FULL TRANSCRIPT
Slava Rubin (00:00)
In this episode of Smart Humans, we talk with Nicole Paulk who's the founder and CEO of Siren, the biotech company. We dive into the world of biotech and what is possible. In this market, the economy is hot and so is the stock market, but yet biotech is still struggling. What is happening with BigBio or what is happening in the world of biotech startups? Well, Nicole is leading the way with a brand new company, changing the way viruses can impact oncology and solve cancer.
She talks to us about all the intricacies of what it's like to create a startup in this space and why she left the world of being a professor to take on this extravagant challenge.
Slava Rubin (01:05)
Hello and welcome to the latest episode of Smart Humans. I'm excited for today's guest. We have the founder and CEO of Siren. We have Nicole Paulk with us. Nicole, welcome to the show. Yeah, so we're gonna be talking about a topic that we don't always discuss, which is biotech. We have an incredible entrepreneur here. And we always like to start in the same first place, which is how did you get into the world of alternative investments?
Nicole Paulk (01:17)
Glad to be here.
Slava Rubin (01:32)
Obviously you're an entrepreneur and that's your ultimate investment, but take us back to childhood, growing up. How do you end up where you are today?
Nicole Paulk (01:41)
So if anybody knew me before my Siren days, I was a professor in the biochemistry and biophysics department at UCSF here in San Francisco, which is where I'm at. And that is a really interesting lens from which to look at the world. Being a professor at a hoity-toity University means that everyone in the world wants you to sit on their scientific advisory board or advise them in some capacity or to be like an
expert witness on a trial about patent litigation or like whatever, but like you have this, you have this very interesting lens into the world because everyone wants to have your name in your face, like on their pitch deck or on their website or being able to say that you're on their Rolodex of KOLs that they use for doing diligence on deals and these types of things. And it's wild. Like you go from one minute, you're finishing your training, right? So I did a PhD at OHSU in virology. So engineering viruses to deliver genetic medicines and then.
Did a postdoc at Stanford, same stuff, virology, engineering viruses, deliver genetic medicines, all this type of stuff. And then you go from being a trainee and then like one minute later, you've got like the title professor and all of sudden your phone's just ringing off the hook. Cause everyone, everyone wants to have you involved in some way. And you're like, nothing's different than last week when I was just a postdoc. But now that I'm a professor, everyone in the world needs to say they know me. And so it was wild because everything from huge
public corporations with 10,000 employees want you on their advisory board, all the way down to teeny tiny startups being spun out of another company or out of an academic lab with like two students and a dream on paper, but no data yet. And every size company in between all reaching out and saying like, would you advise us? And so you kind of got this kind of secret insider's perspective that particularly for
like the two different worlds, like publics and privates, like the public companies, you get to know if you sit on their scientific advisory board, like what are all the cool things that they're working on that the world doesn't know about yet that they haven't put out a big, huge press release about and, and the public companies, right, they just throw money at these programs. So by the time it reaches a press release, like that thing is set in stone, like it's happening. And then like the alternative world.
these teeny tiny like stealth, they haven't even come out of stealth yet. These teeny tiny stealth biotech companies that have like some unbelievable innovative cool new thing that the world has never seen that they've just discovered, that they've just patented, that they've spun out into a company. And they're like, can you help us? It's usually involved in some ways with viruses. That's my background is in virology and gene therapy. So it usually involved that in some way, or at least an application into that. And
you they come to you and they're like, Hey, would you advise us on anything from like, you know, how do we set up our company to, know, how do we, how do we decide what indication to go after? Cause the, new biology that we uncovered, the new discovery, the new thing could be applied to many different things. Or maybe they already came in and they knew they were going to work on, you know, heart failure. But they needed to know like, how do we turn this discovery we made into a viral gene therapy that we could use to treat heart failure and these types of things. And so.
you got to see like the two ends of the spectrum. It was like these nascent, nascent early ideas that are stealth. No one in the world has heard of it. Sometimes they haven't even published the paper yet because they want to like keep that secret and they're still stealth and they just went out all the way up to like, I'm a 20,000 person public company and we need you to help us advise on our eighth program that we're going to try to bring to market and get FDA approved. And so you got to see.
like this entire spectrum of like what it takes to go from like right the classic zero to one what it takes to go from zero to one in a private company with two million dollars, know, 12 months of burn and one shot on goal. They've got one asset and one program and like if this doesn't hit their toast and like a public company that's like we're to take 10 shots on goal and as long as one of them works, we're fine. We'll scrap the other nine doesn't matter. But we're queuing up our sixth program and we'll just throw money at this.
and getting to see the different ways that science can get done, and the different expectations and the timelines, and what are the data package expectations and what's market, and what are the investors interested in, the early stage investors, what are they into, versus some late stage crossover IPO, big huge bang private equity, these types of groups. What are the of expectations that the market has around?
Like how many patients are you going to need in order for us to get excited? And what are the, what are the indications spaces that are hot right now? And where's right classic like move where the puck is going. Like where's the puck going as far as sentiments out there in both the public and private markets for kind of what kind of science people want to see when it comes to medicines or medical devices and all these types of things. And so being a professor just gave you such an interesting.
lens through which to kind of see the world as it pertains to biotech and kind of life sciences and therapeutic development, which is kind of my wheelhouse. And so it was wild to kind of get to experience that as an advisor to all these different groups for so many years, and then had no intentions necessarily of leaving and starting a company. Like that was never, ever, ever on the docket. That was not a plan. I was gonna be like, I was gonna be a good girl. I was gonna be a professor forever.
⁓ that was the plan and they're super hard to get. So anyone who knows this space knows that you don't just up and try to become a professor and then leave, right? These are like, it's like a five year bachelors and then usually like a five to 10 year PhD and then like a five to 10 year postdoctoral fellowship. And then I was an instructor for two years and then you become a professor and it could be like seven years to get tenure and like another, another seven years to get full tenure. So it's like, no one just passively does this. It's.
you know, a labor of love that takes a lifetime. So if you'd have told me at the beginning of this, they're like, yeah, you're gonna, you're gonna do this, but then you're gonna bail after a few years and you're gonna start a company. I would have told you you're crazy. But that's absolutely what happened.
Slava Rubin (07:35)
I have question about that, which is why
were you so excited about viruses? Where does that start from, from your childhood or growing up or how do you get into that at all?
Nicole Paulk (07:43)
Yeah
Not in the slightest. Growing up, I was the little miss sports girl. academics, I I always got straight A's. I was the valedictorian, all those types of things. But that wasn't the plan. That wasn't the focus. was just like, sports, sports, sports. my god, sports. ⁓ Everything. So from volleyball, soccer, track and field, baseball, you name it.
Slava Rubin (08:01)
Which sport was it?
Nicole Paulk (08:07)
I just wanted to be involved in something competitive. Like, get me on a team and let's go. Which I think actually ended up serving me quite well in many other future roles, like being a professor and a CEO, being on team sports. But viruses was never the plan, biology was never the plan. And then in about undergrad, I...
really started falling in love with just microbial life period. Didn't have to just be viruses, like bacteria, viruses, parasites, just these microscopic things. And just how interesting and engineerable they were and kind of the misconceptions that the public had that all microbes are scary, right? All bacteria and viruses are bad. And that just could not possibly be further from the truth. I think we are now, like in very, very modern 2025 times, starting to appreciate like,
Most folks now, even if you're not a scientist, have heard of things like your gut microbiome and that's a good thing. And like you want bacteria in your gut to like help you digest food and there are good bacteria and there are bad bacteria, but there are plenty of good bacteria. Same thing with viruses. There's a common misconception that like all viruses make you sick. And it's like, we couldn't be further from the truth. There's about like 30 that most people study. And yeah, those 30 make you sick. And it's the ones that you can name like influenza that causes the flu and rhinovirus.
as colds and chicken pox and these types of things. But like the vast majority of viruses on earth do not make you sick. So I just was kind of enamored with this like very small little world, all these little microbes and the fact that there was all these misconceptions around like them being, that was an undergrad, but that was just like not studying them yet, but just kind of like taking classes and being like, this is so fascinating. Like they're so wild, like all these different flavors and kinds and strains.
Slava Rubin (09:38)
I in college.
Nicole Paulk (09:49)
⁓ And then one of my undergrad professors, I was at a very small undergrad university, so Central Washington University in Eastern Washington. And on the entire campus, there were only two professors who had grant money from the federal government such that they could actually pay you to do research in their lab, like actual, like pay you in cash, pay you in cash to do research as opposed to just giving you credit. And...
about the second year of my undergrad, I had dislocated both my shoulders at that point four times. So like sports was done, because my shoulders were just toast. I had dislocated them three times playing volleyball and one time snowboarding. like sports was done for me. And so all of a sudden I was going to lose my scholarship, right? I had a full ride and I was going to lose my scholarship because I couldn't play anymore. And so I needed money to like pay for tuition, pay for rent.
And I found a professor in the chemistry department. I was not a chemist, but I found a professor in the chemistry department and she had a grant from the National Science Foundation and she was allowed to pay the students who did research in her lab with cash. so was like, all right, I'm gonna start doing research because I need money. she, because this was like a very kind of like undergrad university, she gave me all this responsibility.
the kind of responsibility you would give like a master's student or a PhD student, but I got as a bachelor's student because that's all there were at this university. And so I kind of fell in love with doing research and getting to run experiments and all these types of things. But my interest was in virology, but there was no virology professors with grant money. And so I kind of like, I toggled these two worlds of like this biochemistry and nanochemistry, which was what she was in, but learning how to like,
think through experiments and experimental design and how you actually set things up in order to be able to test them and about how to set up a proper hypothesis and all these types of things, like the fundamentals. But then I was reading voraciously all these books about hemorrhagic fever viruses, Ebola, and just being like, man, this stuff sounds so cool. And then when it was time to finish and finish my bachelor's, I was like, what am I going to do with my life? And my chemistry professor, she was like, well, have you
you seem to really like research. Have you thought about going and getting a PhD? And was like, no, but I like this. I like this idea. And then like, forward, going and a PhD in virology and the rest is history.
Slava Rubin (12:04)
there.
The rest is history.
Yeah, so I mean, guess in short, you're super alpha and then you dislocate your shoulders. You don't get in your scholarship money. You need money. You get a research job. You fall in love with research and there it is. If you have better shoulders, you probably wouldn't be a researcher. There you go.
Nicole Paulk (12:12)
I'm
And there it is.
I probably wouldn't.
Who knows? Maybe I'd be like really cool in some other dimension. Maybe I'd be like a beach Olympic volleyball player. ⁓
Slava Rubin (12:34)
Exactly, exactly. So changing chapters
here, we always love to know how our speakers are investing their own net worth. So obviously a good chunk of your own personal net worth is in private equity in your own company. So let's just park that aside and ignore that as part of your 100 % allocation. So the traditional way of investing is 60 % into public equities, 40 % into bonds. That's not exactly how most of our guests are allocating their money.
How do you think about allocating your entire net worth? Are you 60-40-0-0 into alternative investments or are you some other ratio between public equities, bonds, and alternative investments?
Nicole Paulk (13:14)
Absolutely. So I, again, kind of from that interesting perspective from sitting on all those scientific advisor boards, which I still sit on, I love the gamble, the risk, the excitement, the backing founders. So I actually do quite a bit of angel investing ⁓ of my own funds into companies, not only that I advise, so usually one of my criteria, if I would advise you, that means I believe in your company, because I'm not going to give you my precious, precious time.
Slava Rubin (13:28)
Great.
Nicole Paulk (13:40)
If I don't think that you have something that the world genuinely needs and wants. And so I actually, for the most part, like if I'm going to advise for you, I'm also going to invest in you. And that's kind of like a package deal. And so I actually do quite a bit of angel investing and it's all in things that I find fascinating and interesting kind of in my space. So in the biotech space, like are you a company developing something that either I think the world is also going to agree is fascinating or something that just me personally, I'm like, I definitely don't want.
You know, I don't want skin cancer and I want like, you know, I want better hair or I want, you know, I want something for something I think I might end up developing. And I'm like, yeah, like what if I end up getting diabetes? I should probably do something with diabetes and like, or like osteoarthritis or something. Like I'm already, about to turn 42. So I'm like, man, my back hurts. I should start investing in things for like back pain and longevity plays and these types of things. So I would say like a good, maybe 10 % at least, maybe even more.
of my investments are actually in private, usually still stealth, but not always companies that are doing things in the space that I find fascinating and I want to use as like an end user and an end product. And then the rest kind of right? Class like domestic and international bonds and kind of classic ETFs and these types of things. And they kind of invest through Vanguard. And most of the private companies that I invest in, I would say,
Slava Rubin (15:00)
Sorry, so
do you think instead of 60-40-0, you're like 60-30-10?
Nicole Paulk (15:03)
Yeah, that's probably fair. Probably a 60-30-10 where the 10 is the kind of like private companies. ⁓
Slava Rubin (15:08)
And the 10
is like 100 % private companies, so you're not really into like investing into real estate beyond your primary home or crypto or things like that.
Nicole Paulk (15:17)
Not on an individual basis. again, for like conflicts of interest reasons, because I do so much advising, I try not to do investments in single public companies because I advise far too many of them. So for competitive reasons, I try not to do that. ⁓ I'll just index the ETFs in a space, so in like a biotech space. So cover it that way. So that way, I don't do the mistake that I hope all of our politicians don't do, which is invest in individuals, ⁓ public stocks.
Slava Rubin (15:28)
Okay.
So you like doing like indexes or ETFs?
Nicole Paulk (15:46)
that where I have like competing advisory relationships and I want anybody to feel like I'm putting them at risk or those types of things. So on the private side, yes, I'll invest in everybody when they're individual as an angel. But once you hit public, then I'll come in through an ETF or an index or something like that, but not individual ones. Otherwise, it just goes crazy if you accept federal funds. ⁓
Slava Rubin (16:03)
Okay, great.
Of course, of course.
And then how about crypto or are you investing in crypto?
Nicole Paulk (16:11)
I'm not, I'm not against it, but I'm not. Well, like haven't had the time to really dig in and sit down with any of my friends who do all of these things and be like, all right, sit me down. What's the move?
Slava Rubin (16:14)
All right, well maybe you should.
You might want to diversify a bit into some crypto, maybe one or 3 % of your net worth. It could work out well. And then any other hard assets, like are you collecting any watches or art or anything like that, or that's kind of...
Nicole Paulk (16:37)
All that
fun money, that goes into Siren.
Slava Rubin (16:40)
Okay, perfect.
What do you think, changing the chapter again, what do you think of the current market? And it's like a very open ended question. You can speak to the economy or the stock market, you can speak to where we are with multiples, where we are with inflation, obviously with Fed cuts. It's really just what's Nicole's point of view as to where we are in the world as it relates to the economy and the market.
Nicole Paulk (17:06)
So I'll answer this from a biotech lens, because that's the lens I know. So if we talk about the greater kind of macro market and how that influences the biotech market and how that influences the ability of drugs to get approved and get to market and these types of things, it's a really fascinating time. So anyone who follows the biotech kind of life science, big pharma space right now knows that we are in what can only be categorized politely as the darkest winter.
in the better part of 10 or 20 years. So the biotech kind of specific market, right? The XBI is as suppressed as I think it's been in the last 10 to 20 years. And it's not because there's not innovation, it's not because there's not great drugs, there's just all kinds of reasons where like, if you really break it down, I think, like at its super most simplistic level, we had COVID, right? The COVID pandemic hit, and there was just an absolute groundswell of support for like getting a vaccine and like,
trying to develop things that would help with treatments, with symptoms, all these types of things. And it was like an absolute heyday where like valuations went up, stock prices went up, everything went up, everyone was super into it. was, the sentiments hadn't been that high in quite some time. And then we kind of got things working, right? We got vaccines, we got treatments, and then all of sudden sentiment kind of crept back down again. Cause historically big pharma, Novartis, GSK, Merck.
know, J &J, all these companies. They don't, and I say this with all the love in my heart for Big Pharma, but they don't have necessarily the best public sentiment, right? It's similar like politicians. They're not particularly popular, but for a brief moment, right, for about three years, like, boom, everything went up, sentiments were super high, valuations were high, stock prices were high, and then things kind of came crashing back down once we started to get all the fruits from those labors, once we started to get vaccines and treatments and therapies.
And that it really went kind of across the entire industry. So even companies that weren't doing anything to do with COVID and who were working on things for, know, diabetes and heart failure and cancer and all these, all the normal things that we all need drugs for, they all also felt that suppression in the market and kind of the prices coming down and all those types of things. And that has continued to hold and then just kind of get worse and worse and worse as the greater macro market and like,
rates and everything have just really kind of just stagnated. And we really went from this like Zerp era where it was very easy for companies to raise money and get loans and debt and these types of things to now the environment we're in where that's very much different. And like those two things combined, like sentiments being low and causing the prices to come down along with kind of the greater macro economic market and like interest rates and these types of things have just meant that like the biotech winter has been
really challenging for the field, regardless of whether you are a huge public biotech. I mean, you can look up the god-awful reports about how many companies are trading under cash, all the way down to the teeny tiny startups that are struggling to raise a pre-seed or a seed, and kind of all the companies in between. And so it's a really interesting moment in time. We're seeing this reshuffling of kind of what folks are interested in actually continuing to fund and push forward. And you're getting a lot of what were, quite honestly.
bad companies that had gone public far too early, needing to basically be either reorganized in some way, acquired for pennies on the dollar, or actually going bankrupt and coming off the market. And so you're seeing kind of a healthening, I think I just made up a word, a healthening of the market where the companies that are surviving are the ones that actually have phenomenal drugs.
going after big indications where there's a nice market. I think we've still got probably, I would predict another one to two years of like the greater biotech market being pretty suppressed. But these things are all.
Slava Rubin (20:56)
Why
is that? mean, today as we record, like at a high level, the stock market is pretty much at an all time high. Obviously, you're...
Nicole Paulk (21:04)
Greater stock market,
yes. Biotech specific things, still not up there. Still not up there.
Slava Rubin (21:08)
Right. So even though
AI and all this technology excitement is helping to lift, you know, definitely the Mag-7, Mag-10, whatever, you're really starting to see the small caps and others really starting to get a bit as well. You're saying biotech is just not catching that.
Nicole Paulk (21:24)
It's also increasing, but not at the same rate to get back up to where we were in 2021. To get back up to 2021, I think you're going to need another year or two. And some of that is we are starting the greater biotech space, particularly the smaller companies, to implement all of these AI tools into our workflows and coming up with not only in terms of the back office, but also on the science end and incorporating these into the discovery pipelines. And so you're going to start to see in about one to two years the simultaneous, oh, actually,
We don't need to raise $2 billion and take 15 years for each one of our drugs, which has historically been the numbers for each new drug you bring to market from like zero to one. Like we conceived of this idea on a piece of paper and like now it's FDA approved and you can go get a prescription for it from your doctor. That process typically takes about 15 years and takes about 2 billion with a B dollars per drug. And I think like those days are over as we start thinking about
like the influence and the pressure that China is putting on the US. And this is like a fascinating topic we can get into if you're interested. ⁓
Slava Rubin (22:27)
Sorry, so what
will 15 years and 2 billion turn into? What amount of years and what amount of cash?
Nicole Paulk (22:34)
So that will depend on what kind of modality you are. Like, are you a small molecule drug that you can just swallow versus are you an intravenous drug with like a protein? Like maybe you're a cell therapy or these types of things. So you can cut many years off, but it will depend on kind of what your modality is. So maybe you can get it down to five years. Maybe you could get it down to 10. Some of that will depend on how much.
Slava Rubin (22:49)
Let's say it's just a pill.
Five years and how much money?
Nicole Paulk (22:59)
I think to be competitive, and this is where I'll give you a hot take, right? think right now, maybe you could get it down into the high hundreds of millions, like 900 million. But I think hot take the Nicky's take, I think to really be competitive with China. Like not only does the U S need to innovate on regulatory, not only does the U S need to innovate on like incorporating AI and do literally every single step in your workflow in order to be like combinatorially competitive.
with the AI in China situation and the greater macro market, I think you need to figure out a way to do zero to one where zero is discovery and one is FDA approved drug in three to four years for less than, quite frankly, like 200 to maybe even $100 million, all in. We need to figure out collectively how to not just incinerate money when we're developing these drugs. Some of that we cannot possibly do on our own. We will need regulatory help.
But this new FDA seems very interested in doing that with the space. There's talk of, for example, dropping phase three clinical trials. So most folks probably know for drugs, right, you do a phase one, then a phase two, then a phase three trial, and then you can go up for approval. And there's talk of dropping that phase three trial and kind of putting a little bit more weight on that phase one and that phase two trial. But that could cut off. That's the most expensive trial. It's the last trial. It's the one with the most patients.
Right? So if we did that, if we dropped the phase three trials, that alone cuts, like it could be like for a really long, like a breast cancer trial, like thank goodness we've gotten so good at treating breast cancer. Those trials can be like five, six, seven, eight years. So you can cut all that time off, that development time off, ⁓ still run two clinical trials, right? Phase one and a phase two. So you're still proving this thing is safe and efficacious. You just cut off that third, like really, really kind of duplicative trial.
So there are many things we can do on the regulatory front to really speed things up. And companies just need to do their due diligence and make sure that like, you're really sure about this one asset and that you can find ways to be more capital efficient, right? Like perfect example, right? We're about to be a clinical stage company. We start dosing human beings with our first asset and our first program, like in early 2026, we have six people.
Normally, in a normal biotech environment, say, pretend it's 2021 and you're just some biotech, biotech new co, and you have a clinical program, it would not be uncommon for you to have raised $200 million at that point. You're still preclinical. You have not yet dosed a person. You are about to dose a person. And you probably have a head count of somewhere between 35 and 50 people. We have raised $30 million and we have a head count of six.
So it's like, you have got to find out ways to be way more capital efficient, both in terms of people and headcount, to just move faster, to be competitive in this environment with China. Because China can queue up a clinical trial in three months. In the United States, like today, September 2025, as we are recording this, it takes about a year. Like our drug that's been ready for a clinical trial has been ready for a year, but it takes a year of paperwork, just paperwork.
to submit to the FDA to ask for permission to do a trial. So like there are many ways where we can, without compromising any safety, any efficacy, any anything, but just like improvements in like the bureaucracy, we can make these drugs so much cheaper and so much faster so that we can be competitive in the market with things like China and incorporating AI into this will just make it even, even better.
Slava Rubin (26:36)
Super interesting. So the Fed just cut rates for the first time.
Nicole Paulk (26:40)
Yes, thank goodness. And hopefully
three more times before the end of the year as the rumor goes.
Slava Rubin (26:44)
All right, well there's the hot take. So let's just ask you that. And then I'll ask you the next question, which is let's do some lightning round here. Do you think in the next 12 months, recession, yes or no?
Nicole Paulk (26:58)
Ugh, the optimist in me says no.
Slava Rubin (27:01)
All right, perfect.
The Fed funds rate, ⁓ obviously it was cut a quarter point. How many more basis points will it be cut or not in the next 12 months?
Nicole Paulk (27:11)
I don't think much more, I do think they will do at least another one before the end of the year.
Slava Rubin (27:15)
How about in the next 12 months?
Nicole Paulk (27:21)
I hope they will do another two. I hope they will another two. I'm not confident enough, but I hope they will do another two.
Slava Rubin (27:23)
Okay, so 50 basis points.
⁓ inflation, it's going to go up, stay flat or go down.
Nicole Paulk (27:35)
Stay flat in the short term, like before the end of the year, before the end of 2025. And this time next year, hopefully down, I think down. I think down.
Slava Rubin (27:42)
This time next year.
Whoa, that's a hot take.
That's a hot take. And then the stock market. it gonna?
Nicole Paulk (27:51)
I think because
it's gonna have to. Like, we're coming into election cycles, like, get moving.
Slava Rubin (27:58)
All right, you heard it here first. So the stock market, the actual Dow or the NASDAQ, is it gonna be flat in terms of price versus today, up or down?
Nicole Paulk (28:11)
I think like greater macro like like big seven, those types of groups, think up for sure. Biotech, think is gonna continue to stay, ironically, I think it's gonna continue to stay a little bit flat or like a tiny bit up, but nowhere near as much up as like the.
Slava Rubin (28:26)
So you led me to my next question, which was between all these parameters and rates coming down, where is biotech? Where is that as an index, not an individual stock pick per se, but where is that market going to be in the next 12 months?
Nicole Paulk (28:44)
I think it's still going to be quite frankly, like pretty flat, but that means like, if you believe in these technologies, which like, at like first principles, like we are an aging population. Everyone is getting things like cancer, obesity, diabetes, heart failure. Like those are fundamentals. Like you don't have to, like the prediction markets, you don't have to worry that like these things are going to.
Slava Rubin (29:04)
The Four Horsemen of Death.
Nicole Paulk (29:08)
not only exist, but continue to rise and keep going as we become an aging population. Right. People are having less and less kids than we've ever had. So like we are becoming a rapidly aging population, not as bad as places like Japan and other places, but like those will continue to exist. There will never not be a need for like heart failure, diabetes, cancer, drugs, obesity, these types of things. like it's almost on first principles. Like these things will absolutely swing back because it's always like, it's always
Even like the way the market itself is like, it's always cyclical. Go up and it'll go down, up and down. Biotech is no different. We are absolutely in a trough. There is no exaggerating it in any way, shape or form. We are in the bottom of the trough and the man it hasn't moved in a couple of years. It is a dark, dark winter. But like it will come up because everyone is going to continue to need heart failure drugs and cancer drugs and diabetes drugs.
And when it comes up, it'll be great. So now's a great time to buy. Prices are super suppressed. So if you believe on first principles that people will continue to get sick, it's a good time to buy.
Slava Rubin (30:09)
All right, perfect segue to Siren. You had, you foreshadowed this already. You had a killer professor job. Most humans don't walk away from something that took decades to earn. You created a startup saying goodbye professor and tell us about Siren. What is it? Why'd you create it?
Nicole Paulk (30:25)
So one of the really interesting things that came out of being a professor and being in that role, right, I advise all of these companies and I would always have the exact same initial, I call it like the whiteboard brainstorming meeting, right? It's like the first meeting of the SAB and everything, they get all these smart professors together and they're like, okay, so we have like this cookie, this edge, this thing that we discovered that we patented and we started a company, but now we need to decide what we're gonna go after with it.
You'd start wiping out like, okay, well, you could go after heart diseases or liver diseases or kidney diseases and let's map all those out and how many patients they have and okay, could you do a gene therapy for that, right? So gene therapy is engineering a virus to deliver a copy of a gene that you were born missing. And every single time the conversation would have the exact same path where all of sudden they were like, well,
the payload, the medicine we put inside the virus, because the virus itself is not the medicine. The virus is just an engineerable little FedEx truck that can deliver the medicine anywhere you want in the body. So the payload in this case would be the gene that you were missing because we were always treating genetic disorders in kids. So it was like, well, no matter what, we have to change the payload because that has to change for every disease because every disease is missing a different gene. since we have to change that, why don't we change everything else so we can own the whole tech stack? So we want to change like
the virus and we want to change the manufacturing platform for how we make the virus and like all of the component parts that go into making one of these drugs. And I was like, well, you can, but like now you've made this from like a, you're two years out from the clinic to now you're six years out from the clinic and this isn't going to cost a hundred million dollars to get to the clinic. This is going to cost like $800 million to get to the clinic. And it's just like, this is not capital efficient, right? The five most expensive drugs on earth.
are all cell and gene therapies, right? So these are one, two, three, four. There's now one that's about five million with an ⁓ five million dollars per dose, right? So fun fact, most people maybe didn't even know there are FDA approved viruses. You could go get a virus for some of these disease, to treat some of these diseases, but they're the most expensive drugs on earth. They're really expensive to make. And I was just like, this isn't going to scale. Like, you know,
Health insurance in the US is already like a hot mess. I am rooting for Mark Cuban and everyone in the space who's trying to actually improve things, but it's a hot mess. So you take a drug that's now $4 million and you wanna give it to the 300th disease. We've got a handful of these. We've got like five, six, seven of these that are FDA approved. And they'll allow it to be charged that much, because they have a kind of like this first mover advantage where it's this new
very technically challenging space and the first few drugs you can charge that month. But like the 500th viral gene therapy is not going to get to have a list price of $4 million because you would just break insurance and Medicare and Medi-Cal and all these programs. So it's like from first principles, my lab was kind of thinking about like, are ways that we could make this entirely new modality class of drugs? Like what are ways that we could make this more affordable?
Because there's just no way on first principles we could ever have that many drugs with list prices in the millions. Like this needs to get down to like, you know, $10,000 kind of a thing. Like we need multiple zeros to come off. And so we started thinking through this kind of academically, like what are things that we could put inside of a virus that could treat more than one thing, right? Every virus that has ever been engineered on earth for treating a disease, they're always what we call one for one.
So it's one virus that can treat one disease, but you can't use that virus to treat a different one. So you can't use one virus to treat diabetes and also congestive heart failure. You would have to make a different virus. And so it was like, you were always re-engineering from scratch every single component part. So it's like, imagine you build cars and not even one bolt was able to be used across like your two different form factors and your two different cars. It was just like, we've got to start finding some redundancy where we can reuse parts. And so we were applying that logic, but now to viruses. And it was like,
Could you make a virus where every one of the component parts, including the medicine payload that you put inside of it, doesn't change? And so we lovingly referred to this as the universal payloads project. Could you think of a payload that could do something you need biologically, but that could be used to treat more than one disease? And so I started thinking about that bioinformatically and from first principles and got very excited about.
a variety of different things. don't need to get into the nuanced biochemistry, but got excited about a variety of different things and started testing these and got very interested in the use case of using these viruses in cancer. And they had never been used in oncology before. They had only ever been used to treat like genetic disorders in little kids, but never a really huge indication space like cancers and solid tumor cancers, which are the predominant cancers that most people get. And so fast forward.
years and years and years of work in academia and then spinning out Siren, ⁓ we basically and kind of engineered two worlds firsts. So it's the first virus in this class of viral gene therapy, A, B, or adeno associated viruses. The nuance doesn't matter, but the first one of these viruses that has ever been made that can treat more than one thing and the first virus to be used in oncology. And so trying to really bring this virus into a much bigger market, producing this in a much more cost effective way,
⁓ producing it once and then being able to use it like 10 ways to Sunday and all of these different cancer indications so that we could dramatically bring that price down so that you could really improve access and get things to market much more quickly. We don't have to do all of that discovery work over and over. So again, trying to get to that goal, my hot take goal, which is that to be competitive with China in this rapidly advancing AI environment as it pertains to drug discovery, you have got to figure out how to be able to get a drug.
from beginning to end in four years for ideally less than 100 million, but maybe more realistically under 200. But in the 100 to 200 million dollar mark, how could you do that? One of the ways is don't make a new drug for every single disease. Make one drug that can be used to treat many things. The current best-selling cancer drug of all time is a drug called Keytruda that many folks have probably heard or they've taken themselves or someone in their family has taken. It also goes by pembrolizumab
This is the best selling cancer drug of all time. It's the best selling cancer drug in like the last 23 years running. It has been the goat. It sells about, now it's up to about 23, $24 billion a year, this one drug makes. And it's used, don't even quote me on the numbers, I don't even know what it's up to now, but it has FDA approvals in like dozens and dozens and dozens of different cancers.
So it's this one drug, they make one time, they figured out how to make it, do all the process optimization, everything. And now it just gets tested like every last cancer you can ever imagine, both alone as a monotherapy and in combination with other drugs. And so like that is the way to make a successful drug that doesn't need a lot of time and doesn't need a lot of money is to make a drug that can be used to treat more than one thing. And so we wanted to kind of bring that concept.
over into the virus world and be like, could you make a virus that could treat more than one thing? And that's kind of Siren. So making the world's first universal gene therapy that can go after oncology.
Slava Rubin (37:53)
So you want the Keytruda viruses.
Nicole Paulk (37:56)
Exactly, we want to be the Keytruda viral gene therapy. It's to go off patent, the Keytruda is, so they really need, they really need another stocking horse to bring in some funds, so.
Slava Rubin (37:59)
There you go.
Nice.
So when you say that to do more than one thing, you're referring to more than one cancer treatment or you're referring to other things besides oncology.
Nicole Paulk (38:14)
both simultaneously. So not only can our drug called Siren 101, not only can you use it to go after different solid tumor cancers, you can use it to go after brain cancer, potentially breast cancer, colorectal cancer, like different types of cancers, but also it can be used in things like infectious disease and autoimmune indications, things like allergies, these kinds of things. So there's use cases outside of oncology as well. that's the dream for any drug, for any biotech, it doesn't have to be Siren, this could be any company. Like the dream is you make a drug.
that has use cases in multiple different indication spaces. And then within each of those, like lots of different, lots of different kinds of subtypes, like that's the dream.
Slava Rubin (38:51)
So your contributor is called Siren101. Nice. And when did your company start?
Nicole Paulk (38:53)
Siren 101.
So we ⁓ spun out of UCSF back in 2021 and then stayed stealth for like a good three years before we came out and started talking to the world. we were cooking in the kitchen for a minute and then came out in 2024.
Slava Rubin (39:10)
Nice, and how much have you raised to date?
Nicole Paulk (39:13)
So we did a seed with Founders Fund back in 2021 and then had a safe in between there when we had won this very large grant from the state of California. And they were gonna scoop us when they were gonna announce this big non-deluded grant that we had won, but we hadn't come out of stealth yet. And we're like, oh man, we'd better come out of stealth. And they were like, oh, also we need cash matching for you to win this grant. So we like very quickly did a safe. And then we did our series A last year in 2024.
And so all in, think we've raised about $30 million in dilutive from VCs and then like another four, five, six in non-dilutive from these various granting organizations.
Slava Rubin (39:54)
Who led your A?
Nicole Paulk (39:55)
Our A was led by Tau and then all the seed investors, Founders Fund, Lux Capital, Innovation Inverse, all those groups all came back in.
Slava Rubin (40:02)
Sorry, who's at the end?
Nicole Paulk (40:04)
T-A-U.
Slava Rubin (40:05)
Okay, cool. so, and you said that you're about to, like, where's the drug at now in terms of like your FDA approvals in the process?
Nicole Paulk (40:14)
Exactly.
So we just finished like all of the animal studies. There's like these very pre-prescribed animal studies that you have to do that the FDA requires in order to queue up clinical trial in humans. And so we've just finished all of those. There's like the classic ones people have heard of, the ones in mice. And then you also have to do, they have this rule called the two species rule. They want you to test it in two different species and it has to be one small mammal and one large mammal. So our small mammal studies where the mice.
And then our large mammal studies were actually in pigs because pigs have a very similar, we're going after brain cancer. Pigs have a very similar brain shape and anatomy and orientation to humans. So we could actually test like the real rig and the real drug and the real everything in pigs. So we've done all of our mouse and pig studies. Those are all done. We actually just vialed like the vials of our clinical virus that will go into humans that all just got vialed actually like last Thursday. So this like just happened. And so now we're,
preparing this massive, when I say massive, I mean massive, it's like a 20,000 page briefing book ⁓ called an IND, Investigational New Drug, and it's all of the data from all of those studies and in minute detail. then detail on top of that detail on top of that detail. So we prepare that and that's gonna get submitted this December. So the hope, the cross, fingers crossed, hold me to it, we're submitting on Christmas Eve Eve. So on December 23rd, we'll submit that packet to the FDA.
And then they review it for 30 days. That's the congressionally set timeline for INDs is a 30 day review. So hopefully by end of January, we'll have an open IND, which means we have the green light to start dosing humans and start the clinical trial.
Slava Rubin (41:47)
And is that phase one, phase two or phase three?
Nicole Paulk (41:50)
So this will be, this is fun. So one of the meetings we just had with the FDA back in April was we asked for special permission to combine our phase one and our phase two trial. So you normally can't do that unless you ask for special permission. And because all brain cancers, not just the one that we're going after first, but all, there's 125 different cancers that can happen in your brain. All of them have no effective therapies. So all of them are considered like,
rare orphan, know, massive unmet medical need. And so very often you can ask for permission to combine your phase one and your phase two, and they'll give you the green light to do that because like they know that the patients are like truly, truly, truly desperate and need therapies quickly. And so they allow you this like regulatory speed up. So we asked for permission to combine our phase one and our phase two, and they said yes. So next year, when we start, it will actually be what's called a combined phase one, two trial. And the hope would be.
Slava Rubin (42:39)
Okay, great.
Nicole Paulk (42:41)
⁓ that that can be actually the only trial and that we can potentially skip our phase three because we'll get things like accelerated and these other designations that the FDA offers for when you're a little bit later stage and that this could actually be our only trial.
Slava Rubin (42:54)
So traditionally the phase one is a checkbox for what and phase two is a checkbox for what?
Nicole Paulk (42:59)
So normally a phase one, and this is a common misconception, everyone thinks all clinical trials are like, does the drug work? No. Phase one is just to show, is the drug safe? Then a phase two is, what is the dose that works best? And then a phase three is, does this thing actually work and is it better than the current standard of care? So that's where you do the head-to-head competition with whatever the current drug is in that space. So phase one is just safety, phase two is just best dose, phase three is.
does this thing work head to head when we compare it against the current standard of care?
Slava Rubin (43:31)
Awesome, and then your phase one, phase two combined, how long should that take starting next year?
Nicole Paulk (43:36)
So it depends on how many patients we dose and some of that depends on like the patients we get and how big their tumor is. So we've been approved for a trial that can dose somewhere between 18 and 31 patients. So it'll kind of depend on how big the patient's tumors are, how many we get of different types, but somewhere between 18 and 31 patients. So you're looking at like a two and a half year ⁓ all in for the whole trial.
Slava Rubin (43:58)
Okay, great. And my understanding is you have an open fundraise, is that right?
Nicole Paulk (44:04)
We do. we have a fun little thing that we're doing again, not because we needed the funds, but kind of more to run and run an interesting experiment, right? I'm such a scientist. So we are doing a community round where we actually got really enamored with the idea of bringing actual like cancer patients onto our cap table. But that's not something that really has.
ever been done in like a therapeutics company in the biotech space. That's not, I mean, it happens in tech, but it's not something that biotech has ever really kind of picked up on and glommed onto. And I started hearing about it from some other folks on our cap table. We've got quite a few kind of tech CEOs on our cap table. And they're like, have you considered doing a community round and bringing patients on your cap table? And I was like, I've never even heard of it. Like, what are you talking about? And they're like, have you heard of like, there are a number of these platforms where you can, where you can allow like private non-accredited.
investors to come in and join your cap table. And I was like, are these angel investors? And they're like, no, no, like, it's not technically like an angel investment the way that like I angel invest. And like started reading up about it. I was just absolutely enamored with this concept. And so we queued up one of these to bring in up to an additional 5 million. We've actually already raised three. So it's just we worked better than I could have ever imagined. And yeah, we wanted to give, at first we thought, we'll just allow it.
patience to come in and then other people that were like in our in our interested in our community and interested in what we were building got interested in it and it just kind of ballooned into this whole thing we couldn't have ever even imagined and so yeah technically that's open for a little bit longer I don't think I'm allowed to say the date ⁓ online but it's open a little bit longer like people can go to our campaign
Slava Rubin (45:36)
What's
the minimum investment?
Nicole Paulk (45:39)
Only $250, so it's meant to be like super, super approachable for absolutely anyone. ⁓
Slava Rubin (45:44)
And do you have to
be accredited only or it's open to the retail?
Nicole Paulk (45:46)
It's open to retail, so you can be non-accredited. You do not have to be a rich person. You can be a normal person.
Slava Rubin (45:52)
Amazing,
amazing. And obviously you don't know the answer to this, but if you have to guess when they would potentially get their money back, is that like in a week, a year, a decade? Like what's the timing? And obviously there's no factual, but like your opinion.
Nicole Paulk (46:02)
So the time, yeah,
this is all like forward looking statements that are predictions and nobody knows definitively, but realistically, right? Like any company, any private company in the biotech space, like when you get your money back is when either one of two things happen. You IPO and you go public, right? You get listed on the stock market or you get acquired by like a big pharma company. So you have an M&A transaction and both of those are actually very likely to happen at roughly the same time. So most of the time in biotech,
you will really start to get both like private equity and all the big New York banks and everybody being interested in running your crossover round, which is the round you do right before your IPO. And same thing, you'll start to have big pharma being interested in thinking about kind of acquiring you. And it all happens at roughly the same time. It'll be right when your phase one data posts. So even though we're running a combined phase one, two trial, you'll still get data sequentially. it's...
It's a phase one and then a phase two trial. There's just no gap in time the way that there would be if you had run them as separate trials. So once our phase one data posts from that first cohort of patients, right, you publish a paper, you go out and you give a big talk at all the big medical conferences. Once you start sharing that data, then folks, all the acquirers, all the big pharma groups, and then all the banks, they will all start to come knocking at about that same time. You can choose whether or not to take those leadings or not, but like.
those will all kind of happen at the same time. And so we'll start to have the first data releases from patients about, it's kind of like every six months. So it's like six months after the first patient, there's a data release. Then another six months after that, there's like another data release. So in kind of this six to 12 month cadence, you have these data releases. So I would imagine approximately six to 12 months after we have the first patient dose is when we'll start to release data. And that's when all those various groups would start to be interested in those conversations would start happening. So I would guess we are at a minimum.
a year and a half away from those kinds of conversations really happening in earnest, whether it's with a bank to start thinking about an IPO or whether it's with a big pharma company to get acquired. And then those conversations typically take a year. So I would imagine we are about two and a half years from like a realistic probability of something being able to be returned. But always TBD, it could be longer than that.
Slava Rubin (48:14)
Awesome.
Of course, super interesting. So everybody likes to know how our guests are, who they are. So what is it that you like to read or listen to?
Nicole Paulk (48:26)
So I am an uber nerd, probably not surprising to everyone who's listening to this doing my background. I kind of only read about viruses.
Slava Rubin (48:35)
Is there like any specific newsletter or magazine type or?
Nicole Paulk (48:40)
Well, I read the
primary literature, like the papers, like things that are coming out in like the New England Journal of Medicine, Science Cell. So I have no good book recommendations to give folks because all I read is the primary literature.
Slava Rubin (48:49)
No, no, no, no, but...
Nicole Paulk (48:55)
That's also like where you should go if you're interested in innovation.
Slava Rubin (48:58)
No, no, but what was the names? You said the names really fast.
What was the names of those publications?
Nicole Paulk (49:03)
⁓
the best journals in the world where you're going to find the leading science being published. So there's the main three, it's called Cell, Science, and Nature. There are three individual titles. And then on the clinical side, you'll have the journals like the New England Journal of Medicine, the Lancet. And this is where all the clinical data gets posted about these clinical trials and the exciting advancements that are coming up. So if you want to know what drugs are about to be FDA approved, I can guarantee you 100 % certainty that paper is going to be in the New England Journal NEJM.
So you'll know like, this is a year out from approval. I could probably get enough, you know, a prescription for this in about a year. So it gives you this insight into what's coming.
Slava Rubin (49:39)
Awesome. Anything else besides cell science, nature, the N-E-G-M as you say, or is that?
Nicole Paulk (49:44)
You want to
get into the nerdy, like, the viral gene therapy space, we have, the viral gene therapy journals. If you're like, I love viruses now, my gosh, she has convinced me, I want to read all about these. So there's the journals from our societies. So there's one called Molecular Therapy. And there's another one called Human Gene Therapy. And that's from both the American Society for Cell and Gene Therapy and the European Society for Cell and Gene Therapy. So that's like their flagship journals of those societies. And that's where we all publish all of our data.
So if you really want to geek out and hear about viruses, those two.
Slava Rubin (50:14)
There you go, you just nerded it out for us, that was awesome. And then
in our final segment, we always love to know your predictions for three years out. So give us one individual public stock and one private organization, which is obviously not your organization, because obviously we love your organization, but we don't even sell your book. So what will be your two picks for three years out?
Nicole Paulk (50:32)
Three years out in public market, I'm still gonna answer in biotech, because that's what I know. One of the favorite companies that I have, even though I don't invest individually, I do like ETFs and indexes, I love BridgeBio Gene Therapy. They've got just phenomenal programs, a really good management team, they manage money well. I think they think really strategically about the market. So for me, like BridgeBio all the way on the...
Slava Rubin (50:58)
What's the ticker?
What's the ticker? You know?
Nicole Paulk (51:01)
I think it's BBIO.
Slava Rubin (51:03)
Okay.
Nicole Paulk (51:04)
And on the private side, who am I interested in? I think, that's not Siren. On the private side, who am I interested in? I think.
One thing that I think is fascinating that I think is just starting to become palatable for the market for us to talk about, because it used to be like in the hushes, everyone was like, longevity plays, longevity plays. But we can't talk about it because it's it's snake oil science. And I think we're starting to get to a point where like, no, real scientists are talking about how important it is to like actually be paying attention to these things. Also, fun fact, like not everything has to be like you live forever and we're going to cryo preserve you.
No, like not dying of diabetes is longevity. gosh, what's an individual company? I don't know that there's an individual company. I think just the space. I would pay attention to the longevity space because it's about to become really important.
Slava Rubin (51:44)
Wait, what's the pic? What's the pic?
Okay.
So,
got it, so you're longevity in the private. All right, awesome. Well, we have covered a lot of information, everything from you started out being a valedictorian and a hardcore athlete who dislocated some shoulders and that's really how you became a professor and who you are today. You have a crazy background, UCSF, Stanford, you love viruses more than the average bear
Nicole Paulk (52:00)
Long, long journey. ⁓
Slava Rubin (52:25)
My favorite line that you said was, microbes are not all scary. That should be one of the takeaways that we understand here, which is totally amazing. You don't do the 60-40-0, you do have 10%, but you focus there on all angel investments in the areas and the stuff that you like. As it relates to the market, it is the darkest winter in biotech, but you do think because of sentiment and macro, those things over time could shift. You think it's still a couple of years out.
We still have to be very competitive to lower our costs to bring drugs to market. You know, the average takes about 15 years and $2 billion for one drug, but you think it could come down to three to four years and maybe $100 million, which would be amazing. You're obviously a fan of removing phase three, but we'll see how that happens with ⁓ government and all that good stuff. You don't think there's going be a recession. You do think inflation is going to come down. God bless you. And the stock market is going to do okay, but biotech not so wonderful.
You told us all about Siren, which you did a wonderful job of explaining it. There's the viruses, the payloads, the platforms. Who needs to redo everything? You're like, hey, let's just figure out how to have one payload that solves everything, which to my small brain doesn't understand how that all works. But since you have a big brain and able to do gene therapy and all this good stuff, you have figured it out. You're going to create the Keytruda for viruses. The first thing that could do more than one thing, do stuff in oncology. It's called Siren 101. Actually, it's an incredible new startup.
that you happen to be the founder and CEO of. You've raised lots of good money from lots of good investors and you're doing a community round now. You're actually going to be starting dosing next year, which is super exciting. And we all want to see what happens next because we all hate cancer and we would love for you to help solve it. And you're finally, your picks were BBIO in the public space and you wouldn't give us a pick in the private space. So you longevity across the board. Nicole, thank you very much. You are very interesting.
Nicole Paulk (54:16)
This was wonderful. Thanks for having me.
