Attacking Cancer With Code And Winning - EP 48 Jake Becraft

We're going to treat them one more time. If they come in in 3 more weeks and they look even worse than this, we're going to recommend they go to hospice. We'll make them as comfortable as we can. They came in that— so now 6 weeks after, after 2 doses of our drug, they came in at that additional 3 weeks and 40% of the tumors had melted off. It looked like— I mean, they were just dying off. You could sort of see them. It didn't look pretty. Particularly pleasant, but the patient was describing to the doctor that they felt like they had more energy, that they felt better. And then over the period of about 4 or 5 months, their disease just disappeared.

Off of the 2 doses?

We continued to give them doses every 3 weeks into their tumors. That patient now, 15 months since— 16 months since starting our trial, is still on the trial, has no more detectable disease. Those are the sorts of things that I think as a scientist, it just makes me go like, holy shit.

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Jake Becraft, thank you so much for having us here. We're at Strand Therapeutics right in the heart of Boston. We're near Fenway.

Yeah, a block.

Yeah. Yeah.

And go catch a game tomorrow.

And I think it was the second time I've been here and it was a cool building. We got Double Helix in the background for people watching at home. I'll take a crack at the, I guess, the 30,000-foot explanation of Strand, and then you'll help me do better. Yeah. And then we'll dive in. I'll explain it. Yeah. But I mean, I think it's fair to say you guys are trying to cure cancer.

Yeah. As a place to start.

Yeah. Yeah. And so, you know, during, I think, the pandemic, lots of people would've heard about mRNA and the vaccines and, you guys were working on technology related to that even before all that started. And then my read on things is, are advancing mRNA in all these new ways. And I think that was part of the story is people heard so much about mRNA during COVID and then it was like, well, what's happened to that technology since and where can it be pushed? And I know lots of people are working on it, but you guys, like I said, yeah, you were on this ahead of time.

Yeah, we, uh, we have the advantage of, of time, right? So, uh, I moved to Boston to do my PhD starting in 2013, and at that time there was this little quiet startup actually up— my PhD lab that I joined, Ron Weiss's lab at MIT, it was off campus, and 6 floors up there was this startup that had just come out of stealth. They were called Moderna, and they just raised like $100 million, and they were doing mRNA technology. And we thought that is, you know, mRNA is this incredibly promising, um, tech. It essentially is a way to— a very fancy way to deliver proteins into a cell, right? So mRNA, you can make any protein sequence you want, any protein sequence you want. You encode that protein onto the messenger RNA, you put that messenger RNA into a cell, and the cell will essentially make that protein. And so for vaccines, it's very rapid, right? You can very rapidly rapidly take a virus sequence, put that into the vaccine, and have your cells making this viral protein, which then your immune system can be trained on. But all of medicine for the past 30 years has moved from these small molecule drugs into what we call biologics. It's these synthetic proteins that we make and we deliver to patients. We make those proteins in a lab. It's very, you know, it's not really scalable. It's not a all sorts of different manufacturing processes you have to do. And at the end of the day, you take the proteins and you inject them into patients. Sometimes they work the way they're supposed to, but a lot of times it's, you know, it's sort of an abstraction for how your body is used to processing the proteins. You have to get the protein actually into cells, or you have to get the cells to actually make the protein to get the full biology of how it works. And that's what messenger RNA allows us to do. There was all sorts of different ways people had been trying for years, but mRNA to me represented the first ability to encode a protein onto one singular scalable modality, deliver that into a patient, and have that patient's body actually make that protein naturally. The vaccines were sort of this, you know, we jumped the line with technological progress because the vaccine technology for mRNA was the first use case that people were using. And because of the pandemic, we sort of probably jumped 5 years forward in the acceleration. Operation Warp speed, scaling up clinical trials just from a medical need perspective. But what we were trying to do was say, okay, we're pretty sure vaccines are going to work, right? I didn't know that they would be as early as we did, but what's the next step? How do I go from injecting an mRNA into your arm and having your muscle cells make a virus protein to being able to direct the mRNA wherever it needs to go in your body, you know, to a tumor, to your kidney, and be able to then therapeutically create proteins that can either kill a cancer or or, you know, reconfigure some disease cells to a more healthy state. And that's what we were trying to bridge the gap on.

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Yeah, once you go from vaccines to therapeutics, like the bar of selectivity is much higher, right? So if you think about it this way, a vaccine is really just simulating an infection. Right? So it goes into some cells in your body, those cells make a viral protein, and then your body attacks that protein as if it's an infection, as if it's foreign, and then it learns what that looks like, and on and on and on. And then you have this, you know, whole-body protection against the virus. Um, when it comes to, say, making a protein that causes cells to be killed by the immune system, which is what we're trying to do with cancer, right? We're trying to get the get the mRNA to go into the tumors, have the tumors create a protein that the immune system will then recognize and come and kill those cells because we want to take the tumors out. You don't want those proteins expressed anywhere else. And it's even more complicated because the tumors can be all over the body. They can be deep inside of the body. They can be in the lungs, they can be in your liver. And you don't want the immune system attacking any of the healthy cells. That's where you get, you know, all sorts of toxicities that are associated with cancer drugs. And that's a very very small needle hole to thread, right? And so what we figured out was if we could program the messenger RNA to identify the type of cell that it actually inevitably goes into— so the mRNA is the sequence, part of the sequence is the protein payload that we want the cell to produce, and then another part of the sequence is this logic system that essentially goes into the cell, senses what's around, and is able to say, oh, I'm inside of a cancer cell. I should actuate my program and cause this protein to be produced. But if it ends up in the liver cell or in a kidney cell, then nothing happens. Essentially, the program is inert and nothing— no protein that causes the immune system to respond is going to be produced. And that is very difficult. We spent 6 years before the company started working on that tech, and then we spent the last 6 years here really perfecting it. And now taking it into patients.

So it's been about a 12-year journey so far?

Yeah, 12 years. Yeah.

Okay. You use some of the language like we program it to do these things, the certain cells are— you speak about these things almost in semiconductor-ish language, software language. So when you're saying, okay, the liver is is not going to absorb this and it's programmed not to. I mean, like, exactly what do you mean and how does that work?

Yeah, so, you know, inside of all of our cells, all of our cells are different, obvious, right? They sort of come from stem cells. As your cells differentiate, they become all of these different cell types. That's not just how they look. Inside of those cells, there's all sorts of processes, different sorts of genetic material, that are responsible for directing the cell to do whatever it is— a liver cell to filter out your blood, a kidney cell to cleanse out different sorts of toxins, your lung to absorb oxygen into your bloodstream. Those elements of the cells that are constantly ongoing are recognizable. So for instance, inside of every cell in your body, you have these different genetic elements that the cells express in order to sort of hold its state. So you have a stem cell, it can become any type of cell. As it differentiates and becomes, you know, lung, liver, kidney, whatever, what have you, it will express these different genetic control devices that sort of hold its cell type. It changes how it expresses the genes. All the same DNA is in every one of the cells, but different genes get turned on depending on the type of cell they become. And so what we did was we assayed every cell in the body and sort of understood what was turned on and turned off and what elements that existed in the different cell types, and then we built sensors for those elements that were— that exist in all these different cells.

When you say sensors, you mean like a sequence?

Yeah, it's essentially just a genetic sequence, okay, um, that recognizes a genetic sequence that is inside of these cells. Um, so, you know, the lung cell turns on a genetic sequence that allows it to sort of hold its gene expression in a certain way, and so we a sequence of messenger RNA that recognizes that inside of the cell. They actually bind together and it will tell our messenger RNA sequence essentially, okay, you're in a lung cell. And so, you know, if we're making a lung therapy, it would be actuate inside of here. If we're not making a lung therapy, it would be do not do anything because this is not where you're supposed to be.

And you guys, I mean, there's a lot to get into here, but I think the first major trial you guys are doing is with melanomas. Okay. Right. So if you, if you're injecting this into the melanoma site, do you have to build all those? Is it staying somewhat localized there or do you have to build in sensors then for like every major organ system and your blood and yeah, it just seems like a lot of stuff you would have to put in to ignore.

So this this maybe gets to the broader view of how we're constructing Strand as a company and how we're bringing this technology forward. So our first program that's in the clinic right now has treated about 35 patients so far, most of whom have stage 4 melanoma resistant to existing therapies. That is what we call an intratumoral therapy. It's a— we take the messenger RNA, encapsulate it in a nanoparticle, and inject it directly into the cells themselves. So the bar there, of course, for like how complex your sensor technology needs to be is much lower since most of it is being delivered directly into the tumor via the injection. Next year, we're launching a second clinical program for the next drug in our pipeline, which is going to be administerable much more of the similar way where most cancer drugs are administered, which is IV. Okay. Most cancer treatment clinics in America and the world are infusion centers. That's sort of how the medical infrastructure is set up to treat. Also, you know, vast majority of cancers aren't accessible to a doctor to be able to inject directly on the surface. And so there's a huge unmet need in especially what they call second-line treatment for melanoma. Right now, we have, you know, if you don't respond to traditional therapy, if you have stage 4 melanoma that's metastasized, your chances of survival plummet off a cliff. And so we knew that we could develop our first drug in this sort of setting where the specificity bar was lower, but also for, for us, where we could help a lot of patients if we were successful, with the idea that we would then build a more advanced drug that would not only answer the question of like, can we treat more tumors, but it would also answer the question about our technology. Can our technology achieve this? For decades, messenger RNA and LNP-based delivery technologies have been limited to just going to the liver. You know, every, every application in this space that goes through the bloodstream basically targets the liver. Whenever you see someone saying that they're targeting the liver, that's similar to someone telling you they have a fast car because it's falling off a cliff very rapidly. It's like it was already going there. You just sort of leaned into it. And so our view was, can we build an IV, you know, blood-based delivery device for tumors using this technology? And now we've, we've proven that's possible too.

All right. Well, let's, let's do the melanoma first. Yes. So you've been running this clinical trial. You said 32 people?

About 35 patients.

35 patients. And this is, this is the part where I always get excited. And then you also get, you know, I'm always cautious as well because you hear company trying to cure cancer, clinical trial. And then typically what happens is like things don't go as well as the trial goes on as people had hoped. But so with these, from what I was reading over the last week, I mean, out of these 35 people, like you said, they were— sounds like they had very few other options. Yeah. And you guys, you've been publishing about this over the last few months, last year. I mean, it seems like it's gone. I know you're always limited a little bit in what you can say, you know, as far as like the FDA goes and everything, but it seems like it's working quite well.

So when you do a Phase 1 clinical trial, you, you really have to go in understanding the types of patients that you're going to get. From the FDA's perspective, a Phase 1 clinical trial is about safety. You're in cancer. You are going into sick patients, but you're not just going into sick patients really because it's, you know, because no one knows the value of this drug and no one knows the safety of this drug. The patients that end up, you know, being able to come on to the trial are really out of options. I mean, for the most part, a Phase 1 first-in-human trial, the doctor is having a conversation with the patient, which looks like you can go to hospice and we can make you as comfortable as we can. We're out of options, right? Or maybe, you know, throw a Hail Mary.

Yeah.

But as a company, you understand that you're getting the patients that no drug has worked for, right? They've not only have they taken all the approved therapies, They're also taking a number of experimental therapies that are further along in development. And then after nothing works, then they come to your trial. So your chances of seeing anything are extremely low. Of course, like as a scientist, as a human being, you want these patients to— you want to offer hope, you want to, to have something happen. And so there's actually a story with the very first patient that entered our trial.. So they had tried all sorts of different therapies. They weren't really responding. They had metastasized. The melanoma had metastasized into their lung. It had metastasized to their lymph nodes. Not a good look. And then by the time they came to our trial, they were actually advancing so rapidly, like between— in less than 2 weeks between screening to see if they were eligible for our trial and actually getting our drug, which which took about 13 days, they had like 40 more lesions appear on their body. They were rapidly, rapidly advancing. So we gave them, um, first dose of our drug. It's just into one of the tumors. We inject the mRNA that causes that tumor to express this protein, which causes the immune system to attack that tumor. But then as it attacks that tumor, the immune system sort of learns what the tumors look like and then is activated to go off and kill other tumors. That's how the mechanism works here. That patient came in 3 weeks later and they looked even worse. Really, it was just like the rate of progression of their disease was like a freight train moving down, moving down the rails.

It was—

felt unstoppable. The doctor called us. This is the very first patient we had ever treated as a company and said, you know, we're going to treat them one more time. If they come in in 3 more weeks and they look, you know, even worse than this, we're going to recommend they go to hospice. We'll make them as comfortable as we can. They came in that, you know, so now 6 weeks after, after 2 doses of our drug, they came in at that additional 3 weeks and 40% of the tumors had melted off. It looked like, I mean, there was just, they were, they were just dying off. You could sort of see them. It didn't look particularly pleasant, but the patient was describing to the doctor that they felt like they had more energy, that they felt better. And then over the period of about 4 or 5 months, their disease just disappeared off of the 2 doses. We continued to give them doses every, every 3 weeks into their tumors. That patient now, 15 months since— 16 months since starting our trial, is still on the trial, has no more detectable disease. Those are the sorts of of things that I think as a scientist, it just makes you go like, holy shit.

Yeah, that must be— this is crazy, right?

I mean, yeah, that's— I think that that is professionally the most incredible. Like, I don't think I'll ever forget the time, like, getting the call from the doctor on that second scan where they were like, a bunch of the tumors are gone. The tumors we didn't inject with the drug are gone. It's, you know, and that's now happened across a handful of patients.

And does that person keep getting treated now or are they— now the body is just recognizing it on its own or—

We're continuing to treat them just because of the, you know, how, how long, how bad their disease was.

Yeah.

So in clinical trials, right, you're trying to, you're trying to answer core questions, which is, does this drug work? Is this drug safe? But you're also learning about like like, how should we use this drug? Because this is really a new era of medicine, right? We're sort of, I think post-COVID, everyone thought we were standing on the precipice of mRNA. This is just the beginning. But like I said, the problem was COVID pulled all the timelines for mRNA vaccines up about 5 years. The rest of the technology, like what we were working on, was not pulled, we weren't pulled up other than more people, my grandma knew what mRNA is. You know, we became a household name for good or bad for some folks. But I think that once we, once we made that technological leap, we are now standing on this like precipice of genetic medicine. And Astrand is sort of trying to lead that way. We're also, you know, we have to learn everything about these drugs. How do they work? How does the body recognize them? What's the best way to treat disease with these sorts of approaches?

So in And I, again, I know it's always tricky because you don't want to be— when you're in a clinical trial, you don't want to be too boastful about what's going on. The FDA frowns upon stuff like that and you don't want to do it anyway. But, you know, like out of those 35, I mean, you mentioned a few had seen similar, somewhat similar results to the one patient you were talking about. But like, what can we say about the group as a whole?

I mean, overall, the the percentage of patients that are responding is many orders of magnitude, many multiples of the sort of percentage you would expect in this population. You know, and I think the current response rate of patients in this setting is something like 9%. So once you— it's 90 or 99. So, you know, if you, if you have stage 4 melanoma, if you fail the first-line therapy, which is this drug called Keytruda or Opdivo, these checkpoint inhibitor drugs, If that doesn't work, you're about 50% of patients that will work for the other 50%. You are maybe 9 to 11% of patients will respond to the other drugs that are available currently. We have many from a percentage-wise. These are— this is a low number of patients. Important to understand. But, you know, a whole handful of them have are responding and doing well on this therapy. It's going to take— you know, we're going to have to get to much larger numbers of patients. We're going to have to get to more rigorously controlled settings before we can really start talking about percentages that I think are meaningful. But the thing to sort of— the thing that wowed us, the thing that has, has wowed a lot of folks is we didn't expect to see anyone, right? I mean, these aren't— these aren't even the patients you would normally treat if your drug was approved. These are truly some of the end-of-the-line therapeutic option patients. To see one patient respond, it would be remarkable to see a percentage that is higher than the normal standard of care for patients with much less severe disease.

Yeah.

Is borderline unheard of. Yeah.

Yeah, but when people— I'm sure some people would hear about that first patient and be like, oh my God, this is a miracle, you know, and obviously want it to work universally. And do we know, do we have a sense as to like why it worked so well for one person and might not for another person?

Not yet. Like I said, we're in the process of learning about our drug and trying to figure out, you know, what is it about these various different patients that we can learn? Because of course, like, the more we know about the drug, the better we can get it to patients, right? If we know what sort of makes a patient better or worse for the therapy. And then also, this is a therapeutic platform, right? We can reconfigure, reprogram the messenger RNA to express different types of proteins that stimulate the immune system. And so on a long enough timeline, what we'd like to do is build a whole host of different therapeutic options, right? We have this drug that we have in clinical trials right now, but if we reprogram and sort sort of swap in a different protein into the existing mRNA structure that we've built, we can then have other sorts of options for those patients. And so you can imagine a world where you're able to look at the tumors, sequence them, sort of run them through an algorithm, some sort of AI that tells you, okay, this is the sort of subtype classification of this type of melanoma, and they're going to be most susceptible to this sort of treatment. That's, I think, the future that we're moving towards.

Right. So it's like not quite fully personalized at that point, but you have a lot more flexibility in trying different things.

Absolutely. You know, I'm always one for precision medicine over personalized medicine. I think there's this sci-fi future we all kind of want to happen where they look at your disease, look at your tumor, and then beep boop boop, like some computer spits out a new drug and then it's immediately synthesized and then you get that. I'm not saying that that's not a part of the future, but in terms of getting solutions to patients fast, I think that having an arsenal of similar but differentiated drugs with slightly different mechanisms that you can then recombine and put into patients in custom mixes is much more near-term achievable. Drugs, like everything, have to be made somewhere under some conditions. And so the ability to make up large batches of things, achieve economies of scale, and then and recombine them to fit the individual needs of patients, I think is much more personalized and achievable soon.

This question feels dumb in some ways because I'm not sure I know why I care. But as I was doing my research, I hopped on The New York Times just to see what they had written about you guys. I was like, man, this is crazy. This clinical trial seems like it's gone really well. mRNA has been this huge thing. We've got suddenly this new application of this technology. To like literally trying to cure cancer and apparently curing cancer on some level, seems like a big deal. And then as far as I could tell, they hadn't written about you guys or this, you know, and again, I mean, it's like, who gives a shit? But it's like, whatever, the paper of record. I guess, you know, this is a long-winded way of just, I was like, it felt like the, felt like this is a really big deal and that the mainstream media that, yeah, like hadn't picked up on it in a way that I would have thought they would, especially coming out of COVID and with the results you guys had seen. Maybe I just missed something, or I don't think I did, but yeah.

No, I don't think that the Times has approached us. We've been quiet over the last 2 years or so as we started the clinical trial. We, during COVID a lot of reporters wanted to write about, like the future of messenger RNA. I think that I was not everyone's favorite CEO founder to talk to because I kept trying to explain that while it was very exciting that the vaccines came forward, it didn't actually push mRNA technology. We were moving very quick and we were ahead of schedule, but the success of the vaccines technologically didn't move us forward. In 2020, everyone wanted to say, oh, we are standing on the precipice of the future of genetic medicines. I kept saying, kind of. We're where we were, except people know about mRNA and mRNA vaccines for COVID are a thing, but it's still going to be another 5 years before we're there. That wasn't the piece anyone wanted to write coming out of the pandemic. We kept building. Quiet about it. Over the past— it's just been a few months, just been over the summer that we've disclosed some of this data publicly and shown what it did and sort of announced our intention to like expand this technology, go even, you know, bring new drugs to the clinic, new ways of delivering messenger RNAs and really sort of push the envelope. Now, I am very much saying that we are standing on the precipice of the future of genetic medicines.

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And it couldn't come at a better time because it's becoming very clear in this sort of forefront of technology, so cell therapies, CRISPR, all of these different types of technologies we've been developing in the labs over the past 15 years, we have no way to deliver them, right? These engineered immune cell therapies that we've been trying to build, what's called CAR-T therapy, chimeric antigen receptor T-cell therapy, we haven't been able to scale those for patients.

So the CAR-T stuff has worked on blood cancers, but not solid tumors, right?

And it's worked on blood cancers, but it's not a— like, the value of CAR-T as a therapeutic modality has not reached what I think is its potential, because the way that we make CAR-T therapies now is you're a patient, you come into the— you come into the hospital, take your T cells out of your body. We then kill your immune system. We basically give you high-dose radiation or some sort of lymphodepletion where we kill off your immune system. So now you're immunocompromised for an amount of time. We take your T cells into a lab. We put a virus that has this chimeric antigen receptor sequence. That virus puts that gene into the T cells. We then grow your T cells up over time, or number of weeks to months, and then we take those cells and we put them back into your body. As I'm describing that, it probably feels very much like that's not a scalable process. And to me, it's a very, like, Frankenstein, like, brute force project. It's like, we want to engineer the T cells. We don't know how to get to the T cells while they're in your body, so we need to pull them out of your body and do all these things. The problem is that costs hundreds of thousands of dollars just to do, right? This is not about drug pricing. This is about literally the medical infrastructure, the time, the hospital bed and rooms that have to be used, the procedures. That drug then, you know, there's only so many people who can get that per year. There's only so much medical infrastructure that we can get to. And so those drugs largely, even the ones that have been approved, they haven't made very much money. They haven't— for the companies that have them, they have not reached very many patients because there's only so many slots at so many hospitals that can do this. And so those are the two driving factors, right? Are you helping patients? And, you know, in a commercial sense, is this drug actually profitable for, you know, to incentivize further investment in new therapies? And since you really haven't had a success on either of those, the field has sort of mellowed. And a lot of the companies that were developing like next-gen CAR-Ts have folded, gone under. But in my— my impression is that all of that, taking the T cells out of the body and doing these things, it's all— you do all that to solve one problem, which is getting a gene into that cell, right? Fundamentally, that's We're trying to solve solid tumors right now, and we're building these cancer therapeutics. But fundamentally, what we're doing is we're solving how do I get a gene into a cell in the body? And so if we can do it for tumors, we can do it for T cells. And instead of having a protein that stimulates the immune system to attack a tumor, you just put the chimeric antigen receptor, the CAR sequence, onto the messenger RNA.

Yeah, because I thought I saw you guys do have a blood cancer trial starting up, right?

We have a program where it's what we call an in vivo. CAR-T.

Okay.

So our idea is I don't want the T cells to have to come out of the patient, right? That's what causes this to be such an expensive therapy, such a non-scalable therapy. It doesn't like it. It is such a drain on the patients. The medical infrastructure can't support, you know, all of the patients that could get this therapy. We can't give— we can't give every single one of them these therapies because we just don't have the medical infrastructure. Receptor. So if we can change that, and now using the same technology we're using to target solid tumors, deliver CAR, chimeric antigen receptors, into T cells, then we can solve that issue. Same thing for CRISPR, right? CRISPR therapies are— everyone's editing in the liver. Like I said about liver targeting, right? People are targeting the liver because that's where they're at. But all of these new gene editing technologies that we've been building from CRISPR and and prime editors and everything else to try to fix genetic diseases, we can only right now fix genetic diseases if that involves fixing the genetic sequence in your liver. If you need to fix the genetic sequence in your kidney, you're sort of out of luck. And so I think that's really where I see us going as a company is it's not just about solving these big cancer questions. That's what we're doing today. And that's what I think we're— that's how we're helping patients right now. That's our job. But what that tells us is whether or not we have a scalable platform for delivering these proteins, whether that's getting CRISPR into a kidney cell to fix chronic kidney disease, genetic-based kidney disease, whether that is getting a chimeric antigen receptor into a T cell in the body. I really view mRNA as the future infrastructure of medicine. And that's what we're building.

So I don't think I'm going into conspiracy territory or anything, but, you know, I mean, I feel like for rational people, I mean, the view on the mRNA vaccines, I feel like it's still kind of like mixed. I mean, it's weird. It's like, yeah, like almost certainly saved a whole bunch of people. But the vaccines, at least in my general read, is like, like kind of like works, but kind of didn't work like the way fully that it was billed. And I feel like people have a very mixed feeling towards towards this technology and how good it was. Yeah, I don't know. Is that the— do you agree with that read to some extent, or that people have a mixed view?

Absolutely. I mean, I think that—

I mean, obviously there's like a massive spectrum, but like coming out of COVID what—

yeah.

Has this been like net good for mRNA technology or Or were people— I can't tell if people were overwhelmed or underwhelmed.

I think that you have a lot of different variables at play. So for instance, in COVID in general, you have a lot of different, both misinformation and other sorts of personal experience from folks, because everyone kind of experienced COVID. On a long enough time frame, almost all of us contracted the disease, even when it was less serious or after the vaccines, and everyone knows someone I knew someone who had it, and a million different stories, right? We were all part of this, so it leads itself to anecdotal analysis. It's like, well, COVID's not a serious disease 'cause I got it when there weren't vaccines and I didn't die. It's like, okay, that's not how statistics work, but fine. I'd say that the mRNA vaccines got tied up in this bigger issue over bodily autonomy and agency, right? Because it was a— new technology that was proven to be very safe, net positive on society, really allowed us to come out of the pandemic stronger, to protect, you know, our general population. But the way it was sort of forced on people, I think, left people with this like, you know, I'm, I'm not going to eat my vegetables because you want me to eat my vegetables, sort of, you don't tell me what to do, you don't tell me what I put in my body. And I think that's a very valid response to being you're sort of told that you have to take something. Unfortunately, the way people rationalize their want is they create all sorts of reasons and beliefs about the dangers of these or the unproven nature. Well, I got the vaccine and I still got COVID. I think that we're taking a lot of— when we look at whether or not the mRNA vaccines work because you have to continue to get vaccine updates and boosters, And that's very common in highly mutating diseases. I mean, it's been 40 years since we discovered HIV. We still don't have a vaccine for HIV. The flu is a new shot every year, right, to get a flu shot. When viruses mutate rapidly like COVID does, it's almost impossible to have like a single durable response. And it's hard to back that out and say mRNA vaccines aren't— this is what I think Secretary Kennedy had said at one point where he's like, well, they don't work very well because people still get COVID, or they don't work very well because you have to continue to get shots. It's hard to say that that's an mRNA feature versus like that's a COVID feature. You really can't say either one because you have one sample size, which is COVID. So net-net, I would say mRNA vaccines, I think it caused a lot of hype and attention to messenger RNA. And then I think that sort of died off because again, a lot of companies got started in 2020 and 2021 to bring the future of mRNA forward. No one, I think, really developed that correctly. Yeah.

I mean, I don't even fully know how to ask this question, but you were saying coming out in the middle of COVID not everyone wanted to talk to you because you were saying this is the first stage of where this— Yeah. I mean, I think my question is obviously you guys are betting big on mRNA and where it's going. I think the public is maybe a little deflated on the technology to some degree. And it was like billed as, in that moment, as this miracle we had sitting over here ready. It was amazing that we had this out of nowhere in this moment and we developed these vaccines so quickly. And then, yeah, I think a lot of people are like, well, And we were also told, well, this is going to cure all kinds of things. And then it's felt— I mean, science always takes time. Yeah. And people want to see stuff like right away. But yeah, I think my— just my general read, not like I'm like polling the public, is people are kind of like, oh, what happened to that stuff? And like, did it actually work in the way it was supposed to? You know, is it as exciting as we were told?

Well, I think this gets to like broader theme in biotechnology. Something that frustrates me is compared to other startups, deep tech startups like rocket companies or just regular tech startups or AI startups, biotech startups always feel a little less cool, which is I think just a piece of how slow science sometimes moves. If you go to like my LinkedIn, right?

It—

the first thing that it says is making medicine move faster. I think that that is a metric that we should all get behind, which is how do we, how do we get drugs made faster, push them out? I think that mRNA now, where we're sort of standing on this precipice, at least what we're developing here at Strand, over the next 5 years we're going to see transformations in how we're able to treat disease. But of course, the wheels of FDA approvals move at the speed speed at which the FDA allows them to. So, um, as we push that technology forward, the public sort of gets excited about stories, and then, you know, we can't continue to, you know, to, to push a news cycle that is, I guess, in the popular media, going to stay front of mind, right? Because, uh, we can't release a new ChatGPT every single year that— or every 6 months that sort of, oh wow, now it can do this, now I can make new videos. It's, it's sort of like, you know, we make the We have the breakthrough and we make the drug and then there's a number of years you need to test it to prove that it's safe and that it's durable and treat an amount of patients. Yeah, I think that one, again, like I said, during COVID we got an advanced view on how mRNA vaccines would work. I think we pulled up the timelines about 5 years to having an approved mRNA vaccine for COVID versus if we had waited it out, maybe a RSV vaccine or flu vaccine or something would have been approved by now from Moderna or BioNTech or one of the companies working on it. We pulled that timeline up, but we didn't solve the fundamental limitation of messenger RNA as a therapeutic, which is how do I direct it into your body correctly? Like, you know—

Give it some intelligence.

Yeah, give it some intelligence. I mean, we're the only ones who are thinking about, you know, the intelligence. It's not like Moderna wasn't trying to figure out how to get mRNA into the body, but everyone had sort of been using this this idea that if we just engineer the particle, we can make it go where we want it to go. And unfortunately, the science didn't pan out for a lot of companies in that way. Our perspective was more of a first principles thinking, which was, I don't care so much where the messenger RNA goes in the body, so long as I can control whether or not it turns on and expresses. Because if mRNA gets into your liver and doesn't express, it's much ado about nothing. It's an inert molecule that sort of sits around for a day or two inside of the cell. So that was this like first principles aha. How do we, you know, what is the issue we're trying to solve? We're trying to solve specificity of expression, not specificity of delivery. So that's what we went about. That's why we built the programming platform in the first place. And that's what I think is going to be the unlock block on the future of genetic medicines. And that's what we're in the process of proving out. Yeah.

When you're talking, I mean, early on in our conversation, you were saying we started out in melanoma, we're looking at this more general purpose intravenous type therapy, which would go throughout the body and make these right choices. Yeah. So how— I mean, that sounds amazing. So how— where are we on our confidence scale of knowing whether something like that would work or not?

So on the, on the intravenous tumor delivery side, we're, we're very confident. I mean, we've, we've built the drug. It's now being manufactured. We're doing some final safety tests for the FDA. And then earlier in the early part of next year, we'll present all of our data to the FDA and essentially ask their permission to start treating patients. Patients. That's what's called an IND or initial new drug filing. So we're— we've built the drug, we have all the efficacy data on it now. We're very excited. It looks very similar, if not better, in efficacy to the drug that's in the clinic right now that's direct injected. But it also looks very safe. The sensors are working in all of the animal models that we have tested it in, and it's incredibly exciting. That will then go into patients about a little less than 12 months from now. We should be dosing our first patients in that trial. And that's the real test, right?

For which type of cancers?

This will be a sort of all-comers where we're looking specifically at lung cancer.

Okay.

So we'll treat a number of different types of patients in the phase 1 as part of the safety analysis, what's called a basket trial. So we're an all-comers trial where, you know, anyone with advanced stage solid tumor disease would be eligible for our phase 1 trial. Trial, but where we're really wanting to sort of develop down a pathway towards is lung cancer. I think that that's the— that's a huge unmet need. And if we can show the similar sorts of efficacy that we've shown for melanoma patients with the direct injections now being able to deliver IV, that'll be— that'll be pretty big.

So it goes in the body via IV. And then going back to this question I asked before, it just seems like you would have to put so many RNA switches in to ignore all the organ systems, all these different cell types. How do you mark for everything?

Yeah, so it's sort of the process is we're sort of take a nanoparticle, we design a nanoparticle that we know can get to the tumor, right? So you sort of have our messenger RNA, we encapsulate it in a nanoparticle, and then we need that particle to be able to take the messenger RNA A to the target, right? If it doesn't reach the target, then there is no drug, right? It doesn't matter how much it avoids other tissues. If it doesn't go to the tumor, then obviously it's not doing anything. The difference for us is that we don't care as much where else it goes in terms of like, you know, it's going to go into the liver, it's going to go into the spleen. But what we do once we're satisfied with the particle's delivery kinetics in terms of how much messenger RNA you can get into the target tissue. We then assay where else it's going. So we look at all the other tissues and organs and cells in these, you know, in a number of different animal models where the particle is taken up. It's not— it doesn't go everywhere. It's not going to perfuse through the entire body. That's not how the delivery kinetics of the particles work. But, you know, let's say 60%, 70% of the drug goes to the tumor. We're looking for the other 30%. Or 40%, we find where those tissues are, and then we build circuits that essentially either turn off in those tissues. And so this is actually where machine learning and AI come into the picture, because what we'll then do, we have a huge database of all these different markers of what controls, what markers are inside different cell types, what ones are shared by different cell types. And what makes a good sensor for our use cases. And all of that can be done in silico with some big data computer modeling. And so what we do is once we know all of the cell types that are being hit, being delivered by a particle, we then can very rapidly design these circuits to say, OK, well, here's all the sensors that you're going to need to incorporate, and just generates that. And then we're able to test it. And make sure that we're not getting off-target expression and make sure that the toxicity is acceptable.

So it goes in your body with the IV, it goes into your bloodstream.

Yeah.

And then when you're looking at these models where the other 40% goes, I mean, that's like consistent across different people. You know what I mean?

Yeah. Yeah.

Like in my head, I was just like, oh, that feels such a random process. And like it's going to— like in me, it's going to end up over here and somebody else is going to end up over there.

Yeah, it's interesting, right? Because, well, you're a very unique person, Ashlee Vance. And, you know, I'm— well, you're very unique and everyone here is very unique. And you and I are different people, I think, from the perspective of the biophysics of our blood chemistry and how a ball of fat, which is what a lipid nanoparticle is, travels through your bloodstream and where it is statistically most likely to end up, we're actually very similar, right? The personality is sort of skin deep, and everything else in here is much more uniform. It's not perfect, but we've done a lot of different models, and you can sort of see like the biophysical distribution of this. This is classic drug development. The drugs pretty much go to where you think they're going to go. We're not that unique.

Yeah. And if I, like, if you, to the extent that there's people who are skeptical of what you guys are doing or just how much hope to place in this type of technology, I mean, is that the major concern is that, like, can this actually be general purpose as opposed to these one-off type things. My sense is that must be the big central question is like, how broadly applicable will this end up being?

Yeah. So where we're at now, where I mentioned we've been quiet for a couple of years, we wanted to get to some definitive proof points, which is where we're at now. I'd say where we are today is we know that these drugs work. Work in some patients. That is sort of an undeniable fact. There are patients that are— there are people that are alive today because they were given our drug. That is, you know, that's an amazing accomplishment. First, the bigger question now is how big of a deal could this be, right? How many of those— how many other patients— is this something that could be the standard of care or a standard line of therapy in melanoma? And then for our next drug, okay, so we did it with melanoma. We did it when the tumors are at the surface. That's great. How much further can we push the tech, right? Can we get to these later? That's going to be a question that we answer next year and we'll continue to answer in the, in the coming years. But that's really about that, that second drug, the one going into the clinic next year. It's about answering, I think, a much larger question, which is can we deliver to targeted areas of the body through the bloodstream, right? Starting with tumors, that's great. Once we have that sort of positive in our pocket, we're already in the process of building this, like, you know, can we go to the T cells in your immune system, right? We want to go into the bone marrow and be able to, you know, engineer out things like sickle cell disease. That's sort of where we're going. And as we answer these, like, definitive questions, we're opening up a world of possibilities of so many different types of drugs.

Yeah. Going back to the backstory of where this originated, so you grow up in Illinois.

Yeah.

And then you end up getting a PhD at MIT?

Yeah.

Yeah. And then you guys are— you and a partner are— you're on this mRNA hunt, like we said, way before COVID How did you guys start to figure out? To program this in ways other people hadn't figured out.

So yeah, I grew up in this 1,000-person farming town.

Which one was it?

It's called Germantown Hills. It's outside of Peoria, which is the nearby city, and about 40 minutes outside, small town, no post office, no high school. We had to go to the next town over through some cornfields to go to high school. I then went to the University of Illinois, and then I eventually came out here, and that was 2013.

But your town was like oddly, it was where we mass-produced penicillin or something? Peoria.

Peoria, yeah. So Peoria, I think, has a few different claims to fame. Richard Pryor was from there. Also, the 2000s band Mudvayne was from a nearby town called Pekin. And then in the '30s, during World War II, '30s and '40s, there's an agricultural research facility there that figured out how to mass-produce penicillin that was, like, the defining factor on the Western Front, right? Like, the ability to treat soldiers for acute infection. You know, we had discovered penicillin in, like, I think, the 1910s, but no one knew how to actually produce it. We didn't have industrial biotechnology to just manufacture it up. And so this agricultural research lab in Peoria figured out that you could grow it inside of these melons, you grow the bacteria inside of these melons, and that led to this mass production of penicillin and allowed us to— one of the defining technologies that allowed the United States to win World War II.

So this was in your blood.

Yeah, yeah.

Land. Yeah, yeah.

That's the Everyone growing up in the town knows that story. Yeah, I guess biotechnology has been in my blood even though it didn't feel like it maybe at the time.

Yeah. Okay. So you come out here, one of the capitals of biotech, and obviously are getting nudged in these directions. But yeah, just when I was reading last night, I didn't know MRNA, not only was it not a big thing, a lot of people thought it was a colossal waste of time. But you're, as a student, you're digging into it.

Well, I love when people tell me like things are bad ideas or stupid or a waste of time. Like, I sort of think that means like you're on to something a lot of the time. So yeah, I mean, I came out, I remember the first year I started my PhD. So it was like the fall of 2013. And then my co-founder, Tissou Kou, who I've been building this company with for the past 6 and a half years, he was a postdoc at the time, and we sort of got to this idea of, okay, messenger RNA seems like it has all this promise, right? Moderna, like I said, was just out of stealth. They had just sort of come out and been like, we're going to develop mRNA drugs. BioNTech was a company that's who developed the Pfizer vaccine. They were in Germany. They had already been in existence for a few years when Moderna came out of stealth. Myself, and all of these companies were talking about what messenger RNA could do. I, looking at their technology, started to see, wow, that's so cool. Let's learn more. As we dug into it, found out technologically what they were doing, I thought was going to be limited in its ability to be delivered. I thought, okay, if you can inject this into your arm and your muscle cells take it up and you're making a vaccine fine. And if you're going to try to get it into the liver to do something, fine. I think the technology as it stands could figure that out. But this chasm existed between what can you do in either the liver or in the muscle cells of your arm and how you were going to solve these big ideas of genetic medicine or just of medicine in general. How do you get to tumors? How do you get to the kidney? How do you get to the lungs? How do you get to all these different areas of the body where we may want to intervene? Protein for disease. And our thought process was the limiting factor actually may not be delivery as much as it is specificity, right? How do we— can we program the messenger RNAs? Because what we're trying to solve at the end of the day is how much protein are we expressing and where are we expressing it? We're not trying to solve— get all the mRNA into a certain cell type. Not only did people tell me that that was a stupid idea, then they said mRNA is a waste of time, this will never be a drug, mRNA is too unstable, Moderna and BioNTech and all these companies are wasting their time, you're wasting your PhD. That's the stuff that really excites me. That usually is, I didn't ask you your opinion about it. We just said, fuck it, and kept building. 6 years went by, and Moderna raised a lot of money, and BioNTech raised a lot of money, and they were pushing their technologies forward. But really, when 2018 rolled around— In 2018, after we had been working on this for a number of years in academia, Moderna and BioNTech, they had gone on to raise lots of money. mRNA was still seen as a very hypey, unproven technology. There was beginning to be some signs with the clinical trials they had been running in vaccines that, okay, maybe this could work. Moderna, I think in December of 2018, did a really big IPO, maybe one of the biggest IPOs in biotech history. Very splashy, but still to us, it still looked like this technology was going to be fundamentally limited to being a really good vaccine platform. We decided to start the company, we are everything beyond vaccines. We never went out and tried to develop mRNA vaccines. We've pretty much just been about building therapeutics, about building things for patients that have no other hope in actually pushing medicine forward. Let the other folks, Moderna, BioNTech, and everyone swimming in their wake can work on mRNA vaccines. Build therapeutics. We're going to answer the fundamental questions about this technology, which is going to unlock our ability to build medicines with them.

What exactly is mRNA? Why— you had the doubters, but why was it exciting to you? And as far as this programming, it works So like, what did you guys figure out that other people didn't figure out? It was a big question.

Yeah, they're big questions. So, you know, remember 9th grade biology, right? So inside of all your cells is your DNA, your genome, right? So this is a sequence that every single cell in your body holds inside the nucleus. And the DNA has genes encoded on it. The genes are basically proteins. Proteins that your body needs, that your body reads the, the gene off of the, the DNA and turns it into a protein. But in order to do that, the proteins are made in the cytoplasm. So imagine cell right here, nucleus in the middle. The cytoplasm is all the jelly surrounding it between the membrane, the outside of the cell, and the nucleus. Um, that's where all your proteins are made, but your DNA can't leave the nucleus because that's where it's protected And of course, damage to your DNA has all sorts of bad consequences, one of which is cancer. And so the way that biology has evolved is that your DNA sends the message out to be turned into a protein, and it uses messenger RNA. So inside your nucleus, your DNA becomes messenger RNA, basically copies itself into a messenger RNA molecule, and then ejects that from the nucleus into the cytoplasm. The messenger RNA is basically just a direct sequence copy of the DNA, but now it's in the cytoplasm. It can be recognized by things that are floating around out there called the ribosome and turned into a protein. Essentially, you read— that's where the gene gets read and converted into these big globular proteins that make up everything that we are, right? Every, everything that we touch is just protein that our body has made, like in forms of our skin, our bones, everything else.

And so mRNA has existed since organisms existed, but it was like this idea of you could tweak it and do something with it that started to arise.

So the idea that started actually in— there's some foundational papers in 1990, and then a long time of not not getting it to work. And then Kati Karikó, who won the Nobel Prize for the mRNA vaccines in 2007, finally reconfigured how you could build the messenger RNAs to use it therapeutically. So the idea with mRNA therapeutics is rather than deliver, you know, if I'm trying to get a gene or a protein, if I'm trying to get your cell to make a protein that is, you know, for some therapeutic use, right, trying to replace a protein that is, you know, misfiring or a protein that is mutated in your DNA that's causing some disease, if I want to get the right protein back into that cell, I have a few different ways I can do that. I can deliver DNA, but the problem with delivering DNA is I then have to get that DNA into the nucleus of your cell, which creates like, you know, concerns over whether or not the DNA would integrate into your DNA. You don't want that to happen, of course. But it's also just very hard. Your cells, your nucleus is incredibly well guarded by the nuclear membrane for good reason as well. You don't want random things coming coming in and potentially damaging your DNA. So delivering DNA therapeutically, um, you know, to fix, you know, some sort of problem has been very, very difficult. There's been no real successes over the past 30 years of people working on it. The advantage with delivering a synthetic messenger RNA is that you only need to get into the cytoplasm. And so, you know, just getting across the cell membrane, and then your mRNA is there, and it can be picked up by your cell and recognized as if it is your— you know, mRNA is floating around in your cytoplasm at all times. All sorts of different genes of mRNA are floating around in all of your cells. This is just delivering one more copy of messenger RNA that is synthetic, and then your body sort of picks that up, turns it into a protein, um, and then it, it's very quickly degraded too. So messenger RNA is a very, very fragile molecule. You can imagine that, like, how it evolved is a message that your nucleus is essentially sending out saying, hey, make this protein.

So, okay. And so people get excited about it. Some people doubt how useful it will be, and you're looking at it, and then you have this insight as to how you could send more complex instructions to it. I mean, it's like in this era of synthetic biology and treatment creating DNA-like code in some ways.

That's actually— so the lab I was in at MIT is Ron Weiss's lab. Ron is one of the OG synthetic biologists. George Church was on my thesis committee as well. I very much come from the synthetic biology side of this technology where we believe that we can reprogram biology and we are in the biological century right now. This is where the rate of biological research progress and our ability to build all sorts of new tools is at an all-time high. That's actually why I believe, you know, success in this messenger RNA space is going to be such an outsized return on investment, if you will, for the entire medical, the entire medical establishment, because what we're going to be able to do with mRNA technology is actually deliver all these different types of advances, right? So, you know, there's new ways to edit DNA so that we can fix, you know, genetic, uh, uh, you know, single genetic problem. Things like everything from sickle cell disease to polycystic kidney disease need to be addressed with, you know, something that can, can edit the DNA. So can we— we're building all of these good editing technologies, however, we can't deliver them to, to where they need to So that is the big question of what we've been trying to answer at Strand from day one. How do we deliver safely and effectively to various areas of the body?

I got you. Yeah, because I think sequence the genome, CRISPR came out, I was told we're in the synthetic biology era, everyone's just going to be— you sit at your computer and you dial up new genes and cures for everything. It's turned out to be quite the opposite. Quite difficult. Every time I talk to people in the CRISPR field, it's always hard to edit large sequences of DNA to get it to, like, go exactly where you want, to do exactly what you want. So there's been all this promise. Yeah. And it's just— it's— and it's still exciting, and you can kind of see it. But yeah, the— as far as, um, doesn't roll out like sort of— there's like Moore's Law pace all the time, you know what I mean?

No, no.

Until you have time to step back?

Well, I think the problem is that the sexiest thing to do here is build really fast cars. The biotech synthetic biology establishment, the research labs, everyone has been addicted to building better and better vehicles. We keep saying, okay, well, Audi's nice. What about a Porsche? What about a Ferrari? What about a Lamborghini? What about a Bugatti? We keep building them. Meanwhile, we're driving them all on these gravel country roads. And so we keep getting faster and faster cars, and we're like, oh, well, we have 12 cylinders in this sports car. Why is it not going any faster? And you realize you're driving it on this shitty road, because building infrastructure is just fundamentally not sexy. It's why the joke in Washington, DC for 20 years is it's always infrastructure a week whenever you want to change the narrative. Why can't we build infrastructure in this country is because it's not sexy, no one cares about it, it takes a long time. This is why I've changed the saying, like mRNA, I view mRNA not as— I don't view us as an oncology company. I view us as demonstrating success in oncology to start in order to help those patients, but as a way to prove that this can be an infrastructure for how we're going to deliver all of these different cars. And so the way I see it is the last, especially 15 years, has been a car-building bonanza. We've built so many incredible vehicles. And we're driving them on these shitty roads. And if someone comes along and actually just begins very quietly to start putting down really nice, wide, smooth, well-paved roads that can can show and actually get the cars moving at the rate that they need to be, that is going to be fundamentally what unlocks the future of medicine.

Okay. It's a hard question to ask because this is your company. You've bet your life on this. You've raised a quarter billion dollars. Obviously, you believe in this. When you're in my seat, it's like, this sounds amazing. It feels like the promise of what I've been hold for 20 years, finally we have this mechanism. Yeah, I mean, it's like, how sure are you that this will work on that broad scale you're describing?

I mean, how sure am I that this is the right— I think that this is the only approach to me that makes sense, right? Because we've tried and failed a lot of different ways to develop this new era of medicine. But I don't feel that the field and folks in it, not to say anything, not making a value-based judgment on it, but I don't think people have looked at fundamentally what the first principles problems of this are, right? I've talked to people about the future of genetic medicine. What's the cost per kilogram to orbit, right, of biotechnology? I admire Elon Musk and how he built SpaceX around this core critical idea, right? Let's shrink the dollar per kilogram rate of getting something to orbit. What we're trying to do is make it so no matter what therapy you're trying to develop, no matter what therapy you're trying to deliver, you can essentially have a toolbox where you say, I need to get this protein into this type of cell in the body. And I have a solution for that. Right now we build— again, to come back to the car analogy.

Yeah, like, just so I make sure I— when you're talking about these Ferraris and things like that, you're talking about, yeah, we can spend hundreds of thousands, millions of dollars to make a gene therapy for this single gene problem in a child and like cure that one kid, but this is not— this is never going to be applicable. That's so— yeah, well, is that what you mean?

There's In the past 10 years, it seems like every other year or every year we were launching yet another gene editing company with a new— there was CRISPR-Cas9, and then there was prime editing, and then there's, oh, well, what if we do this? And actually this editor is even a little bit better. And we got like all— and I do believe those are incredible technologies and this is more specific and this is better and this is going to be able to edit this way and this is base editing. So it's safer, it's going to be more on target, whatever, whatever, whatever. All of those companies, if you look at their pipeline, are basically going after the same collection of liver diseases because no one has— it's like there's one racetrack in town with these really fancy cars, and they just keep trying to set the record on that track. And you're like, guys, out here is what matters, right? Liver disease, absolutely, let's solve it. There are patients that are I'm suffering, please solve it. But if we don't figure out how to go from liver into the rest of the body, we can make all the fancy gene editing technologies, all the fancy new types of, you know, biologics that we want, but it's not going to matter because we can't get it to where it needs to be.

So you see what you're doing as the only general purpose mechanism that you're aware of?

Well, I mean, I think it's— we're fundamentally attacking the problem differently. I think earlier you asked me a question that I don't know that we got to, which is like, well, why haven't, or why were, what was our insight that allowed us to build this? I think that we just tried this approach because I can tell you from fundraising for this company over the past 6, 7 years, a lot of people told us that it was a stupid approach to solve this problem. They're like, well, why don't you just build a better delivery vehicle? And my response was, was, you know, nanoparticle engineering has been around for 30 years. People have been banging their head against the wall, spending hundreds of millions of dollars trying to solve this problem with that toolbox. I think that the way to success is to take a step back and look at the fundamental problem from a first principles point of view. That's what we did. It was very much not in vogue. I mean, everyone was like, the idea of legacy biotechnology and pharma sort of looks at the problem and goes, goes, oh well, it's all about delivery, right? That's the only way their mind can function. Where, where does the drug go? That's where it is. But this new technology, this genetic medicine, it wasn't where the drug— where the mRNA goes is not where the drug is, because the mRNA has to go there and then it has to make the protein. And so if you control that second step, that protein-making step, you essentially control where the therapy is, because that's what matters, right, therapeutically. But no one agreed with us. Well, a few people agreed with us, of course, to get off the ground. Now more people agree with us, but we have the data.

It's been proving out. Yeah. Okay, those are a bunch of my big questions. So, and then today we're going to take a peek in the lab, and so we'll get to see what happens to these cancer cells over time. Is that the idea? Yeah.

So hopefully you'll get to show off you know, some of what the cancer cells are doing, how we sort of look at this technology, how we sort of look at the responses of the cancer cells, how we assay and make sense of what's happening. And then maybe we'll take a peek over at some of the drug itself and sort of see what we can see on how we make these.

And you guys make everything here?

We make everything here for, for testing experimentally in like animal models and everything else. And we design all of our manufacturing process here because not only do we have to figure out how to, how to design the sequence of the messenger RNAs, we also— this is such a new technology, we have to figure out how to make these molecules too. So we do all of that research here. And then in order to get material that is sort of at the quality level to be put into humans, that requires a different type of lab. So that's made at a secondary facility.

Okay. And then big picture, If we go to your website, I mean, you can see the different— trials is not always the right word, I guess, because that's a certain stage of this, but the drugs in our pipeline, the different things in your pipeline. And if I remember right, I mean, it was like a half dozen things that you're investigating right now. And so that's the mission for the next couple of years is you just have to get these proof points of where this works.

And yeah, so, you know, this idea of building a platform platform therapeutics company comes down to, I think, how do you creatively build drugs that don't, that don't just answer the question of, is this a good drug, does this help patients, but at the same time answers a fundamental question about your platform technology? And so each drug in our pipeline, right, the one that's in the clinic right now, it answers a question of, can you therapeutically use messenger RNA to treat patients? And the answer from our Phase 1 clinical trial at least is yes, that, that is possible. The second drug, the one that comes to the clinic next year, it answers a second question, which is with this programming technology, can we now deliver to targeted areas through the bloodstream that are not the liver? That is the big question that's answered there. And then as we go further along, we answer other questions of like, well, okay, you've proven it with tumors, where else can you go? All of those questions need to be cancer with time, but they're about building drugs that by themselves have multibillions of dollars of potential value and will massively, massively help patients that have no other therapeutic needs. But at the same time, the amount of value that we get back as a company is not just does this drug work and is that valuable to us, but does this technology work in the way that we think it does so that we can build more therapies down the line.

Is it always the liver? Because the liver just absorbs everything.

Yeah, especially, you know, especially fat, um, will, will get taken up by, by your liver really well. And so mRNA is developed— delivered in these nanoparticles called lipid nanoparticles, which are essentially balls of fat that protect the messenger RNA and allow it to sort of get across the cell membrane and into, into the cells. Um, and so when those fats are moving around in your bloodstream, they have a tendency to get stuck in the liver, and then the liver cells take them up. And so what people have done over the past 20 years is, since you can't get 0% of your drug into the liver, we've just made the particles really good at going to the liver and focused on the liver for now. Our approach was, you know, if I can, if I can get the particle to where it needs to be in the body, knowing that 10 or 20% will still end up in the liver, as long as it doesn't and that's not a problem.

Possibly unfair question. I just feel like it's running through my head. It's probably running through other people's heads. I mean, I don't know, you can pick your timeframe, 10, 20, 30 years. You believe in this technology. I know it can be used for different things, but we're talking about curing cancer. I mean, how optimistic are you that you're curing everybody's cancer?

Yeah, I think that, you know, with the cancers that we've looked at thus far, this drug has some of the most promise that, that I've ever seen. It's early. And I think that we all need to be, you know, you need to be careful of looking at like too small of a sample size. But if we can, if it continues to develop in the way that it has over the last year and a half that we've been testing it, it's not unreasonable to think that that we could be out in the world treating patients, at least in this first setting, in just a few years. Our idea is, how do we get these drugs to patients faster? Because people are dying. I think one of the things to understand that sort of motivates me, and I say a lot to the company here, is like, speed is the message sometimes, right? Like getting things done faster. When we hit a 6-month delay, right, if we're, we're going to run a clinical trial and something happens and we're 6 months late, in the event that our drug could have helped a patient, you know, I talked about the first patient that was in our trial, for instance, if we had been 6 months later to the clinic, that patient probably would be dead. And I think that that weighs on me me all the time when I just think about like, there, there really is no time. We have to move these drugs faster. We need to get them further. We need to get them approved. We need to get them into patients' hands. We need to get them into the arsenal of drugs that we use to treat disease. So that's going to be our North Star, is continuing to push the— push technology, push these drugs forward and invest in them as much as we can to get them to as many people as we can.

And like, and again, I realize it's sort of an unfair question because so many things have to happen and you want to be cautious how you start. I just feel like still today, for the most part, cancer treatment feels very crude. It's chemotherapy, it's radiation, it's surgery, it's brute force in a lot of ways. You're doing all these horrible things to your body along the way. Just if I take everything you've said And again, I mean, I'm doing like the optimistic scenario where things, things all work out. It's just what I'm hearing is just you feel like this notion that we talk about all the time of a more elegant, targeted, you know, direct cure for multiple cancers. Yeah. That's just— unless I'm like mishearing things. I mean, it seems like that is at least one one quest that you guys feel like you're on?

And it's, it's what can be delivered with immunotherapy. I think immunotherapy, you know, if you look at some of the top-selling drugs in America are immunotherapies for cancer— Keytruda, Opdivo— those are ways to power your immune system to actually fight the cancer itself. Now, when things like that fail, of course, or, you know, in some other types of more niche cancers or rare cancers, we, you know, these drugs might not work. But immunotherapy thus far, I think, has been nothing short of a revolution in how we've been able to treat cancers. The problem has been that not all patients respond to the first line of immunotherapies. So the question is, how do we, how do we make sure more patients are able to access that? And we have, you know, ideally never a fall-off where you go to these more like aggressive, like high high-dose chemo treatments. I think in the next 10 to 15 years, we might not see cancer completely cured, cured. I would love if that was the case, but I think that what we may end up at least seeing is that it becomes a manageable disease. And if it's a manageable disease, that sort of takes it off of our societal weight, right? So like, when I was growing up, HIV was a very scary boogeyman. Of what could happen. If you have sex, you will get HIV and you will die. In the '90s, that's what it was. That was the message to all of us kids. Nowadays, I think with all the different cocktails and therapies you can have and PrEP and whatnot, having HIV is essentially manageable in a way that diabetes is. While I think we should still push science to get to a cure, that That is a huge, huge advancement. So if we can do that with cancer over the next decade, ideally faster, I think we as a society can kind of stop being so scared of cancer. And with that, we push the envelope forward.

But in that description, you guys would complement the— you are in immunotherapy or you're—

We are in immunotherapy.

But you're more— but okay, because I never know if that's— Like when I heard about the melanoma work, I mean, you're just like clearing the tumor out and—

Yeah, we activate the immune system against the tumor. So our mRNA goes into the cells, then the cells create this protein that signals to the immune system to attack the tumor. And then as it's attacking that tumor, it's activated and then learns what the tumors look like so that it can actually clear other tumors that our mRNA has not inside of. Yeah. And that's how we get these like huge responses.

Yeah. Okay. Okay. Um, Jake, thank you so much for chatting, and yeah, I'm looking forward to going to the lab. Cool. Yeah, let's do it. Okay. The Core Memory Podcast is hosted by me, Ashlee Vance. It is produced by David Nicholson and me. Our theme song is by James Mercer and John Sortland, and the show is edited by the John Sortland. Thanks as always to Brex and A1 Ventures for making this possible. Please visit our Substack, YouTube, and podcast channels to get more of what Core Memory makes. Thanks, y'all.