectious diseases besides HIV that are.

Focused, influenza, strep, staph, etc. We really have been one of the world leaders in infectious disease research for decades.

Interesting. Even more historical question, does this take us back even further from the polio times as well too? Do you know, is there like a even longer legacy of working on, on drugs here like that?

Well, I mean, soc is big in polio, of course, so we've also have a lot of connections with a lot of the other institutions that are around. But yeah, ever since the beginning of ucsd, we've been focused on various infectious threats. Tb, polio, measles, herpes, viruses.

Wow. Okay, so Fast forward to 2019 a bit. How does it first come on your radar? Is it in the news, is it in papers, is it colleagues? Like, what's the first time that you're hearing about COVID 19?

Yeah, it's crazy. I was with my husband and my parents on a cruise to Australia. My dad always wanted to go to Australia and New Zealand, so we did that and we kept seeing it on the news that there was this outbreak in China and everybody's like, oh, it's just going to get stuck there. I'm like, no, it's a respiratory disease. We got to get home. This is going to hit. And so I got back and we set up infection control protocols here at ucsd. We started working on diagnostics and we were the first site for those quarantine passengers on a different cruise ship. Thank goodness mine didn't get it, but people got quarantined. I don't know, don't know if you remember, but they came to San Diego at Miramar and UCSD was helping with those infection control procedures.

Ah, yeah. I feel. Was that like January, February. I feel like it was that time frame, right?

I think it was late February or March. My brother actually, who's part of a disaster management team in Tennessee, I talked him into coming out. He's a pharmacist, so it was nice to see him, but it was a very scary time.

Yeah, nice to have a family all, all in on a worldwide disaster. So obviously everything from there realized, yes, UCYST is jumping in on what's locally available, but obviously a lot more needed to be developed. So how did Operation Warp Speed come together and how soon were you involved there?

From the, you know, actually in beginning of February, I contacted the NIH and said that they need to Quickly assess hydroxychloroquine. Either yes or no, because people were going to start using it and we needed to have a real answer. And to be honest, they said no, they didn't want to do it. And it took them months to get it back up and started. When they finally decided that, yeah, we needed to figure this out for real. And that was May. So I helped them do that. And then newer therapies were being developed, including some here in San Diego and including in my own lab, these monoclonal antibodies. And they needed to be tested very quickly like we did with the vaccine. So we were part of operation Warp Speed to do those tests.

Oh, wow. Okay. So model medicine actually exists before then, at what point did you get to know them And Daniel?

So while I was making. Trying to find new drugs. Everybody needs a new drug sometimes. And we were heavily hunting for the best thing that we could test for. COVID 19. They were introduced to me by a friend and colleague over at Scripps and said, hey, this group has is an AI company and they found a molecule that they think would work for Covid. Could you assess it? So that's how I got to that.

Okay, so this is post Covid outbreak already? Yeah, got it. Okay. And so they obviously did not start on a COVID 19 path, but we're pivoting towards the need. Were they already on that pivot Once you've met them?

They were already on the pivot like a lot of scientists, those at that time. And companies are like, oh, we have this technology, we have this platform. There's a worldwide disaster and pandemic going on. How can we help? So they turned their fancy AI machines and platform and said, okay, find a molecule that would perhaps treat COVID 19. And they did. They found a couple and then narrowed it down and then called me in to assess.

Okay, take us back a little bit around clinical work that you do versus maybe industry. Is it pretty typical that you're working with new startups and new drug development throughout your career as a physician, a clinician and physician?

Not as a clinician. I see patients in the hospital, I see patients in the clinic. But how I really get involved with new technology and companies is around my work as a scientist. So I'm a translational researcher. So I have a lab, but I also do clinical trials. We're really trying to move those discoveries that myself or others have into patients as quickly as possible to really make people healthier.

It makes sense. Absolutely. And you talked about, obviously, the clinical trial work for HIV drugs that have come through as well. What point did you kind of take a more active role of, you know, helping companies develop? Because it seems like you went a little upstream saying, let's get involved earlier to make sure that the things are coming through the clinic. You could have a hand in and control. Not control, but make sure that they maybe have higher potential of efficacy, if you will.

Yeah. What I saw mostly within Covid, but I had seen it before with HIV and other viruses, is that a lot of companies have a really whole bunch of really smart scientists, but they don't have clinicians oftentimes who can make that connection with this drug works really well in the lab. It works really well in mice, it works really well in monkeys. But we got to get it to humans. And how do we make that transition and how do we do that test that's safe and ethical? And also how do we talk to the FDA about these things? Big companies, of course, have people like. Lots of people like me there, but small companies who have really good ideas and really good products don't have people like me. So that's where I come in to help.

Got it. Interesting. I mean, you think of San Diego, maybe it's just us as San Diegans, we think of like decades and decades of therapeutic research into a certain regard. And like you mentioned, big drug companies have this. It feels like, though, especially when you look at model medicine, it's a bit of a nascent, still startup scene. Is that how it feels like? It's still kind of a fledgling kind of startup environment, even at that therapeutic or therapeutic meets tech quarter.

You know, what I've seen with model medicines right now is that they have really good tech and they just need to get something over the finish line to really get to the next stage of their development. And they have a few molecules that are close to that. One is their drug for Covid. And we can talk a little bit more about that because it's a really special drug, in my opinion. So Covid is. I'm going to get a little bit in the weeds and happy to redirect if you want, but it's a RNA type virus, but there's lots of RNA viruses that cause respiratory infections, influenza, rsv, Covid, all hit us really hard. And those are all RNA viruses. Well, the molecule that Model Medicines has developed can basically should be able to treat all three of those from what we're seeing in our preclinical studies. And that's a real game changer. If I put my clinician Hat on and somebody comes in with cough, shortness of breath and a headache, sore throat, flu. Looks the same as Covid, same as rsv. I'm sitting there as a doc. Okay, here, take this medicine. We'll do a test but here, start this medicine right now and then we'll figure it out. Really does change the paradigm of how we do clinical medicine. So that's gets me very excited about model medicine drugs. But they've also used their platform for finding a few molecule molecules for cancer which is also a problem. It should also be fixed. So I'm pretty excited about this platform that the model medicines has.

Yeah, obviously we all, everyone wants that outcome and there's a lot of companies in San Diego solving going after a lot of different areas. This cancer specifically. Obviously a lot of different ways people are going about it. We've got the density of genomics as well, which has given us a whole new set of tools. Right. In that regard, can you take us through a little bit more of the technology I guess that model medicines focus on and just how it is able to apply to so many areas?

Yeah, so there, you know, Everybody's focused on ChatGPT now, but AI has been steadily getting better and they have an AI platform where they take a whole bunch of, they take targets. So in this case they took targets for a particular enzyme that RNA viruses have and they make a library of those and they tell AI and say, okay, here is also a big database or library of molecules and we want you to pair up those molecules that you think that can inhibit that particular protein or that enzyme and come up with hits for that. Well, it's amazing, but AI can sort through all that noise to really find the molecules that hit it the best. And that's in a nutshell what their platform does.

Wow, really cool. Okay, so I can understand how you feed it to certain libraries. So is it really, I mean is it really. When we're talking about the tech piece, is it really code based databases or is this libraries of chemicals that are being tested or molecules that are being testing and really take us through that piece especially for more the tech software side listener.

Well, I'm not a tech guy, but from what I can, what I understand is that there are these large molecules and they're, that they're testing and then there's this large target database. So it's not just one protein that they're specifically looking at. With viruses there is, these proteins look similar but not exactly the same and they can feed all of that and their platform at model medicines can handle that complexity of data. And what's interesting, with at least this first group of molecules that they're looking at, it has a new mechanism of action. People have inhibited this protein before in different ways, but it's never been able to broadly across all classes of viruses. But this AI has figured out a molecule anyway that looks to be very broad acting so it can hit multiple viral proteins at the same time.

Okay, got it. And so what's your involvement day to day like right now?

So now that we have the molecule that we're interested in, we need to do a bunch of preclinical testing and have done that. So we take it to the lab and we show that it works in one virus, we show it looks in another virus, we show that it works in a mouse that has influenza or Covid. And then we then getting prepared to get enough data to be able to go to the FDA and say let's do a clinical trial. And a lot of that is me talking to potential investors to get it to the next stage to where we can do that big clinical trial.

Oh wow, that's really involved in a lot of the areas there. How's that going? Talking to investors is first time working on that piece of it, I'm guessing.

I've worked before with some companies, you know, basically I'm a translator and just talk about what the clinical science shows, what I think is the potential here in different areas. It's always fun. I actually love talking to people and just talking about the science. That's fun. If there's a lot of skepticism that's not really rooted in facts or the data. And we can see that sometimes with investors, but that's okay. That just means it's not a good fit. But I really like it when they get inspired by new technology and have those discussions.

Okay. I mean, you kind of touched a little bit on the politicalness of COVID 19, which we've seen a lot of compared to the science. So that's gotta be pretty noisy, especially when you're out there trying to treat and now try to obviously find cures for that. You mentioned obviously the noise that is around COVID 19. Right. There's political noise and skepticism around that. Maybe the more elephant in the room question is, do we still need to cure COVID 19 right now? If three years later, what's the work that's being done for it?

This regard, Covid is still a thing, despite all of us being tired of it, including myself. New variants are popping up every Day we just had a horrendous winter that was not just COVID 19, but influenza and RSV and that triple demic as they are calling. It was hard in the hospital and it was hard to see in patients. And we're probably going to have more of that now that we have three circulating respiratory viruses. And with the new variants, COVID 19 is going to be with me for the rest of my career. And as we all get older, we're going to become more susceptible, so new treatments will be needed. Thank goodness that we had monoclonal antibodies. When we did, the variants knocked those out. We now have other medications like Paxlovid and Valkyrie also have some resistance problems and not the best tolerated, but thank goodness that they're there. I kind of view this as what happened with hiv. When I was an intern, HIV medicines came out as the cocktail and I saw these patients get. They were on their deathbeds in the hospital and they just walked out. That was the first miracle in my life and I said, I want to be part of that. That is exactly what I want to do with my career. And that was amazing. But those medications, despite them saving so many lives, were horrible. They were horrible to take. They were just all the time, they were just not the greatest. And if you ask my dad about the current medications for Covid, you know, bitter taste, diarrhea, then there's these rebound issues, all that sort of stuff. Yeah, we're just in the basically the first second generation of COVID drugs and we need to do the same thing that we did for hiv. We have one pill once a day that patients can take and be fine. And now we even have long acting injectables where people can take it one shot and be done with taking medicines for three to four months and it's only going to get better. So we need to do the same thing with COVID and just get the next generation of drugs, the next generation of drugs and really tackle other respiratory viruses that really haven't been on a lot of the treatment paradigm.

So interesting. I really appreciate that. Do you think it's a technology has enabled us to speed up development here or, and, or is it also just like the warp speed mentality of through everything we got at it? Is it a bit of both?

A little bit of both. But let's just take HIV for example. So we found HIV in 1981 and the cocktails didn't really come out until 96. Right. So that's a long time. But people were working on this very hard to find HIV medications and save lives. Now we have a whole bunch. We've learned a lot about antiviral development during hiv and in fact, most of the COVID medications we have now was built directly on the back of what we learned with HIV and really made it possible so that we could find therapies within a couple of years of COVID coming out. We need to be better prepared. Don't get me wrong, we could have been and we should have been, and we should going forward, but that means investing in the science and the research to make these next generations of drugs, but also have the technology so that when whatever random virus comes out to try to kill us, so we can pivot very quickly to tackle it too.

Okay, where do you think you'll look back, I don't know how many years now? Three, five years. And look back at this time, do you think? Especially where you think the technology will have taken us by then?

Well, people will be better focused on viral threats, and I think that's a good thing. And I think that AI is changing the way we approach drug development. I know that a lot of the big companies haven't quite got on board with it yet. They still very much focused on one target, one drug per one virus, one drug per one target. But that's. I think that's outdated. And the new paradigm will be trying to find broadly acting antivirals and maybe even combination of antivirals. That's what we do for hiv, but that is not what we do for other things. And we really need to think about that hard.

Interesting. Where do you think? You mentioned big companies being slow. What about the fda, who obviously is the big hurdle we got to get over. Where do they stand, especially related to model medicine, where it's at in its development too?

They're all about trying to protect us and to keep us safe and really have really good safeguards. But the other good thing about the FDA is that they are bendable. We had emergency use authorization. Drugs come out relatively quickly. They made a few mistakes in hindsight, but at least they were flexible enough to start thinking about these things. And I have found them better to work with lately in terms of getting drugs through so flexible enough to at least talk to you to figure out what the plans are going forward. So model medicine has a plan for how this drug would be tested and it checks all the boxes with the fda. So I don't see a big problem. Problem. Once model medicine gets the money to be able to do their first in human studies, I should say that this molecule has been tested in humans and it's been shown to be safe. So it does help with a lot of the FDA regulatory stuff, but never within the context of COVID or any other respiratory infection. So that still needs to be done. But it offers a really nice opportunity because the FDA shouldn't have any problem with it because they didn't have any problem with it before. We just need to test it in these particular situations.

Got it. And so the FDA related to model medicine, the FDA is probably less concerned with the AI of how it figured out that this molecule works. It's just more that this is the molecule works in humans, right?

Yeah. The FDA doesn't care how you find it. It's just cares on how you're going to test it.

Okay. So it's not like you have to also prove a set of whole new AI to fda. Got it. So what's next for what are you spending your time on this year? Specifically to model medicine.

Yeah, for model. We want to get a paper out. I'm an academic, so I like papers. So I want to try to put a nice package together, show the proof of concept, show this new mechanism. I think that'll really move the field forward. And at the same time, I really want to launch a clinical trial looking at respiratory viruses. And basically there's a thing called a basket trial where you take people who have a collection of similar symptoms. So it can be any of those flu Covid or RSV or even other respiratory rhinoviruses or RNA viruses, and they come in with similar symptoms and everybody gets randomized to the drug or placebo, and then you see if it can fix RSV. You can see if it fixed COVID 19. So that sort of trial is very attractive. And the FDA also likes that because that is very clinically relevant. That's what a doctor would want to do in the emergency room or in the clinic.

Got it. And that trial would be in San Diego, most likely?

Well, it would have to be a big trial, so there would be San Diego sites, but, you know, it'd be a worldwide thing, and that's the reason that it's so darn expensive.

Yeah, got it. Okay. From a San Diego perspective, obviously you've spent a long time here working on infectious diseases. Like, what's your take on the technology communities relative to maybe other communities that you interact with other colleagues in?

Yeah, I came here as an intern in 1996, and I didn't know I was going to stay, but once I started working in the science realm, and seeing the just very collegial and nice and smart people, I stayed. This is the place where biotech happens and really makes new discoveries and can move it along to make us all healthier. And I just love being able to talk to industry colleagues and people at Scripps or SOC@UCSD and just have, okay, here's a problem. Here's how we're going to go about fixing it. You want to be on this team. That's amazing. And that does not happen. I have not had that experience happening in other places.

That's great to hear. I think from an investor's perspective, my own. As an investor, what I see really exciting is the blurring of lines of different mature industries per se. So obviously biotech being a pretty, we would call mature in San Diego and also data science honestly is rooted here in data analytics, which is kind of the basis of AI. And seeing that approach applied to a mature industry we call a blurring of line. And so seeing those two come together is pretty exciting. We think just being ambassadors of San Diego and investors, brand new opportunities where San Diego will lead in saying this great technology applied to this industry or the body. Like I think one plus one equals three. So we're pretty excited about that. Does that feel like that locally as well to you too?

It totally feels like that to me. So we started this PREPARE institute at UCSD and we're bringing in industry and we're bringing in, you know, academics and just all this big group of people because we can blur lines. And we have this big talk with these engineers who are working on a completely different set of problems. Once we brought them in, they're like, hey, you know that thing that I use for that should be used for this. We're like, oh yeah, that's a good idea. But it wasn't until we got into that room and blurred the lines that was happening.

Yeah, that's great to hear. Yeah, I mean that's cross, what do we call them? Diverse teams. Right. And crossing industry lines in that regard and being able to say and kind of to point that you mentioned kind of a translator being able to have people who can talk to multiple groups, not purely just academic, but industry and the investor scene as well too. It obviously shows that we're a tight knit community. So that's a good thing and I hope we do even more and more of that. So great to hear that you're seeing that on your end and it's actually happening. And curing cancer and curing, curing other diseases here as well too. So we're really excited about that.

The other one that I have to say that's been really enjoyable is that there's less ego. It's very problem focused versus ego focused. And you know, we're human, we have big egos I guess sometimes. But boy, when a problem is presented and we're all on the same team to fix it, then that goes out the window and that's just nice to do.

It's actually a really good point that I think is culturally here. Like you can see it in different cities. It's a different culture around that. We're more humble here. So maybe we don't shout from the rooftops about our accomplishments, so we're under the radar. But we also are humbled by maybe some bigger things here. Maybe by the big thing at hand here is cure an international pandemic or humbled by our waves here, by getting in the water and we're all the same person getting pummeled by a 15 foot wave. And then at the end of the day we break bread and we have tacos together, you know, regardless as well too. So yeah, I think it is a cultural thing here. And speaking of tacos, do you have a favorite one?

I do, It's El Cuervo on Washington. First in Washington. It's my favorite and close to the hospital there and I went there all the time as an intern and still it's, it's great.

Yeah, that's a good one. Has not been mentioned yet, but a solid one. Adding it to the taco database as we speak. Well, Davey, Dr. Smith, thank you so much for being on for obviously the career you have pointed in this direction of infectious diseases saving us all and so appreciate it and keep up the great work. Thanks for being on the podcast.

Thank you. It's been fun.

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