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How Viral Gene Therapy will Revolutionize Cancer Treatment with Nicole Paulk, Founder, Siren Biotechnology

How Viral Gene Therapy will Revolutionize Cancer Treatment with Nicole Paulk, Founder, Siren Biotechnology

Immad and Raj explore biotechnology and the future of cancer treatment with Nicole Paulk.

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Transcription of our conversation with Nicole Paulk, Co-Founder and CEO of Siren Biotechnology:

Immad Akhund: Welcome to the Curiosity Podcast, where we go deep on a wide variety of technical topics with the smartest leaders in the world. I'm Immad Akhund, and I'm the CEO of Mercury. 

Raj Suri: And I'm Raj Suri. I'm the co-founder of Lima, Presto and Lyft. And today we're talking to Nicole Paulk, who is the CEO of Siren Biotechnology, a former academic who is now doubling down and focusing on viral gene therapy to cure some of the hardest cancers around, brain and I believe eye solid-state tumors. Really interesting conversation today. I mean, everyone wants to hear about what's happening with cancer therapy and I've wanted to hear about it from a real expert for a long time. And today was a chance I finally got to do that. Immad, what were you curious to learn about from Nicole?

Immad Akhund: You know, one interesting thing is you keep hearing about these things and like pops sigh, right? Like it's, oh, this cancer is cured, blah, blah, blah. And then you get a little jaded over time, thinking that like OK why haven't we killed cancer? So I really love that. Like there's serious progress. And Nicole just does an amazing job of really explaining it. And cancer is not just one thing that is like hundreds of different pathologies and going deep into what are the different things and what is gene therapy. And I think we learn a lot during this. So I think the audience will really enjoy it.

Raj Suri: Yeah, I think we learned a lot and we enjoyed doing it too because Nicole's energy and enthusiasm was contagious and so I really enjoyed her attitude towards, you know, her optimism towards these very difficult thorny problems too that, you know, are often life-threatening. That part was great to see. I think learning about gene therapy too was really, really interesting, as you mentioned, and this technology, where it is in the curve today and where it can evolve to, really powerful stuff. And so let's dive into it. Welcome, Nicole, to the Curiosity Podcast.

Immad Akhund: Welcome, Nicole. Thanks for joining us. Let's talk about Siren Biotechnology. So you started this company in 2021. Give us a quick preview on what it does.

Nicole Paulk: So this was all work based out of my lab. So prior to starting Siren, I was a professor at UCSF here in San Francisco in the biochemistry and biophysics department. Although I did neither of those two things, I was a virologist and a viral gene therapist, which is a fancy way of saying we use viruses as medicines. And one of the earliest projects in my lab that we whiteboarded out that fast forward like five to seven years later became Siren, was every viral gene therapy, which is where you use a virus as a medicine, can only be used to treat one disease at a time, right? You can't treat a little boy who's got hemophilia B with a virus you made for a little girl that's got a muscle wasting disorder, right? They're very different diseases. And so the medicine, the payload that you put inside the virus… needs to be different. That just makes this really hard because you have to do these one at a time. So we wanted to ask a pretty audacious question. 

We were one of the only viral gene therapy labs that didn't work on viral gene therapies in that we didn't work on specific medicines. We worked on the platform itself and tried to develop enabling technologies to kind of make any virus cheaper, easier, and faster to make to be used in more and more therapies for more indications. And we wanted to ask a really audacious question. Could you make a viral gene therapy? Could you make a virus that could be used to treat more than one disease? Not just two things, but maybe 200 things or 2,000 things. Could you make a universal gene therapy that could treat many, many, many things. And so now you make it one time, but you can use it like 10 ways to Sunday. And now you kind of get all the economies of scale that happen in so many other industries that you guys cover on the pod and these types of things. And so we wanted to ask that really audacious question and had no intentions of necessarily pointing that ship at cancer and oncology, just were very excited about that concept. Could you make a universal gene therapy? And what would that mean? And what would that look like? And scientifically, how would you go about this completely crazy idea? 

And fast forward, like I said, about five to seven years of work. We figured out a way to potentially do it and actually decided to point the ship at oncology. So we're going to make the world's first universal gene therapy and the world's for the particular virus that we use, which is called AAV or adeno-associated virus. The peculiarities there don't matter, but it's the main virus that the field uses to treat patients. We're going to use it for the first time in cancer.

Immad Akhund: I guess before we dive into that, maybe this is like a little bit of a basic question, but what is viral gene therapy? Like, what's, like, what are you, what is the virus doing? Like, is it changing your genes? Or like, what's, what does it mean?

Nicole Paulk: So viral gene therapy, just broad strokes, is just using a virus to perform like a medicinal act for it to be a therapy itself, which A lot of folks didn't even know that was possible. They're like, no, no, no, wait, all viruses are bad. All viruses cause diseases. No, no, no, no, no, no. That's actually, the vast majority of viruses don't do that. Of all the viruses we've ever discovered on planet Earth, from all of these, you know, searching efforts and these types of things, the vast majority actually don't make humans sick. I think if you ask most people on the street, name a virus,

Immad Akhund: Isn't that just because they ignore humans? Or are you saying there's viruses inside us that don't want to say anything?

Nicole Paulk: They're all over you. You're crawling with them. They're everywhere. They're on every single thing. They're all, it's just like bacteria, right? Where it's like, you know, you've probably heard of like, you know, your microbiome in your gut and probiotics, you know, good bacteria. There are viruses that are doing the exact same thing.

Immad Akhund: But they're all parasites, right?

Nicole Paulk: By definition, all viruses are obligate parasites. They can't live on their own. They need a host to help them live. But it doesn't necessarily mean that they're harming you, whether you means a human or you means a cow or goat, a dog, a blade of grass, whatever it is. It doesn't necessarily mean that it's harming you. It just means that it needs you to help it survive. But most folks, if you ask them, name me a virus, they can only name you what we call a pathogenic virus, a virus that causes disease, right? Chicken pox. cold virus, measles, mumps, polio, you know, these types of things, like the things we vaccinate little kids against. But they can't name you a virus that doesn't cause disease, even though it's overwhelmingly, like 99.999% of viruses on earth. don't make humans sick. They're very good at getting inside of you, but they don't make you sick. And so we can use those as tools to deliver things like medicines inside your body. And so that's what viral gene therapy is. We leverage and harness all of these other viruses, the vast majority of viruses on the planet, to use as delivery tools to deliver medicines.

Immad Akhund: What's the most kind of successful, productionized kind of example of a viral gene therapy?

Nicole Paulk: So these are all very new. There's only about five of them here in the US, so you can count them on a single hand. And they've all happened in the last, you know, just as many years. It's been about one approval every year for the last five years. And by far the biggest blockbuster in terms of has made the most money. This is a viral gene therapy called Zolgensma. And this is to treat basically a disease called spinal muscular atrophy, which is just like it sounds, like a muscle wasting disorder in these kids. And what can happen if you don't treat this, and there was no therapy before this, and this is very common with viral gene therapies, they get brought in as a last resort. Because what often happens with these genetic disorders, where you're born with this disorder from birth, is that either you were missing a copy of a gene that you needed or you had it but you had a mutation in it in a really critical spot such that the protein that that gene codes for wasn't being made. And that was the case in this particular disease. There was one gene that's involved and these kids either were missing the whole copy or they have a mutation in it. And it's really important to keep the muscles from wasting and atrophying away And what ends up happening, unfortunately, with these poor kids is that left untreated, which was the standard of care, basically, before these gene therapies came along, you know, they would usually die at about the age of three, because their diaphragm would stop working. Because your diaphragm is a muscle that helps your lungs pump, you know, oxygen in and out of your blood. And so, you know, when your muscles stop working, then they usually asphyxiate and die.

Immad Akhund: But now… What does the gene therapy do? Does it actually fix their genes somehow?

Nicole Paulk: So this one is not a gene editing gene therapy, but that is a class of gene therapy. This one just goes in. So it's a virus, like a little icosahedron, a little viral shell that's made of protein that goes in and delivers a functional copy of the gene that they're missing. It doesn't insert it into their genome. That's a common misconception. You can actually keep it outside of the chromosomes, right? All of our DNA exists on, you know, double-stranded DNA that exists on chromosomes. but you can have DNA inside of you that's not embedded within a chromosome that can still express forever. Oh, really? So it just gives you an additional functional copy of the gene that you now have, and your body can recognize it because it's written in the same language as your DNA. And it will just read it and be like, oh, I need to make this gene, and it'll just start making copies of it. And this is as if you were, you've had it the whole time. And then now these kids are developmentally normal. They're completely fine.

Immad Akhund: Presumably you have to keep getting injected by this virus.

Nicole Paulk: No, that's what's so extra special. And that's what separates viral therapies broadly with non-viral therapies. The huge win, the big kind of leverage and difference between viral gene therapies is that they're one-time treatments. because you don't lose that piece of DNA that they give you. You keep it forever. So again, even though it's not integrated into your genome, it can circularize inside your cells. And when it's a circle, it doesn't have a free end for your cells, little enzymes to come in and chew it up. Because if it's a perfect circle, there's no free end. And so it can just exist forever as this extra, what's called extra-chromosomal, which just means not integrated into your chromosomes, as this extra-chromosomal little circle, and you'll have it forever. So as long as that host cell, so in this case, in these kids, right, these are gonna be muscle cells, as long as those muscle cells don't die and they live for, in which most muscle cells don't, they're with you forever. then you'll have expression from that forever. So it's a one-time treatment. And that's very different than the normal drugs that we take for things that afflict us, where it's like, OK, you're going to have to take this every day because it only works so transiently. So that's a huge, big difference between many other classes of drugs and viral drugs, is that they're one-time therapies, and then you get to experience the benefit for life. It's very amazing. It boggles my mind, and I've been in space for 17 years. It's crazy.

Immad Akhund: To go back to the thing that you're working on, the adeno associated virus gene therapy, you're trying to make it so it does more than one illness, like it doesn't just do like this thing only does spinal muscle atrophy, you want to make it so like this, like you take this magic virus, and it gives you like 10 or 20 different.

Nicole Paulk: So the concept we came up with in my lab, we were like, okay, Every single viral gene therapy on earth, whether it's coming out of academia, a small startup, some small midsize company, big pharma, it doesn't matter. They're all going after what we call these genetic disorders, where a single gene is missing or has a mutation and you just need expression from that one gene in order to be basically functionally cured. That's like the lowest hanging fruit. That's where you start. But a number of diseases either have multiple genes involved, or they span multiple tissues, or in our case, we're going after things that have a shared mechanism. 

So we're going after cancers, where one of the most common ways that your body, or not that your body, that your tumors in your body get so large such that you start having symptoms and you go to the doctor and you're like, something's wrong, and then they do a scan and then they see your tumor. One of the reasons it was allowed to get so large is because through a variety of different mechanisms, and the details don't really matter, but through a variety of different mechanisms, they can basically evolve a little invisibility cloak, quite literally, so that your immune system can't see them anymore. And as long as your immune system can't see them, because normally, like every one of us on this call right now has a tumor, You've had one almost every day of your life. But it's a single cell. It's not a big, gnarly mass. It's a single cell. And every day, your immune system is going around in the background. It's part of its background to-do list of things you do every day. It just goes around and it finds cells that are a little bit weird. It's like, something's off about you. You don't seem right. I'm just going to chew you up before you become a tumor. It does things like this with inflamed cells, cells that have weird flags on their surface, cells that are just off, they're not right. Your immune system knows how to fight cancer. It's been doing it every single day. But if the tumors evolve a little invisibility cloak so that your immune system can't see them, then that's how they get the ability to grow and grow and grow, and then you get the symptoms from that mass, and then you go in and you go to the doctor. 

So one strategy in the cancer field is, can you take a tumor that's invisible to your immune system and just make it visible again? And then your immune system can come in and actually be the cancer drug and eliminate the tumor. And so we can use viruses to express certain types of payloads that can basically make tumors visible again, so that your immune system can go after the tumor and fight it itself. So you become the cancer drug.

Raj Suri: Sounds pretty amazing. What are the challenges you have with this type of treatment? I mean, you've been working on this for 17 years. It sounds like in that 17-year time horizon, it looks like it's kind of been successful with this, you call it spinal dystrophy, is that right?

Nicole Paulk: Spinal muscular atrophy, and then about four other diseases, about five that have been approved. So, it's been slow coming, we're just getting to the point, you know, there's like the hockey stick graphs in every field doesn't matter the field. And we're like, right at that moment where it's like tilting, it's not vertical yet, but it's like, the tilt just happened in like the last literally one to two years. And I guarantee you in the next five to 10, you will start hearing about gene therapies for diseases that are much more common than these very, very rare disorders. For like, for folks that are our age, that are probably the same age as much of your listenership, you will receive a viral gene therapy in your lifetime. Probably not in the next five years, but like you will receive one in your lifetime.

Raj Suri: That's amazing. I've said that a few times. It's truly amazing.

Nicole Paulk: There's folks working on ones for diabetes, heart failure, male pattern baldness, cancer, right, like very common things. So like, we will all receive one in our lifetime, whether it's for a disease you have now, or whether it's for a disease you haven't even developed yet, but that you're going to get 15 years from now.

Raj Suri: Wow, that's so you can do preventive gene therapy?

Nicole Paulk: You can. So that could be, some folks consider vaccines a type of viral gene therapy and other people are like, no, no, no, they're very different. They're separate camps. So it depends on what camp you're in. But I mean, that's already, if you were in the camp that believes that vaccines are a form of viral gene therapy, you've already been treated. If you're not in the camp that believes that, there are other types of prophylactic things that folks could envision. That'll probably be the next wave of things we do. For now, it's definitely still going to be focused on treatment for something you already have, but it's not necessarily a classic treatment, right? Classic means you take a pill every day. This is going to be a one-time treatment that you're going to take, but you're going to experience the benefit for the rest of your life.

Raj Suri: What are the challenges this type of treatment has? Obviously, it's taking a bit of time to get some momentum, so there must have been some challenges that have been overcome, and there might be some challenges that are remaining.

Nicole Paulk: So as is true in almost every field, the big challenge in the beginning when you're dealing with a brand spanking new technology is, oh boy, does it cost a lot of money. It's a brand, brand, brand new thing. When you compare this to most of the drugs every one of us have ever taken when you go to your local pharmacy or your grocery store and you buy something over the counter, those are chemical medicines. They're made of small molecule chemicals that can be put into a pill, you take orally, that are bioavailable orally, they get broken down in your stomach acid and then distributed into your blood supply through your gastrointestinal tract. That doesn't work for many types of drugs and diseases and all types of things. And so viruses kind of came along as a new way we could treat some things that chemicals couldn't, But now we're having to do the classic, the Peter Thiel book, zero to one. We're having to go from viruses not existing as a modality in medicine to being one. And it's just super expensive in the beginning because there's just, in the beginning, there was no infrastructure.

You decide your virus, you're all excited, you're ready to go and try it in the clinical trial. You need someone to make vats of this stuff. If you've ever been to a brewery, those huge stainless steel tanks that they brew beer in are very similar to what we make viruses in, these huge stainless steel bioreactors. But boy, the methods and the techniques around growing viruses at scale is a challenge. And so we're kind of decades behind some of the older modalities that we've been working on for 50 years. So we're really good at cranking those out. It's kind of like the first time we switched from making cars by hand to doing it in assembly lines, to getting robots to help as part of that process. You have these step change moments where the cost dramatically drops in terms of your rock hogs to get that thing off the ground. And so because this is still a very new, early, brand new technology, it's still really expensive. And so to put a number to this to give some sense, a brand new chemical drug, the stuff that you would take orally in a pill, today, you should probably budget that that's going to cost you about $1 billion that you're going to need to raise either through venture capital financings when you're private or on the public market after you IPO. 

You're going to need to raise about a billion dollars on average to bring that thing all the way to market. Versus a viral gene therapy, it's more like two to three billion. So it's quite a bit more, pales in comparison to the amount of money being spent on things like nuclear fusion and other technologies, but it's a lot of capital. And so it's just been very expensive to kind of get the ball rolling, which is also one of the reasons why we got so excited about wanting to do a universal gene therapy, because now if you have one virus that can be used to treat 200 diseases rather than one, you still only have to make one huge vat of it in that big brewery-looking bioreactor, but now you can use it 10 ways to Sunday to treat all these different diseases rather than having to queue up that whole process each time. So hopefully we can start attacking this from one angle and all of our commercial partners who are doing things like the actual manufacturing can also come up with improvements. Then together, we can layer all of our improvements on top of each other and bring the cost to produce these things down. I mean, this is like the classic growing pains of any new technology, beginning it's expensive.

Raj Suri: Yeah, I was reading about the history of like insulin scale up and you know how difficult they were actually getting. They had to use real like pig and cow pancreases, right, so they could actually synthesize them.

Nicole Paulk: One of those famous companies, right, in Silicon Valley in biotech, right? Genentech, right? So when that spun out of UCSF, it didn't spin out, right? They stole technology, right? So if you haven't read about the history of this, it's a fantastic, there's documentaries about it, books about it, read about it, it's fantastic. But when they spun out of UCSF, right, which was to do things like make synthetic growth hormone and insulin and some other early products. It might be they would spend a whole month with their entire team of medicinal chemists trying to make a nanogram of one of these proteins. And now, fast forward 2024, and that was by hand, a bunch of chemists doing this with all that cool glasswork that you see in movies and stuff. Now, they've got robots doing this and they can make a kilogram in an afternoon just on autopilot and someone just comes and checks the machine like, yeah, it looks good. That's the level of step change. It's many orders of magnitude that they've been able to improve that production process just with iterative improvements over time. We'll get that same step change improvement in viruses. It's just going to take a couple of decades, but we'll get there, I have no doubt.

Raj Suri: Yeah. What's the landscape look like for viral gene therapy, like in terms of innovative companies like yourselves? Who's working on it? What are the different ways people are tackling this problem today? And what do you think is promising and what do you think maybe is not that promising?

Nicole Paulk: So there's actually, you know, if you ask the average person walking around, they probably can't name you a viral gene therapy company because it's a little bit under the radar. But if you're in this space, there's just literally, there's hundreds of companies, and they're all going after different indications, right? So there's about 8,000 known genetic disorders that are caused by a single gene defect, right? So that's a lot of indications we can go after, and many of these can only be treated with a viral gene therapy. Why is that? That's because, particularly for those patients where they don't even have the gene, they literally are missing it. That portion of their chromosome that had that gene on it is just gone, it is missing. They literally don't have it. For those patients, there's no type of drug, there's no of like the armamentarium that we have in the pharmacy, small molecule drugs, cell therapies, antibody therapies, antibody drug conjugates, like all of these different classes of medicines, they all bind to something. But if the thing that you need to bind to doesn't exist, you cannot be used to treat that disease, right? You can't treat something that doesn't exist, right? So that's where gene therapy comes in, because we will give you a copy of the gene you were missing in the first place. So it's the only thing that can treat many of these diseases. 

And so now you've just got hundreds and hundreds and hundreds of companies. Some specialize in muscle disorders, some specialize in liver disorders, some specialize in brain disorders and kidney. You get these specialist companies that are going after different tissues where they feel like they have an edge based off something like the particular virus they're using, the particular delivery strategy, the particular something. They're going after all of these things. Even though there's only been five approvals in the last couple of years, if you look at these big prospectus reports that all the big consulting firms, McKinsey and Bain and BCG and all these groups, these big prospectus reports that they put out of like, what's coming? What's the wave that's coming? 

There's just literally dozens, if not hundreds of things that are going to get approved in the next five to 10 years. You'll start hearing about these because it will be companies working on diseases you've actually heard about. Most of these things like spinal muscular atrophy, you've probably never heard of before. Leber's congenital amaurosis, one of the other diseases, you've probably never heard of it before. But I bet you've heard of diabetes. So, a lot of these indications are things that are going to become much more common that folks are going after. And so, there's just like there's no one standout company that's ahead of everybody else because everyone's going after such completely different things that the landscape is actually enormous. And you actually don't need to be that competitive because there's so many things to go after.

Raj Suri: Fantastic.

Immad Akhund: How good is the FDA about this? Is the FDA part of the reason it costs $3 billion? Do they get in the way and increase the costs? Or are they doing a good job of protecting people from bad?

Nicole Paulk: You'll get mixed answers to this, obviously. If someone just went through a process where they got their drug rejected, they're going to be a little bit sore about it. Versus someone where the FDA has been phenomenal about being a big champion of gene therapy because they know that for a lot of these, and these are often diseases that happen in kids, so for a lot of these pediatric disorders, there is no other drug. Like I said, you can't treat something that doesn't exist, right? So if you are missing the entire copy of the gene, there is no other drug. And so the FDA has been very, very helpful in putting out guidance and helping folks like hold their hand, be like, here's what we want you to submit to us. Like, here's how you do it, and building templates and examples and these types of things. 

But as is often the case with regulatory oversight, you can overreach at times and it can be a challenge. A lot of this comes down to, do you have good executives and good advisors and good board members and good scientists who know the process, who've been through this to advise you on common mistakes? The number one thing I get brought in on, so even though I'm CEO of Siren, you name a company in the gene therapy space, I probably sit on their scientific advisory board or at least advise them in some way. Or if I don't advise them, I have diligence to their deck. on behalf of a VC firm, so there's probably not a deck I haven't seen. Whether it's for financing, an in-license, an out-license, an M&A, a CSO hire. doesn't really matter, I've probably seen them all. One of the main reasons I get brought in as an emergency KOL or subject matter expert is because someone did a boo-boo early on in their process that doesn't get realized until two to three years later. That's what's so scary about entering a space if you're not really a pro at it, is that you can make a mistake in the first six months of your company that feels so inconsequential. and then you won't realize it until three years later.

Immad Akhund: And then you can't really go back. These mistakes are actually hurting people, right? Not necessarily hurting people.

Nicole Paulk: It just means the FDA will come in and say, oh, we have a question about this. It's called CMC, chemistry, manufacturing and control. So it's like the process in which your virus is made at that super, super pure clinical grade. And they'll be like, oh, hey, we noticed something funny about some aspect of your virus in this 5,000-page report that you need to submit to us. Tell us a little bit more about this. And you'll be like, we gave you everything we have. We don't have any more data on that particular characteristic. And they'll be like, oh, well, it's really important to us. So can you develop a new 250-page report on what you're going to do about it? And you're like, but that would mean we would have to pause everything we're doing, because we would have and then develop whole new experiments. Yeah.

Immad Akhund: Imagine the world if the FDA didn't exist. But you still wanted to make sure. I just want to get like, I want to get a rough idea of like, how much of the cost of the 3 billion is like, you know, FDA versus like, it's going to be a cost to get anything in production anyway, like, is it half the cost 90% of the cost 10% of the cost?

Nicole Paulk: No, no, no, no. I think preparing for regulatory interactions. So you have several meetings with them before you start a clinical trial and then you have meetings with them during the clinical trials, right? There's three clinical trials, your phase one, the phase two, and then the phase three. And then after that is when you go up and you ask, can I sell my drug on the market? Right, so there's usually, you know, four or five, six meetings that you have with the FDA throughout that entire process. That whole process takes usually sometime between six and 10 years. So, you know, you're looking at like maybe a meeting a year-ish with them, right? So, I mean, in that year's burn, you know, it might be I don't know, 5-10% of your company's expenses going towards prepping for that meeting. 

Most of the expenses are still around the actual manufacturing of the virus in those big giant vats. That is really expensive. The actual raw costs of doing that are quite expensive because When the field started, we just borrowed from other fields, usually antibodies. If you've ever heard of the drug Humira, the most successful drug of all time, it's an antibody that we use to treat rheumatoid arthritis. It sells about $22 billion a year, and it's been the biggest drug for the last 20 years in a row, which most people find surprising that it's not a more common drug. And it's an antibody. And so when the field, when the viral gene therapy started, we borrowed a lot of techniques and instruments and methods from them because they were another protein-based biologic that was out in the fields. We were like, you know, you can only use what's out there, you know, until you have to completely innovate from scratch. And so the field just did a lot of borrowing in the beginning. We'll borrow it and tinker with it. That kind of works. Run with it. But no one did a completely from scratch mechanical engineering approach, and pretend nothing that exists exists. From scratch, what is the best way to engineer a method to produce these viruses at scale? I think that's probably what's going to need to happen is that we stop trying to tinker with all of these old technologies that were meant for something else, and we build something de novo from scratch that was meant for viruses. 

And that's when we'll have our step change moment where now it doesn't cost, you know, about $300,000 per dose to make the lot that gets infused into a patient, maybe it'll cost $2,000 instead of $200,000 to $300,000. It'll happen, but we just need some more innovation on the manufacturing side, which is a very unsexy place to start a company or to invest if you're a VC. Everyone's like manufacturing. boring. I want the sexy thing. But that's where the need is. We need to actually improve on the manufacturing front in order to enable all of these other therapeutics companies to actually produce their stuff at scale of cost. So we'll get there.

Raj Suri: One question I have just for you, Nicole, you sound so enthusiastic about this space. It's very infectious. Infectious like a virus. I'm kidding. 

Nicole Paulk: [Laughs] I get that a lot. 

Raj Suri: Yeah, it's a bad joke. But where are we in this moment in time on, you know, curing cancer, right? I feel like there's been so much progress in the last 10 years. Maybe you can just kind of point out the landscape. I mean, I've heard of CAR T. I've heard that we've been able to cure some forms of leukemia and blood cancers. It sounds like you're going after solid tumors. Maybe just like stepping a little bit back and like, what's the landscape and where we are today? And which cancers are we the furthest along? Which cancers maybe do we don't have any idea about?

Nicole Paulk: In general, we kind of separate the cancer world into two buckets. There's solid tumors, which is like all of the stuff that makes you solid. And then there's blood tumors, right? So things that happen in your blood and bone marrow. And those are two categorically different worlds. They almost don't overlap. The way you would treat a blood-based cancer is very different from how you would treat a solid tumor. And there's almost no drugs that cross over. There's different drugs for each camp. In the blood cancer space is where we've made some of the biggest advances. We actually use the word cure in a number of blood cancers, and we haven't gotten to the space yet where we can use the word cure in really any solid tumors yet. But in the blood cancer space, there are several, not just treatments. There are real actual cures. We can cure you of that blood cancer, and you will be fine. And in the solid tumor space, it's just been a little bit more challenging. There's a lot more heterogeneity when you're talking about like a whole organ, like a heart or a liver or a kidney than it is with blood and these types of things. 

And then we play around in the solid tumor sandbox. And within that, there are certain tissues that get a lot more focus and a lot more attention and a lot more funds. So things like breast cancer get a whole lot more money than other diseases. Adult cancers get a lot more money than pediatric cancers, which is actually a little bit surprising. Normally, you go into a hospital. I just came from being a professor at UCSF, one of the premier teaching hospitals. Normally, the richest department on campus in every hospital, I don't care where you are and what state in the US, it's always pediatrics. They're the only ones operating in the green. Everyone else is like lucky if they're just in the black. They're almost all operating in the red, and they're all being subsidized by pediatrics because everyone will give money for sick kids. Always, right? There's no group that pulls on the heartstrings more than sick kids. And yet, in the oncology space, almost all of the money goes to treat adults and not kids. So it's a very, very weird separation that I don't really have a good answer for. 

Cancer obviously occurs much more commonly in adults than kids. It is predominantly thought of as a disease of aging. It's something you get as you get older and not something that you're born with, hopefully. But in the solid tumor space in adults, which is the space that we play around in, there are just tissues that have been forgotten. And I said that if I was going to leave academia, I wanted to work on the biggest, gnarliest, hardest challenge that no one else was going to go after. And in the cancer space, that's the brain. Doesn't matter what brain cancer you're talking about.

There really hasn't been an advance in the brain cancer space that has been meaningful, right? Where you get years of improvement, not months or weeks or days, right? Some of these drugs get approved on like, you know, it extends your life by seven days, you know, and it's like, Do you really want this drug? So the brain is kind of like the white whale. And I said, if I was going to leave academia, I wanted to work on something big doesn't mean it's going to work. But like, I want to work on something really big and gnarly. And for me, that's the brain. So we're attacking brain cancers where there's just been no advances. So, shooting my shot.

Immad Akhund: I heard that the normal path for these biotech companies is very different from software startups. And the normal path is you get some funding, you IPO, and then you sell your company to Pfizer or one of the other big. And Moderna was kind of rare because they actually went all the way. They stayed as a public company and produced their own things. Is that also what you see happening in viral immunology stuff, that it's going to be this kind of path, or do you think there will be more long-term companies?

Nicole Paulk: It's a little hard to say. In the biotech world, they're kind of like how we split cancers into blood and solids. In the biotech world, we split everything into either you're a platform company or you're a single-asset company. Either you have a platform that can make many different types of drugs, uh, that could go out for many different types of things. Or you have like your one wheelhouse, like this is my one asset and we're going to try to use it, uh, still might be able to be used for a couple of different diseases, but like, this is our one thing. This is our one shot on goal. We don't have two or three things at the pipe. Like this is our one baby. Right. And, and that's like, it's very split into those two things. So for the single asset team, for the most part the goal is to get acquired whether that's you get acquired while you were private or whether that's you get acquired after you go public the goal is to get acquired because you just don't really have like this this pipeline of things coming up uh you might have again you know a couple different seasons you could go after but you don't have this R&D churn where completely new assets are getting developed all the time the way that a platform company does. 

I think for a single asset classic biotech program, the goal is to get acquired by a big huge pharma eventually at some point when it makes sense. um you know particularly as you start selling things at scale and you really need their like sales and marketing or their their mass production facility you know capability health these types of things versus a platform company like what moderna was where they actually have and they now i just mean platform companies not just moderna but platform companies have the ability to be constantly generating new assets from this core kind of IP platform that they have, and if they can manage to produce those things well on their own, it doesn't mean they produce them in-house, they might still be done with a manufacturing partner, then it's feasible and realistic that they could manage to be a revenue-generating company, much more the way that you see things in the tech world. Whether they're public or private, it could happen either way, but that you actually get to the point where you are selling, making, manufacturing, everything, the whole process, start to finish, zero to one, the whole thing, yourself. And so that's a little bit rarer. 

It's harder to do, but it's absolutely not impossible. And I think you'll start to see more of those, particularly in the viral gene therapy space, I think is one place where that is going to be true. And that's because most of the big pharmas either haven't bought into the gene therapy space yet, or they did buy in. The big ones here are Novartis, Pfizer, Bayer, and Roche. Those four have all bought in very strongly into the viral gene therapy space. They bought early players, early viral gene therapy companies. The challenge is that they all bought into what we would consider kind of Gen 1 or Gen 2 companies that had earlier tech, like around how you make the virus. And it's pretty out of date now. So if they want to keep playing in the space, they're likely going to need to buy back in and buy a much more modern company that's going to be able to bring them back up to the way we're up to Gen 5 now on the way we make viruses. So many of them are going to need to rebuy their way back in, and they will likely buy a big platform company that's got really cool tech, really cool IP, really cool assets, really cool manufacturing methods that can help revolutionize that big pharma's gene therapy division. 

But the normal reasons you would partner, which is that they help with our manufacturing and they help with our sales and marketing and distribution, those aren't things that those big pharmas are good at when it comes to the viral gene therapy space. The companies usually are. So there's actually an incentive to not partner or to not get bought because there isn't as much of an advantage to getting their help. Or if you do do it, then you change the dynamics of the terms of the agreement, right? Instead of like, I'm going to give you 80% of this program and we keep 20%, it might be flipped. We keep 80% and you take 20% because we would like some upfronts because the capital markets are still a hot mess or something like that.

Raj Suri: I'm actually very curious, Nicole, to hear your view, what's going to be the landscape 10 years from now. Do you think, is there going to be a point at which like, you know, 99% plus of cancers are cured? Or do you kind of feel like it's going to take a long time before we hit that horizon? And do you think there is, I guess, a follow-up question that would be like, is there a way to prevent cancer with some of these therapies in a way that maybe you don't cure cancer, but you prevent 99% of cancers?

Nicole Paulk: So a number of things there. So on the, you know, what do I think is going to happen 10 years from now? 10 years from now, I do not think we will have cured all cancers. Not even close. I think we will have made major, major, major inroads in a number of cancers, particularly in the solid space, finally for once. But I do not think we will be at every single thing is cured. Could that happen with enough time? Right? I am the biggest optimist you will ever find, because it'd be pretty hard to be a scientist and a CEO if you weren't. Especially in the biotech and life sciences, we have a saying about having golden hands. And in the 365 days a year you're in the lab, about 360 of those days, everything you touch is going to fail. The experiments aren't going to work, the hypotheses aren't going to plan out, something's going to get contaminated. It just doesn't work for some reason. You have to repeat it. The data was noisy. 

But about five days a year, you have these miracle days where you have the golden glove or the golden hand like you talk about in baseball. But you have it in the lab where it's just like everything you touch, it's just working. It's very much like baseball where someone's getting close to throwing a perfect game. It's like, don't jinx it. Don't talk to the pitcher. Don't jinx it. Oh my God. If someone's having a golden hand day, you're just like, you go and you get them takeout and you bring it so that they don't have to leave. And it's just like, you know, it's like this very weird superstitious people are very superstitious about golden hand days. And those five days a year are when like all the leaps happen. And that's like being really honest. The transparent answer. You would never tell this to a VC. 360 of the days that you're going to fund us next year, we're going to launch it. But that's how science works. Most of the things you set up fail. In a few days, everything works and all of a sudden you make these step change moments in history and you have these big discoveries and these types of things. So, The more money and the more people and the more stuff we attack cancer with, we will get to the point as a team optimist person, we will get to a point, there's no scientific reason why we couldn't cure every cancer eventually. But is it going to be 10 years from now? Oh, heck no. Not even close. But are there ways that we can prevent cancers? Absolutely. 

I mean, there's already ways we can prevent cancers, like the HPV vaccine. That is to prevent cancers, right? That prevents genitourinary cancers as well as some cancers of the throat, right? And that is something you do as a preventative. You give these to kids so that they don't end up getting things like cervical cancer and throat cancers and these types of things, you know, 40 years later. So I think vaccine technology is one way we're already preventing cancers. And I think there'll be even more prophylactic types of things, both that are treatments, but also that are non-medicine treatments around getting better about thinking about using foods as medicine. you know, using physical activity as medicine and all of these types of, right, the longevity, you know, atmosphere is, you know, intense here in San Francisco. But I think when we start to layer all these things on top of each other, and we start getting eight hours of sleep, and you start working out with weights, as well as cardio, and you start eating right, and you know, you start taking these medicines, and you start layering all these things on top of each other, I think we can start to make huge inroads into a number of these cancers, that even within the 10 year from now mark, is actually going to be possible. We'll need a few more decades to use the word cures for 99.9% of cancers. Not impossible, but more decades than one.

Immad Akhund: If you look like even further out, let's say like, 30 years or 40 years out, like what are, what are like the most interesting kind of crazy futuristic things that we could do with kind of viral gene therapy?

Nicole Paulk: So I actually give whole talks on this. So I love this topic. And it's usually around combine all of like your wildest dreams with viral gene therapy with all of your wildest dreams in gene editing, which is a type of viral gene therapy with things like AI. And we take those three pillars and we combine those things and like say everything works and it works on an accelerated time span. We got all the money and it all works. Like what's going to be possible. And there, I think you know, when you start getting multiple decades out and you combine the power of these technologies and the ability to iteratively learn from each experiment, right? 

Right now, every single clinical trial that's being done, all of the data is being hoarded and held by that one company, and it's super secret, and it's trade secret, and it's proprietary, right? And I think we're going to realize the benefit to all of us uh, around coming up with ways to share that data so that we can train, train these models in order to try to figure out ways to more efficiently. And I mean that both in terms of capital, but also in terms of time and also in terms of actual human patients to more efficiently make drugs that were not, you get all of these companies that are just like making me to drugs that are just like copycats. It's kind of like how in the tech space, it's like you get someone who's going to copycat someone else's, someone else's software product. And they're, they're, edge is this tiny little thing, and you're like, do you really think you're going to break into the market with that? You really think you're going to take over 30% of like Stripe's business or something? And you're like, really? Really? You know, and we see that in the biotech space, where you've got literally like 31 companies going after sickle cell, anemia, and beta thalassemia. And it's like, guys, there's room for two of you in the market. That's it. No more of you are going to be available on the market. There's going to be not enough patients for you to make enough money to recoup the amount, again, the $2 to $3 billion that it took you to develop that drug. You're not going to be able to recoup those things. 

And so you see a lot of, like, Me Too copycats that I think as we start to share data, because we realize the benefits to sharing data impacts a semi-anonymized way, then it's kind of like that classic, you overestimate what you can do in a year and you can vastly underestimate what you can do in one decade. I think if you were to expand that out to 30 years from now and you combine these three things, viral gene therapy, gene editing, and AI, I think we can't even fathom the types of things that we will be able to do. 

I mean, there's like gimme things like, oh yeah, obviously like any genetic disorder you have, we're just going to make a customized therapy for you on the spot. There won't even be a clinical trial. It is going to be a therapy that was made for you, Immad, by company X. And it was only meant for you. It was truly the definition of personalized. And so it will become a space where you won't have these chronic disorders. You'll have something happen very acutely, and then we will build a therapy for you, personal, just for you, and we'll give it to you, and it won't cost, right, you know, hundreds of millions of dollars. We'll have gotten so good at doing this, like with robots and these types of things that, you know, it's just like, oh, you need this, so we'll just make this for you, and then seven days later, you know, we place the order online and could just happen. And then, you know, Amazon shipped you, Amazon shipped you the virus and you're going to go to an outpatient facility and they'll, and they'll infuse it into you, right? It might not even be infused into you anymore by then, right? It's just going to be a patch. You know, it's going to be like a, the cilampus patches you get at Costco for, you know, for pain relief or something. You're just going to cilampus patch your viral gene therapy on and go about your day.

Immad Akhund: Like, could I just change my eye color or go like a few inches taller and stuff like that?

Nicole Paulk: Some of those things will be challenging, right? Like bone growth, right? Once the growth plate in your bones sets when you're like a teenager and stuff, it's like pretty hard to change that without surgery. But there are not, not all things are permanent. So one of my favorite examples that I love to give, and this is a technology we could do today, right? It's just an ethical thing around not doing it, right? Which is like kind of the next wave we're going to hit, which is like, technically, we can do a lot of this stuff now, we just don't consider it ethical to do. But we will get to a point where we're more comfortable with these things. And that will be a conversation to have as a society in the community. But here's a fun example. So there is a gene called DEC2. So the three letters DEC, and then the number two, So DEC2 is a gene in humans that controls a hormone that your body makes. This hormone is called orexin. And that hormone is really important in helping to maintain your wakefulness. And there are human beings walking amongst us, perfectly normal, perfectly happy, don't know that anything's wrong with them, because there's nothing wrong with them. But there are people walking amongst us who have a mutation in this gene. And if you have a very, very, very particular mutation in this DEC2 gene, you only need four hours of sleep to be completely rested, whereas the rest… Oh, is that why some people only do four hours of sleep?

Immad Akhund: I've always wondered why those people exist. And do they die earlier? I kind of always assumed… 

Nicole Paulk: They're completely normal. Their metabolism is normal, their health span, their lifespan, they are completely and utterly normal human beings. They have no ill effects from having this mutation. They just only need to sleep four hours. 

Immad Akhund: And they still like the things that sleep does, right? 

Nicole Paulk: The restorative benefits that sleep does to your muscles and like clearing out toxins and like clearing out weird you know tangled proteins in your brain and all of the benefits that sleep does they still get those they just only get it from eating four hours rather than eight so it's obviously the thing to do here, we should queue up a gene editing gene therapy where we give people this edit. You could, if you were to edit enough of the cells in your body, right? You can't just edit like only the cells in your fingernails or something, right? You got to edit enough cells of your body that it would work.

Immad Akhund: I wonder how much, like, do these people enjoy the extra four hours? I mean, you basically… Do these people enjoy the extra four hours? I guess.

Raj Suri: No, it's like you're extending life by 15%, right? Because your working time is, you know, longer, yeah.

Immad Akhund: I just feel like, are they just watching TV for an extra four hours? Like, what are they doing? 

Raj Suri: They're reading books. They're educating themselves.

Immad Akhund: They're reading books.

Nicole Paulk: I mean, I think about it, like, genuinely. Now I'm going to flip the tables on YouTube. What would you do with four more hours a day? Honestly.

Immad Akhund: I mean, I really like sleep. I feel like I'm energized afterwards. I worry that if I'm going to be asked… 

Nicole Paulk: Do you like it cause you need it?

Immad Akhund: Yeah. And like, I'm just wondering, like, after, after I do 10 hours of like, intense work or whatever, like, I'm pretty tired. So can I suddenly do 14 hours of extra work? Like, I mean, presumably, you still get like, tired, right? Not like sleep tired, but like, mentally and physically exhausted. So I just wonder, like, what I would do for four hours. Yeah, that's true. I guess like, if it's pure entertainment.

Nicole Paulk: You could read books. You could pet puppies.

Immad Akhund: I mean, I wouldn't mind an extra hour. Four is aggressive.

Raj Suri: I'm taking it. It's taking it home with me. Read and write, for sure. There's a lot to learn. You can make new things. You can code more, Immad. I know you like coding. You haven't been able to do it for a while. That's true. That's true.

Immad Akhund: I could start another company for the four hours.

Raj Suri: Exactly. Start another podcast.

Immad Akhund: Maybe that's how Elon Musk does it.

Nicole Paulk: Exactly. Secretly a DEC2 mutant. I don't actually know.

Immad Akhund: Nicole, this was awesome. Really appreciate you taking this time and educating us. I am looking forward to never getting cancer.

Raj Suri: Yeah, you've got so much excitement for this space. It's great to see, you know, and it's something that can be a lot of, it can be like opaque to a lot of people, but I think you explained it really well. So thank you for doing that.

Nicole Paulk: No, that's the biggest problem with academic professors, right? They walk around with the jackets, with the things, and they try to use all these big words and sound like they're so much smarter than you, but it's so much easier to engage with folks with just normal language and just get them pumped.

Raj Suri: Plain spoken, yeah. I love it. I'm pumped. Thanks so much, Nicole. Cool.

Nicole Paulk: Yeah, this was great.

Raj Suri: Well, that was really interesting chat with Nicole. So much to kind of break down there, Immad, but what did you learn? What was like most eye-opening for you?

Immad Akhund: Oh my god, there was so much  there. I think the bit about how this DNA can sit alongside your DNA. I thought that was really fascinating. I had no idea that like, that was one of the ways we do these things that you're just going to introduce this new DNA. And as long as that cell is around, like it continues to kind of enact that because there's this other method with CRISPR, which seemed very complicated, and I guess you don't need to do that most of the time. So that's one little bit of data that I thought was fascinating. I think the other thing that's super cool is how this whole field is in this kind of exponential curve, right? And like, I'm so used to tech and thinking about the exponentials that we have and like AI and like Moore's law and things like that. So it's kind of cool to learn about like, oh, there's this other, like maybe there's thousands of like in the technological and scientific exponentials that we're a part of. And like, it's kind of cool to hear about this one. Well, how about you, Raj?

Raj Suri: Yeah, those things for sure were really interesting to learn. I mean, I think getting a really good sense as to where we are in the landscape, I think just kind of confirming a lot of the stuff that I was hoping was true, like, you know, we're making good progress on the blood cancers, but, you know, the solid-state cancers, there is actually, you know, some hope there. You know, I'd always kind of thought that, like, that the solid-state catheter were just too difficult. And it sounds like this is really a promising therapy. And I didn't realize that there were hundreds of companies working on this. And it's not science fiction. Like, there's actually, like, real hope there. And I feel really grateful for all the people working on this problem, you know, because, you know, you take it for granted as, like, you know, a normal person that, like, hey, you know, you got this amazing, you know, treatment at the hospital. But think of all the people working on it and sacrificing their own lives. And, you know, as you said, working 360 days in the lab, with only five days of like, you know, actual progress. And, you know, these people are our heroes.

Immad Akhund: The whole thing is a brutal field because like it takes, you know, it's not like it's like software startups, you make something and like six months later, you've got users like we're talking about like 10 years before like you even see anything live like that is like

Raj Suri: Absolutely. And a lot of it goes nowhere, right? Like that's the sad part is like you could work on something for 10 years and it's just gone nowhere and you have to switch tax completely or the FDA doesn't approve it or something. But I feel grateful for people like Nicole who are working so hard on this, you know, with a sense of boundless optimism. These are the really important problems. I mean, you know, when you have someone in your life who has this type of disease, you think about it a lot.

Immad Akhund: So I'm reading this book, Outlive. That's by Peter Attila. I think you're reading it too. One of the interesting things about immunotherapy for cancer is that everything else, like chemotherapy, et cetera, you don't really get cured. You still have that cancer and it can come back. Everything else is kind of basically caveman style, like smash this cancer and smash your body at the same time. Whereas this kind of immunotherapy, it's actually teaching your body to destroy every cancer cell it can find.

Raj Suri: It's surgical versus like a blunt instrument. Yeah.

Immad Akhund: Yeah, the way that Nicole described is like unmasking the cancer cells to the immune system. So it's actually like it's not just a cure. It's like an amazing improvement to the to the field. Like if you can do this, like it's it's like cancer's gone.

Raj Suri: Yeah, absolutely. And it was exciting to hear what else gene therapy could do, too. I mean, wow. I mean, go to, you know, you order something online and you get a personalized patch for you sent to your house. Like, that sounds amazing. And I said amazing, this is my 10th time I've said that, but like, super exciting.

Immad Akhund: Amazing was your word of the podcast today.

Raj Suri: Exactly. Yeah. I'm like, geez, I got to start investing in this space. This is going to be like, wow, it's really going to change lives in a huge way if she's right. And she sounded, I mean, very credible in the space. So I got to do more research, you know, I'm going to read more books and see how I can.

Immad Akhund: There's like a parallel Silicon Valley, right? There's the normal, there's a software one that we're in, but there's a whole other set of VCs. There's another set of like companies like Genentech and all this stuff. I mean, a lot of it also happens in Boston, but it's kind of cool to like, have like that working in parallel to like kind of this kind of software and tech Silicon Valley we're in.

Raj Suri: Yeah, absolutely. And I hope there's no shortage of funding for these things. So they definitely, you know, that's a good investment to make is like to take all these shots on goal and hope some of them work out.

Immad Akhund: That's why I was kind of alluding to a ton of the funding actually happens in public markets, right? There's like small companies that go public and then they actually like The public company is very much like a shot on goal type public company. It's going to be worth zero. It's going to be worth 10 billion. It's like a very, it's a very different type of public company.

Raj Suri: Yeah. I just wonder if retail investors are really educated enough to make these decisions. You know, the public markets, hopefully it's institutions who are a bit more knowledgeable. You know, you can imagine like a GameStop type guy, like, you know, should I invest in this?

Immad Akhund: Like, I don't, I don't think it's a retail investors, but it's kind of cool that happens in the public. I don't know why most software companies are like that. It's like, hey, let's go. I guess because you have too much data in the software company. It's kind of weird. Why don't software companies go public?

Raj Suri: They used to. In the 90s, right? They used to. And it could be 10 million or less revenue and you can go public. And then they added a lot of laws around like, you know, like Sarbanes-Oxley and stuff in the 2000s. So that changed everything.

Immad Akhund: It's weird it hasn't changed biotech as much. Yeah, it is. Or maybe it has. You should get a biotech VC on that.

Raj Suri: We should get a lot of biotech people. We learn a ton from all of them, right? Bob Langer we had. Yeah, it's fun. Nicole. Yeah, we should get a lot more and we learn a lot and it's very impactful. I mean, it changes everyone's lives. So cool. Well, that was great and look forward to the next episode. Follow us on Substack, X, LinkedIn and YouTube.

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