Let the Science Lead: Building Successful Biotechnology | Nicole Paulk (Part 3/4)

Intro - 00:00:06: Welcome to the Biotech Startups Podcast by Excedr. Join us as we speak with first-time founders, serial entrepreneurs, and experienced investors about the challenges and triumphs of running a biotech startup from pre-seed to IPO with your host, Jon Chee. In our last episode, Nicole shared stumbling into one of the most famous stem cell labs in the country via Craigslist, the PhD she describes as the "golden, pure, best days" of her scientific life, and how a K01 grant opened every door. If you missed it, check out part two. In part three, Nicole talks about arriving at UCSF and growing frustrated watching gene therapy companies perpetually reinvent the wheel, building out full tech stacks for single diseases, and writing a frantic three-day, two-pager for a UCSF Brain Tumor gift that put an AAV-based approach in front of oncologists for the very first time. She shares how COVID shutting her academic lab while industry colleagues walked back in as essential workers lit a fire, how she incorporated Siren on paper as a sneaky way to get back to work, fever-dreamed the logo, won UCSF's entrepreneurship course Best Startup award, and landed a $6,000,000 seed from Founders Fund—more money than her entire academic career had ever seen—with no board attached.

Nicole Paulk - 00:01:48: I've got my own time and space and money, and, like, now we're gonna do something cool. Okay. What are we doing? And just kind of being frustrated with, like, even as a postdoc, even when I was still a postdoc, much less a professor, I was already getting started to ask to, like, either be an hourly consultant or to sit on the scientific advisory board for a lot of companies, and that just, like, exponentially went up the minute you got a professor title.

Jon Chee - 00:02:08: I guess, real quick on moving from Stanford to UCSF, was that a similar thing where you just ask? Like, you're just like, "I wanna be at UCSF. I have a grant." And then it happens?

Nicole Paulk - 00:02:17: If you have a K01, people will just, like, bend over the—because it's just like you have money.

Jon Chee - 00:02:22: Yeah. Yeah. They're great. We don't have to pay for you.

Nicole Paulk - 00:02:25: Come on over. The Price is Right. So, no, if you have a grant, like, that's, like, the secret that no one tells you if you are a postdoc. If you have a grant, you can go anywhere. You may not get a tenure-track position, but, like, any university on Earth will take you if you have a grant. It's just most postdocs don't, and so you have to apply for a faculty professorship in a department that has an open billet. And, you know, it's like a whole rigmarole. But, like, if you have a grant, they'll be like, "Yeah. We can go, like, some space over there." Like, it's not a guaranteed position forever, but, like, we've got two benches over there. You can sit over there because then, you know, they get to pull indirects off of your grant. So it's just like, of course, you have money. Of course. Just come on over.

Jon Chee - 00:03:07: Interesting.

Nicole Paulk - 00:03:10: So I was like, alright. What am I gonna work on? Like, oh my gosh. Like, I just wanna—I'm like, imagining, like, I'm gonna go back to my PhD. Like, I want it to be, like, this unfettered, perfect time where we're thinking about, like, what are the problems that only academia can solve because they just take too long or they are too nuanced or they don't have an immediate use case? Like, it's, like, fundamental basic science or something like that. Like, what are the things that can only happen in academia versus things that could probably happen out in the industry, but, like, specific to gene therapy? And I had always kind of been frustrated. I kept getting asked to sit on all these scientific advisory boards for all these companies, these gene therapy companies. And everyone wanted every single time, like, without fail—bless all of them. I love all of you—but, like, they all asked me to sit in the same whiteboard meeting. We would, like, sit down, and we're, like, spitting out the whiteboard and be like, "Okay. We have, whatever, $10,000,000 to go after something. What should we go after?" And you're, like, "Okay. Well, what's your secret sauce? Like, what's the thing? Do you have, like, fundamental biology you've uncovered? Do you have, like, a new capsid? Do you have a new gene that you could target in some interesting way because you found some cool fusion?" Or you're, like, personally motivated by someone in your family that has, like, a rare genetic disease, and now you're just trying to figure out, like, "What's the best path to target that and treat that with the gene therapy?" But, like, we kept coming back to the same beef, which was that, like, well, every AAV gene therapy on Earth, we always have to change the payload. So we only ever treat rare Mendelian monogenic diseases where, like, you're missing either full whole-hog, missing a copy of a gene, or it's mutated, and so you're not making the protein gene product from it. And so all we're ever doing is gene transfer gene therapy. We would just give you a copy of that gene back. I'm making light of something that is very difficult, but, like, you know, essentially simple in theory. Like, we're just gonna give you a functional copy of that gene back and, like, ta-da, you'll be cured. But I kept seeing, like, man, even taking something that was, like, a known process, a known thing to do. Like, we're gonna just take existing capsid, an existing promoter, existing backbone, existing method of manufacturing, all the things, and we're just gonna swap in your new payload for your new gene. And just seeing how hard that is in practice to do—it sounds very simple, but how hard it is in practice to actually do that, particularly, like, you know, in, like, the nascent beginning part of a field, like, gene therapy has not even hit its stride yet and still hasn't. And just seeing how hard that was even when done simply, and then you add the fact that, like, all of these companies were like, "But"—and they kinda, like, sheepishly look off in the distance over their shoulder, and they're like—"But we also don't wanna pay any licenses to anyone for anything. So we want a completely custom capsid, but we don't wanna pay someone else to make one from, like, one of the capsid engineering companies. We wanna own it. So we want a capsid engineering team and a promoter engineering team and a backbone engineering team and an ITR engineering team, and we need a manufacturing upstream and downstream team." And, like, all of a sudden, you're like, "Woah, bro. Like, you need a lot of money now."

Jon Chee - 00:06:29: Yeah. Yeah.

Nicole Paulk - 00:06:31: Just you balloon this, and it is a really big thing. But this also was simultaneous with, like, the market just being crazy. Right? This was, like, 2020, 2021, even early early 2019 where it was just like you just breathe on a piece of paper, and people would be like, "How's a $50,000,000 seed sound?" It was just so easy to get money. And so it's just like these two things went together where it was just like, well, it's so easy to get money, and we wanna own the whole tech stack. So let's just, like, let's just build everything. Let's have these huge teams and these huge projects and have everything balloon. And simultaneously, right, you had, like, these CEOs getting hauled in front of Congress being like, "Explain to me why it's okay that your list price for your gene therapy is $4,000,000. Explain that to me." And although they had valid reasons that, like, this stuff is very expensive, these are very rare diseases. And so, like, you have to recoup costs from the very small number of patients that there are. It was just like everyone was talking past each other. It was just like you had, like, the public and, like, Congress and everybody being like, "Why are these so expensive?" And then you have, like, CEOs and investors and all these people being like, "Let's do mega rounds and give everyone enough money to, like, build out the whole thing so that they own it all," and just being like, "This is, like, such a head-scratcher." I'm like, "Is there another path? Is there another way we could do this? Like, could you make theoretically, like, pie-in-the-sky, academic, like, thought game? Like, could you make a single AAV gene therapy drug product? Like, just one vial. Where, like, from that one vial, rather than only being able to treat one disease, like, what if it could treat two or 20 or 200 or 2,000? But, like, it could treat more than one thing. Like, could that be a thing? What would that be?" And if you could do that, then maybe that would be a way to, like, short-circuit, like, all the perverse incentives and everything going on such that we could make affordable gene therapies that people could access and make them more quickly. And so we had, like, started on this project, like universal payloads project, to just kind of think about that and, like, simultaneous, at that exact moment, heard through the grapevine that there had been a very large gift to UCSF, to the Brain Tumor Center. And the gift from this family was to have folks who were not oncologists, who were not professors in, like, the Department of Medicine in oncology, to come and test drugs that had never been used in cancer before for the first time. So they, like, wanted to do this, like, you know, bench-to-bedside and translational stuff and, like, bringing folks together that had never talked together before to do kind of like a drug repurposing ask. Like, "Let's see if your antifungal drug does something in cancer. Let's just try something new." And it was like, you know, write a two-pager together and submit it to this committee who's reviewing these on behalf of the family. And I was just like, "We should submit an AAV."

Jon Chee - 00:09:20: Yep. Let's do this.

Nicole Paulk - 00:09:22: That has never been done in cancer before. Like, that could be cool, and that could maybe be, like, a universal—we there's, like, all kinds of things we could think about putting inside of an AAV that could be used to treat cancers, where you're not targeting an antigen on the cell surface. Right? This isn't like a CD19 play. There's all kinds of things we could put inside the virus that could express things that could be anti-cancer and of use. And so I was like, "What if you do, like, a universal AAV gene therapy but for cancer?" But we had, like, three days to, like—quick—put this two-pager together. And so, like, you know, didn't sleep for, like, three days and was just, like, immediately immersed myself in the oncology world, which was not my forte.

Jon Chee - 00:09:58: Yeah.

Nicole Paulk - 00:09:58: And I have my virologist—I mean, some viruses cause cancers, but this was not my forte. So, like, didn't sleep, like, really. I just, like, got into it and was just, like, alright. AAVs. Let's—like, that meme of the guy.

Jon Chee - 00:10:09: Yeah. From Hangover?

Nicole Paulk - 00:10:10: Yeah. Like, yeah. Making, like, this thing on the wall being like, "It's all connected," like—and wrote this little two-pager. And, like, lo and behold, I was, like, one of the six labs that was chosen to receive funds from this gift. I was like, me and, like, like, Jay Dowd, like, me and Jennifer Doudna, like, a few other labs. I'm just like, I have no business being amongst this, like, amazing group of, like, very esteemed and established people. And I'm over here like, "Hi. I wanna do, like, a gene therapy with the AAV." And they're like, "That's not an oncolytic virus." And I'm like, "Yeah. Yeah. I know."

Jon Chee - 00:10:45: Yeah. Exactly.

Nicole Paulk - 00:10:46: And they're like, "Whatever. Like, go play in the corner." Okay. Cool. And, like, right at about that time, we had, like, just got started to do some stuff. Like, the data started to look like, "Okay. Okay." I mean, it's still, like, super early. Like, it hadn't narrowed stuff down at all. We were using, like, Addgene comms. I mean, this is, like, academic at best. But, like, you know, had data to kinda suggest maybe something here, and then that's when COVID hit. At exactly what it was when COVID hit. And it was just, like, we couldn't go back in, couldn't go back in, couldn't go back in. And it was just, like, peak spiteful frustration with, like, the system and the man and just being like, "Why can't I go to work?"

Jon Chee - 00:11:22: Yeah. Yeah. Yeah.

Nicole Paulk - 00:11:24: And all of my colleagues out in industry were essential workers, and they're like, "We're we're just essential. Like, we're allowed to go back. No matter what you're working on, like, you didn't have to be working on COVID. You could be working on, like, whatever, robots." But, like, everyone in industry was just considered an essential worker, but academics were not. Even though I was, like, a virology professor.

Jon Chee - 00:11:41: Yeah. The irony.

Nicole Paulk - 00:11:43: The irony is just being like—and and yet there was an incubator, like, on campus for faculty spinouts, and they could come back because it was, like, under a different, like, jurisdictional layer.

Jon Chee - 00:11:55: Classic.

Nicole Paulk - 00:11:56: I was just like, man, I wonder what if I just, like, started a company? Like, wouldn't that be a cool, sneaky way? I was just, like, getting back to work. Yeah. That that was not, like, the grand plan or the vision or, like, "Oh my God. I'm gonna be the next Genentech," and, like, this is the vision. It's just, like, no. It's a sneaky way to get back to work.

Jon Chee - 00:12:14: Love that.

Nicole Paulk - 00:12:15: And fever-dreamed out the logo and everything, like, on my computer. Trying to think of a cool name. I'm like, "I want something that's, like, badass and kinda cool, but not too long and, like, very easy to pronounce and very easy to spell." And I hate it when people have, like, whatever their company is, like, Profliphius, and you're like, "What's the name?"

Jon Chee - 00:12:34: Yeah. Yeah. Yeah.

Nicole Paulk - 00:12:35: "It's the Latin god for soil," and you're like, "You're a CAR T cell company. Yeah. I don't understand." So I was just like, "I wanna, like, this big powerful name." It's easy to spell and, like, kinda had a cool connotation to it and stuff and tried to find something that had, like, an open domain and an open trademark, and—and just really liked the name Siren and so kinda went with that. Like so I incorporated it on paper, but it's not, like, told anybody. I was just like, I'm just, like, scheming. I'm like, "What if I start—" Yeah. Yeah. Yeah. Incorporated on paper. UCSF had this cool program. It's like a course you could take with your trainees. It was like this entrepreneurship 101 course, and it was like, over the course of the course, we will literally just, like, start your company. Like, we will just, like, as part of the class, like, we will teach you, like, how to get incorporated and, like, what goes in a data room and what do you need in a pitch deck and, like, how do you interact with VCs and just, like, all of the brass tacks, like, how to get a lawyer to help you draw up the docs and, like, whatever. So, like, you just actually do it as—as the course for credit. But it was interesting because you have to—you as the professor actually have to take it with, like, it can be, like, a single person from your group, but, like, I took it with, like, a trainee. And I was like, "Let's take this entrepreneurship one class and, like, learn how to start a startup." And then the final is you pitch to real VCs. So they, like, bring in a bunch of VCs from here in Silicon Valley. And so, like, we pitched and we won, like, best starter of the year, and then, like, took that cute, lame little pitch deck that we went that was, like, "Oh, bless." So bad. But, like, bless that little pitch deck that we made, and we, like, won a little Catalyst grant from UCSF.

Jon Chee - 00:14:06: Cool.

Nicole Paulk - 00:14:07: And, like, I went out and, like, I knew a bunch of VC. Like, I was a KOL that often got asked to do diligence from being a big famous professor at a big university. Like, "Hey. You know, can you diligence this deck for us scientifically?" And so I just pinged a bunch of folks. And I was just like, "Hey. What if I sent you something that, like, I might do?" And to this day, like, to my dying day, this will continue to be amazing to me that, like, I got absolute, like, tier-one marquee, like, S-level investor, like, Founders Fund, Luxe Capital. Like, people I have no business talking to were like, "Yeah. Like, if you're in, if you're gonna leave and do this and, like, you're gonna be the CEO, not the CSO. Like, you have to be the CEO. Like, if you do this, like, this sounds super cool. Like, yeah. A universal gene therapy that can be used to more than one thing. That sounds dope. We love it. How quick till you can be a decacorn? Okay. Yeah. Yeah." But it was, like, back in—it's just in—now in '21, and it was just, like, the heyday of raising and of the hype and of everything. And we spun out, and we went to the little—it was, uh, actually a Bayer Pharma. There was an incubator across the street that Bayer Pharma was running called the Collaborator, and I had consulted with them forever. So I was just like, "Hey, guys. Like, can I just, like, have a bench?" Yeah. Tough space. For sure.

Jon Chee - 00:15:30: Yeah.

Nicole Paulk - 00:15:31: So we, like, got a bench in the Bayer Pharma Collaborator, and I had $6,000,000 from Founders Fund, was just, like, more money than my lab had, like, ever had, but a lot. And it was just, like, so weird going from, like, academia where you have to, like, just hustle so hard for a crummy little grant with, like, $50,000. And, like, every single time you wanna bill anything to it, you gotta, like, fill out, like, a TPS report for, like, why you need mice. And you're like, "Well, because I do." And yeah. Like, all these progress report, like, just all this oversight and, like, all these thing—like, all the admins you have to please and all of these layers of bureaucracy and stuff both within your university, but also with the NIH and just everything. It was just, like, going from that whole experience out to, like, you're just in a collaborator with other, like, super hungry startups, and you've been given money. It's like it was just wired to Founders Fund about, like, "Here's—here you go. Call us if you need us." And you're just—and everyone, like, leaves you alone. And there's just, like, there's no committees. You don't have to ask anyone for permission outside of, like, you know, you need some, like, permits and things to, like, order chemicals and stuff from, like, the city and the county. But, like, outside of, like, a few permits and things that you need from, like, the city and the county and the state, you just get free rein. And I was just like—

Jon Chee - 00:16:51: What? This is—

Nicole Paulk - 00:16:53: —crazy, y'all. I—oh my God. I have more money than I've ever had both professionally or personally. Like, I have an amount of money that ends in "million." Not like 5,000 or 10,000 or 100,000. Millions of dollars and, like, space, and we can just, like, do science that I think up. And, like, I didn't have a board because Founders Fund is well-known. They don't take board seats. They are about as anti-board as you can imagine. They have whole manifestos on this. You can go read about it. So my partner, Scott Nolan, did not take a board seat. So I did not have a board for, like, the first three and a half years of Siren's existence, and it was just like, amazing. The best thing that has ever happened. And I think more companies should start without boards because we didn't waste. It doesn't mean that there are not times where a board is useful. They obviously can be. But, like, man, I would hear my other friends talk about their boards and just, like, how brutal. They're like, "Oh, man. I got a board meeting next month." And I'm like, "Yes. Next month, who cares?" And they're like, "I already have to prepare for it. Like, basically, as soon as my one board meeting ends, I immediately start preparing for the next one, and they're so awful." And it's just like I spend so much time, like, dealing with all these emotional people and their whims and their wishes and creating these decks and dealing with problems that they have with me or with the company or with the data or amongst themselves. And I was just like, "I don't have any of that. Like, it's amazing." And I genuinely think that we are a better company today because we didn't start with a board where there was this, like—and I say this with love, genuinely. Like, I'm not saying this to be flippant. Like, a lot of board mechanics are exactly that. They are mechanical, and it serves no purpose. There are absolutely important times for a board where they do important things, and you decide important things, and it's important to have oversight and governance. But those moments are few and far between, particularly when you're a really early company. And there's not, like, comp committees, like—no. Like, when you—like five people, you know, it's just—it's a lot simpler. And so we got to move so much faster. And I actually think to do better science because we weren't kind of being baby monitored. And maybe that, you know, only worked because I had come from being a professor. And if I had spun this out as, like, an undergrad or a grad student, we would have never worked because I wasn't aware enough of kind of how things needed to be and knew enough. So I don't know. But, yeah, not having a board for, like, three and a half years was really magical and really special, and not just because, like, so kid running around crazy in a candy store with no supervision, but, like, I actually think it made us a better company for all kinds of reasons. And if I could change the world, the biotech world, I would wish upon other people. I wish on behalf of them, like, my make-a-wish for them would be that they could have a period of time in their company where they didn't have a board so that you can kind of get back to that, like, PhD moment where it's just pure. And, like, I promise you no early-stage startup is dicking off with the money. Like, they're all hustling and trying to find a way to use less money to do more and using it efficiently and diligently. But, yeah, just that ability to kind of have pure unfettered, unbothered, and undistracted time to just really go hard and let the science take you where it will. I think that could be, like, a transformative. And maybe something like that will happen now in this new world where time pressures are immense. Like, you have to beat China because now, you know, they eat your lunch. So in this world, what is the cheat code? How can you find a way to do more with less, both, like, achieve more in less time, achieve more with less money? Like, crazy wild thought. Like, at minimum, right, folks are having one board meeting a quarter. And I would say at minimum, most of those companies are spending at least two weeks preparing for each board meeting where at least, you know, the most senior folks are doing almost nothing else for those two weeks. So we were talking eight weeks a year at minimum that you could get back if you didn't have that. Eight weeks. That's, like, at best. I mean, I know folks who are spending a whole lot more than eight weeks a year preparing for, giving, and then dealing with the aftereffects of their board meetings. Like, is there something we can do there? Is there some—like, the equivalent of the YC SAFE where, like, let's not overcomplicate things that don't need to be comp. Is there an equivalent thing to, like, the YC SAFE but for boards? Is there, like, a more efficient way to simplify the genuine need to have some level of oversight and governance and, I mean, obviously, the audits and thing whatever. But, like, is there an equivalent to, like, the YC SAFE that could be done to make boards more efficient so that we could get some of that time back? Because, I mean, you talk to investors too, and you're like, "Are you excited about the boards?" Like, to go to board meeting, they're just like, "No. They're awful. No one wants these. Why are we doing them? Like, we're just going through the motions." Like, can we somehow reinvent them in a more useful way? And what would that look like? That's a fun—like, I would love to get lost in the forest for a week with some folks and, like, think about, like, how could you reinvent them? What's the equivalent of the YC SAFE but for boards?

Jon Chee - 00:22:17: I mean, that's an interesting beginning for Siren. It kinda reminds me of your PhD-to-postdoc experience where you go from, like, wandering and then you go to Stanford, which is, like, optimization. Yeah. Focus optimization mode. But I think it's always like this. You have to have that moment of, like, exploration first. And then when you find it, then you start. But, like, I think it's kinda like at the very beginning of our conversation. Like, my friend's daughter who had a parent-teacher conference—she's in kindergarten, already focusing.

Nicole Paulk - 00:22:49: Yes. Like, woah.

Jon Chee - 00:22:51: Like, let them finger-paint. Like, yeah.

Nicole Paulk - 00:22:54: Let them finger-paint for a bit. Let them wander and dream and think and mess up.

Jon Chee - 00:22:59: Yeah. For sure.

Nicole Paulk - 00:23:01: Yeah. And now, Siren is just, like, laser-focused. Like, we are so laser-focused, but I think one of our great advantages that we have over other people that I don't think other people could catch up and do is the fact that we had that time. Right? We were stealth, and so people didn't know we existed, and we weren't being bothered. We had no board, and we were given—we had, like, more than enough money. I mean, $6,000,000 was, like, just an unfathomable amount of money to me. So I just always chuckle when people are—you know, you see whoever—I won't name company names, but, you know, their seed was, like, a 100,000,000, and they still can't achieve anything. It's like—

Jon Chee - 00:23:39: Yep. For—

Nicole Paulk - 00:23:40: —years. And you're like, "What? What were you doing?"

Jon Chee - 00:23:43: Yeah. Yeah.

Nicole Paulk - 00:23:44: That is so much money. You still couldn't manage to, like, cobble anything together. But, like, you know, we had more money than I could ever dream of, $6,000,000, and just, like, this unfair time. And, like, what we did with it was, like, kind of heretical. It's like, alright. You have all this money from, like, this tier-one—I was like, Founders Fund, like, marquee investor. And everyone's like, "Alright. What are you doing with it? Like, passing you the mic. Like, tell me this crazy, big, epic, like, uh, Silicon Valley thing you're gonna do with it." And I'm like, "We're gonna go all-in on CMC." Everyone's like, "Bro, what?" And I'm like, "I have advised so many companies where, like, I was either already on their SAB or an hourly consultant or I got brought in as an emergency KOL when they went on CMC hold or clinical hold, and their clinical hold was almost always a CMC hold." And I was just like, "I just keep seeing folks"—I mean, we're, like, doing all kinds of discovery stuff to, like, actually get a name development candidate ready, but, like, that was happening regardless. But, like, in addition, all of this CMC stuff and I was just like, "Man, once that ship has left the harbor, like, you can't bring it back." So it's like once you have put your flag in the ground and said, like, "This is how we're making our virus," like, you can't go back. So it's like you have this one shot. And, like, your company might live to be, you know, a 50-year or more company. You never get those first months and years back because once you start and you're like, "We're making the virus this way, and now we've submitted an IND," like, it's set. We are starting to get more flexible now in this new regulatory environment such that you can make small changes to CMC in a way that even single-digit years ago was not allowed. But, like, historically, it has never been that way. It's like, once it is set and it cannot be changed—and so I was like, "No. We need to, like, have time to, like, test all the conditions, all of them, and, like, really do some of, like, the most boring experiments that are, like, thank God we didn't have board meetings because I'm just, like, imagining showing them this, like, upstream optimization of, like, viral manufacturers. It's like the most boring plots." I say this with all love, my heart for CMC. It's amazing. I love it. But, like, you know, relative to, like, some big splashy, like, "Oh my gosh. We just did RNA-seq, and we have, like, all this new cool data that we can show you. We've, like, mapped all of these interesting relationships between cells and viruses," you know, like, cool stuff versus, like, "These are viral yields." But we spent years, like, really just nailing that, and now we—I'm gonna—I'm gonna knock on wood. Probably shouldn't say this out loud, but, like, I feel so confident in what we've built and, like, the data that we're getting that, like, there's no fast way to catch up and cheat code, and we ain't gonna publish that. So, you know, like, that's our sauce. And, like, no one would give a company money to go and spend three years, like, optimizing upstream and harvest and whatever. But we did that, and it was, like, super unglamorous. And there's no talk you can go give—I mean, you can absolutely go talk about CMC, but it's not gonna get you, like, a presidential symposium or something. But, like, it was just one of the smartest moves we ever did was, like, start really boring. Like, focus on this, like, what feels like a very, like, "Oh, well, once we make it, then we'll optimize everything and make it perfect." Right? Because the thing you always hear is just like, move fast and break things and, like, do this as fast as you can and, like, and, like, kick the can down the road. Like, "Oh, we'll figure that out later. Let's just, like, show that it works. Show that it works." And I was just like, "I feel like we can do these in parallel. Like, $6,000,000 is a lot of money. Like, I feel like we could both come up with our development candidate, like, do our discovery work, but also, like, work on CMC because that's, like, the thing that always slows everybody down." And, yeah, zero regrets. I mean, part of the reason we stayed stealth was not because we were, like, working on some extra super mega secret thing. It was just that, like, if we came out of stealth, we would have to, like, be out giving talks. And, like, those just aren't interesting talks. Like, no one's even like, "Oh my gosh. And we're excited to have Siren here to give the presidential symposium on plasmid optimizations." You know? So it was like, we stayed stealth just because we didn't want anybody to know that, like, we had no big shiny talk to come give, and you didn't have to, like, put out, you know, a steady cadence of press releases. So it's just like, "Yeah. Let's just stay south. Don't let anybody know that we're working on this stuff." And it was so smart.

Jon Chee - 00:28:10: I guess a question for you, like, what is the consideration of, like, staying stealth or, like, going stealth or just, like, debuting, like, as—as soon as you make your company?

Nicole Paulk - 00:28:19: I think I would have answered this differently in—in the past versus now. Right? The—like, the answer now and, like, whatever it is, March 6. Right? This answer in this current moment in 2026 is that it's a whole new world. Right? We now have folks who—like, it doesn't matter who—I mean, some of it doesn't even matter who patented something first. Like, it almost doesn't matter. It's just like, who's the first to get Phase II proof-of-concept data in humans regardless of if you publish it or not, regardless if you have a patent or not, regardless of if you were the first or not, regardless of if you were the splashiest or not? Like, nobody cares. It's just who has the best data in Phase II proof-of-concept and who got there first. And so if you think coming out of stealth can make you move faster towards that goal, you should do it. And if you don't think that's true and you can move faster by staying a bit of a secret, then you should do that. But it will be different for everybody. Different diseases, different modalities, different places in the world, different investors you might have gotten money from, the different kinds of goals of what you're trying to go after. Like, it'll all vary, so there's no one answer. But you kinda have to ask yourself that question now in a way that you may not have had to before. Like, you know, single-digit years ago, nobody was concerned with publishing a paper. And now people are concerned that you might enable your competitors because people can catch up to you so quickly in certain field. In some fields, there's still, like—it takes too long to replicate these things. But some stuff is just like, man, with enough money, you can just, like, robot-queue this stuff up in a weekend. And, like, what took you five years? I can do it in a weekend.

Jon Chee - 00:29:56: Off of publication?

Nicole Paulk - 00:29:57: From publications. Right? So it's like you have to consider that now before you publish. Same thing with patents. Like, it used to be. Right? Like, patent the minute you do something to practice, the absolute minute you reduce it to practice. Not even, like, the whole thing, just like the first inkling of something that could maybe possibly become a patent. The minute you reduce its practice, patent it. And now it's just like the script has changed, and now it's "Hold that IP. Don't tell anybody." And, like, you just keep that secret until as long as you can. And don't talk about it. Don't write it down. Don't put it in your data room. Don't tell anybody about it. You just, like, get as far as you can to buy as much time until you have to patent it, like, right before you're about to start your clinical trial, then patent it. And even then, you, like, carefully time it for right that, like, whatever, 16, 18 months or something where it's private before it becomes public. And, like, that gets timed to, like, the day, the precision around it. And it's just like it's a completely different world.

Jon Chee - 00:30:56: That's wild. I didn't know that, by the way.

Nicole Paulk - 00:30:58: It is a completely different—and all of this has shifted in, like, the last single-digit years. Like, this—so, yeah, like, how I would have answered this question the day Siren started is completely different from how I would answer it now. So we're just started the, like, accelerationist peak of the exponential line, and it's like, you're just, like, looking up and you're like, "Ah. Like, oh my gosh. It's asymptotic." It's like you're a kid again, and it's like the ground is lava and you're jumping between sofas with your brother. Like, things are changing under our feet so fast. Now more than ever. Like, you need, like, the sanity of just kind of grabbing the table and being like, "What's real? Like, where are we, and what are we working on, and what's real, and what can I depend on? What is not going to change?" Right? That, like, kind of classic famous talk that, like, Jeff Bezos has given where he was like, "The question I ask at Amazon is, like, not what's changing. It's what's not going to change." Right? What can I count on being true even a decade from now, which is that customers are going to want products cheap and with quick shipping? Right? Like, I feel like now more than ever with, like, just the dynamic with everything with, like—with AI and all of the kind of scientific advances that we're all having and the pressures to move faster from other countries and kind of the interesting scientific and dynamic moment we're in where it's like, you almost need to ask not what's changing with AI. It's what's not changing, and what can I depend on, and what can I ground myself and my team with? What can we still forecast about, like, how we should be thinking about our department goals and our corporate goals and our project goals and our personal development goals? You have to ask both sets of questions. What is changing and what do we need to do to be prepared for that change? What can we do now? And let's anticipate and all those types of things. But also simultaneously, what is going to stay the same or that will change, but at, like, a—a predictable pace that we can use to kind of ground yourself so that you don't run into that same problem that, like, I started to feel the moment I showed up at Stanford, which is, like, everything is changing, and it's so much, and it's so big, and you start over-optimizing, and it—you need everything to be predictable and perfect. And all of a sudden, you feel overwhelmed because it just feels like "You know nothing, Jon Snow." You know? Yeah. Yeah. It's like nothing is real, and everything feels like it's AI slop, and everything feels impossible to predict, and everything feels like it's moving so fast. And you feel like you've never felt more behind on the literature, and you just can't possibly stay up on what your field is doing much less like other fields where you wanna be well-read outside your space and all of the changing things that are happening, you know, with regulations and just everything. And it just feels, like, overwhelming. And it's like, at some point, you have to kinda just—what isn't changing? What can I count on? What can I depend on? What do I know is true? And kind of ask both sets of those questions at the same time so that you can, like, still keep going and not feel so overwhelmed with everything going on because it is just—this is the craziest slice. I mean, I'm biased because we're living through it, but this is the craziest slice of history, I think, maybe ever. Sure. So it's a wild time to, like, have textbooks being written in the background about, like, everything that is happening while at the same time, you're like, "How do I make payroll? Like, how do we run this mouse experiment in, like, the most cost-efficient way? And what are the readouts that we care about?" You know, it's, like, crazy to have, like, both those things happening at the same time and trying to kinda stay sane, which is hard.

Jon Chee - 00:34:15: Yeah. Yeah, dude. How big is your team now?

Nicole Paulk - 00:34:18: Oh, we're crazy small. We are—

Jon Chee - 00:34:20: Okay.

Nicole Paulk - 00:34:21: —five people. We are a clinical-stage company. Five people.

Jon Chee - 00:34:27: Love that.

Nicole Paulk - 00:34:27: But I think that is the future. I think gone, possibly forever, but at least for right now until we, like, sort out up from down because everything's so dynamic right now. At least in the short term, this is the future. This is the way. Gone are the days of, you know, a $200,000,000 Series A and hiring 50 people and a completely built-out C-suite and having platform teams and product teams and asset teams that have completely built up—you have a built-out pipeline on your website as a series seed company? Six things. You're going after six things with completely different modalities, not just six different assets in one modality class. You have different modalities going after different diseases in different tissues, and it's just like, how on God's great earth are you gonna do this? Like, just those days are gone. Now is the moment of, like, nimble, small, fast, focused. Doesn't mean you can't be a platform company. We are a platform company, but gone are the days of bragging to other people and comparing yourself to other companies based off what their headcount was. Right? Look at the question you just asked me. "How many people are you now?" Right? Because normally that used to be a metric. It was like, "Oh, you're 200? You must be doing so well." Now I hear 200 people, and I'm like, "Oh, I'm sorry."

Jon Chee - 00:35:52: The reason I ask is because, like, for Excedr—I mean, we're not like a therapeutics company. We lease equipment. But I remember we were, like, fully remote before COVID, and that was, like, super weird. And, like, we're super small, and we just, like, punch above our weight. But, like, I even remember early prospects would look down on me because we were small and work remote. And they were just like, "Yeah." I was like, "For what?" Like—like, what is, like, just a bunch of people actually mean? It's like it's the work itself that truly matters. And, like, efficiency is cool. Like, I—I don't know. Like, efficiency is freaking rad. And I guess, like, what would you say were, like, the key contributors to get to a clinical stage?

Nicole Paulk - 00:36:33: It's no one thing. It's a combination of things. I think it's you had a founder—a technical scientific founder CEO who, like, this was their baby. So, you know, I was not in this for the money. So I was like, you know, for the first five years of the company, I think I was the lowest-paid person. I was paying myself nothing, and it didn't matter versus, you know, a hired brought-in CEO. It's like, "Oh, yeah. So my base pay starts at 800,000, and I need a 50% bonus and an annual increase every year." It's just a different perspective.

Outro - 00:37:02: That's all for this episode of the Biotech Startups podcast featuring Nicole Paulk. Join us next time for part four where Nicole unpacks operating without a board for three and a half years, calling it the best thing that ever happened, going all-in on unglamorous CMC optimization from day one, and pushing back with every fiber of her being on the perception that a first-time female technical academic founder CEO is the worst possible thing you could be. If you enjoy the show, subscribe, leave a review, and share it with a friend. Thanks for listening, and see you next time. The Biotech Startups podcast is produced by Excedr. Don't want to miss an episode? Search for the Biotech Startups podcast wherever you get your podcasts and click subscribe. Excedr provides research labs with equipment leases on founder-friendly terms to support path to exceptional outcomes. To learn more, visit our website, www.excedr.com. On behalf of the team here at Excedr, thanks for listening. The Biotech Startups podcast provides general insights into the life science sector through the experiences of its guests. The use of information on this podcast or materials linked from the podcast is at the user's own risk. The views expressed by the participants are their own and are not the views of Excedr or sponsors. No reference to any product, service, or company in the podcast is an endorsement by Excedr or its guests.