Tough Tech Today with Meyen and Miller

Unlocking new mRNA Treatments with Jake Becraft, CEO of Strand Therapeutics

• Jonathan Miller, Forrest Meyen, and Jake Becraft • Season 2 • Episode 2

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In one sentence: Unlocking new mRNA treatments will save lives, but it's not as simple as that.
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Overview
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Jake Becraft of Strand Therapeutics is an expert in designing and programming mRNA, critical strands of genetic material that provide instructions for making proteins. As one suite of tools in the emerging synthetic biology toolkit, mRNA is a twenty-first century harbinger of life. 

Yet, with all powerful tools, there are risks of accidental or intentional misuse. It is this shared responsibility among the scientific, private, and public realms that Becraft advocates for thoughtful, anticipatory stewardship of these influential technologies. Stunningly, it's no longer science fiction to consider pre-making vast numbers of vaccines for every conceivable pandemic vector and their mutations. This, the 'Manhattan project for vaccines', is a matter of national defense, Becraft argues.

We are joined by contributing expert Malvika V. Miller for an episode featuring a wide-ranging discussion on synbio, STEM advocacy, national security policy, and more.

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Topic Timecodes
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[01:04] What Strand Therapeutics does
[03:24] Using messenger RNA technology for cancer and other rare diseases
[07:20] What is unique about Strand’s tech and its therapeutic delivery mechanism
[11:31] Targeting mechanism for constantly-changing heterogenous targets
[16:18] Biohacking and open-source science
[20:32] Biohacking security and regulation
[24:46] Increasing importance of biotech security
[29:33] Starting Strand Therapeutics
[32:14] mRNA vs. DNA
[35:38] Current challenges of synthetic biology field
[37:56] Prioritizing at Strand across many use cases of mRNA, a platform therapeutic
[40:41] Making medical developments more efficient and quicker
[42:28] Cancer as a key focus at Strand & strategy outlook
[43:20] Different perceptions of justifiable speed in developing consumer products vs. biotech
[46:23] Perception that COVID-19 vaccine was “rushed” & trusting regulatory agencies
[50:22] “Manhattan Project for vaccines”
[57:13] Who supports and pays for such a defense project

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Show Notes
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Time is a critical factor. And if you advance your drug a year faster, and that drug is the drug that would have cured or put her into complete remission with that breast cancer as opposed to succumbing to it within two years, then that year that you could have advanced that drug is incredibly, incredibly important. Welcome to Tough Tech Today with Meyen and Miller. This is the premier show featuring trailblazers who are building technologies today to solve tomorrow's toughest challenges. Welcome to Tough Tech Today with Meyen and Miller. We have the honor of having on the show, Jacob Becraft, CEO, Co-founder of Strand Therapeutics. And we also have with us our guest biotech expert, Dr. Malvika V. Miller. So welcome both of you. Nice to be here. Jacob, let's launch into this. Tell us what you're working on with Strand Therapeutics. Yeah, so, Strand Therapeutics is a next generation messenger RNA gene therapy company. That's a lot of words to say that what we focus on are diseases that can be that can be fixed or really cured by transfer of some sort of therapeutic gene to correct an underlying genetic issue. And so this technology really came to a head or really came into media's attention in 2020, as the same technology was used to create the COVID vaccines, really using a messenger RNA, and rather than delivering a you know, synthetic protein for the coronavirus. To train the immune system, we were able to encode a part of the coronavirus onto that messenger RNA and deliver it into patients and then patients bodies can learn how to fight off the coronavirus. In much the same way, we can use that same underlying idea that we can encode any protein we want. And rather than encode a piece of the coronavirus, we can encode proteins that direct the body to kill cancer cells that direct different tissues to function correctly again, and all of that can be done with the same what's called this platform, messenger RNA therapy is known as a platform, you can plug in any sort of encoded protein on it, and then express that from the messenger RNA. And so what Strand does that's a little bit different is we build messenger RNAs, not for vaccines, but for these other sorts of chronic and deadly diseases. And we use this type of technology that was spun out of the Massachusetts Institute of Technology that allows us to take that next step that allows us to go from vaccines, which are relatively simple, in kind of mRNA therapeutics terms into these these cancer and rare disease therapies, which are a bit more complex. So to clarify then for all of our listeners or viewers, this is saying that what we've been hearing in the news for a year in terms of the rapid development of sort of mRNA-based vaccines that we can repurpose that kind of same inspired technology to go after cancer. Exactly. So a lot of the current mRNA companies, they are going after cancer in another way. So where cancer is really seeing this renaissance right now is in an area called immunotherapy. So immunotherapy, or cancer immunotherapy rather, is the idea that since cancer is technically different than your body that cancer is when your body has kind of gone beyond itself; it's jumped the shark and it's begun attacking itself or growing out of control. Since that change actually indicates a separation from what you would consider yourself, your immune system should be able to recognize when those cells change over. And so the idea with immunotherapy is that you can train the immune system to attack cancer cells the same way that you would train your immune system to attack the coronavirus. And so what the current vaccine mRNA companies like Moderna or BioNTech have have focused on doing with their mRNA therapeutics are building what they call cancer vaccines. So they've built coronavirus vaccines, they've built influenza vaccines, and they're also building cancer vaccines, which is where instead of putting a viral protein on the mRNA and delivering that in a context to the patient, they put a cancer protein on the mRNA and then deliver that into the patient, which is also a fantastic approach and really represents a revolution in both our ability to do gene therapy and the therapeutic understandings of how we treat cancer, the difference that that strand takes is that our technology allows us essentially, to take a given piece of messenger RNA, a piece of messenger RNA will go into any cell in the body and express whatever you encode onto that. But in order to use mRNA, in a more rigorous therapeutic context, what you have to do is take that messenger RNA and engineer it with certain features, so that it will only express in the tissues that you want it to, for example, if I have a drug that I want to go into a tumor cell, and directly tell that tumor cell to start killing itself, I don't want that same RNA to go into the liver and tell the liver cell to start killing itself, that would be really unacceptable. And so what what we do in order to go beyond vaccines, is to engineer these messenger RNAs with this, you know, cell type specificity with all of these different kind of control mechanisms over themselves. And then they can be delivered into the body, they can get into the tissue that they need to whether that's a tumor, whether that's the kidney, whether it's really wherever we can program it, and then they can actuate their therapeutic in any number of ways. That's really fascinating. So Malvika, I'd like you to react to that because you have expertise in drug delivery. And the way that these... could go wrong, which is in the medical community... usually what we're looking at is how to keep people from getting worse. I've loaded some self-destruct codes to my body. It's a complex problem making sure you get the right cargo to the right place at the right time, right? That's the holy grail in drug delivery. And so, Jake, my question for you is, of course, we have the mRNA, which is the ultimate therapeutic, and then we have the vehicle by which it's being delivered. And for example, Moderna, BioNTech, Pfizer, they're using these lipid nanoparticles and a lot of people have heard about, you know, lipid nanoparticle particles, some people are scared about them. And so just decoupling the actual therapeutic from the cargo, how are you approaching this specificity of where you're targeting? What is that technical pillar that's behind Strand's technology. Yeah. So I come from a background of synthetic biology, and synthetic biology is this field that has emerged over the past 20 years to say that what we can do with any piece of nucleic acid, whether that's DNA, or RNA, or whatever, it inherently has what's called feedback loops, or feedforward loops in it, the same sort of programming technologies that we put into computer code can be put into genetic code. In your body at any given time, there are thousands of genes that are turning on, and then some of the genes are turning others off and they form these very complex regulatory circuits. And what synthetic biology says is we can take that circuitry, that regulation, and we can re-engineer orthogonal systems to fit our own accords, right? So we can build synthetic gene circuits now that rather than in your body, a gene circuit might be responsible for responding to a spike in glucose, and some of the genes in your body need to respond and make extra insulin and, and yada yada yada like that, what we can do is we can make a gene circuit that goes into a cell and can sense the type of cell that it's inside of, and kind of have this this circuitry, this algorithm that's encoded onto it, that can give you this specificity. But Malvika, you bring up a really fantastic point, which is kind of specific to the messenger RNA space, which has to do with delivery. And delivery isthis huge problem that all gene therapies have faced, whether they're viral based or whether they're synthetic like lipid nanoparticle based. And so the way that we approach this issue is that we develop and partner and license, a number of first rate lipid nanoparticles from great groups that have developed different sorts of technologies that can help our therapeutics get to around where they need to be. As anyone who's studied the lipid nanoparticle field knows, people have tried to functionalize particles, right? They've tried to stick different

sorts of targeting:

make a lipid nanoparticle that has a targeting antibody or something on it so that it will bind to a given tissue. The problem is that every targeting technology that I have come across is fundamentally not specific enough, right? There's always some amount of leakage if you deliver it into the bloodstream, the lipid nanoparticle, maybe 60% of it ends up in the tissue that you want it to, and 40% still ends up in the liver. And so what you're facing there is this next level of specificity that you need. You need to still have a nucleic acid, an messenger RNA in our case, that is specific to whatever your ultimate goal tissue is. And so... the way to think about it is, if you think about the body as an entire city, the lipid nanoparticle gets you into the correct neighborhood, you choose the correct nanoparticle to get to the right tissue or organ system. And then the engineering of the messenger RNA gets you into the correct house. When you say (non-expert here), lipid nanoparticle, I'm thinking of lipid in terms of like the lipid bilayer of soap or a cell or something, and then that these are like magic dust that's able to somehow go... it seems like it's a case of Whac-A-Mole, but somehow you've been able to make these little nanoparticles be able to be more broad in a good way with the way that they target. Like something that's going to be shifting around like to me like a cancer cell is inherently going to not look like a normal traditional cell, right? And so I don't understand quite how you're able to keep up with, with the changing face. Right. And that's actually one of the problems with relegating the targeting to just the lipid nanoparticle kind of what Malvika had brought up here that if you just take the approach that you're going to take a lipid nanoparticle and put some targeting technology on the outside of it so that it can bind to a cancer cell, for instance, you have a incredible heterogeneous target that's constantly changing. And that's actually the same for tissues throughout the body... your tissues are very heterogeneous, they're very hard to pin down with a single target that you can reduce and then put that on the outside of a particle. And so we don't really take that approach. We use a number of different lipid nanoparticles that can get us near the tissue, knowing that if that lipid nanoparticle also goes into some other tissue, that's okay, because the RNA is not going to be active in that tissue, it is going to have circuitry inside of it, once the RNA enters the cell, it will still not be active. And so it'll pretty much be inert, and it'll just get degraded in those what's called non-specific targets. But what you said right there about the lipid bolayers... That's actually the exact point. So a cell, the outside of a cell membrane, going back to kind of high school biology, is made of these lipid bilayers. Right, these long chain, polarly charged lipids polar and nonpolar lipid species that form these these bilayers as the membrane of our cell. And so what a lipid nanoparticle is essentially is a similar type of molecule still made of charged lipid species, that then can encapsulate something like a messenger RNA. And when the lipid from the nanoparticle interacts with the lipid bilayer of the cell, you then can have a sort of fusion or endocytotic event where the cell kind of takes that lipid and gobbles it up into itself. And then that's how you facilitate the transfer of this synthetic material that is outside of the cell into the inner workings, the cytoplasm of the cell. So once it once it gets gobbled up, Strand Therapeutics is really working on that extra set of instructions, once it's inside the cell that is specific to the cancer cell or whatever. So then, then it'll encode it and if it's a healthy cell, it won't read the self-destruct code. And if it's a cancer cell, it'll read the self-destruct code and be gone, tight? That's your key portion of the chain that you're working on. Yeah, 100%. I really liked that analogy you used of the neighborhood and finding the house. And so now like Forrest mentioned, you're now in that neighborhood, you find that that house and now you want to self-destruct or not self-destruct, depending on that house, how good is the information that we have on the specificity from tissue to tissue or from house to house? Like that's really what we need to make sure that this technology would work. And so yeah, how good is that information out there? Yeah, I mean, that's a great point. And so there's a wealth of information out in the world around these sorts of different biomarkers and it kind of depends on what you are specifically targeting, right? How are you discerning a cancer cell, or any type of cell from another type of cell... you need to find something that is differentially expressed or something that is fundamentally changed. And then you also have to have a sensor for whatever that's changing. It's a lot like the early days of computer science where you had to almost build a custom computer chip, for any sort of case that you wanted, because all of the different sensory components and different actuators, nothing was was kind of individually unified. And so what we're doing now is we profile these different cells, we look for different biomarkers, things that we can differentiate the cells based on these these differential expressions, and then we feed those in. And we do that... originally when we were at MIT, we were doing that using different databases. NIH and NCI have a lot of fantastic databases on all of this different information it's mind boggling the sort of information that people have accumulated. But you know, since then we've developed, inside the company, a lot of different sort of proprietary techniques of how do we identify these biomarkers that we care about? What do you think about some of the work in the biohacking space where it's maybe not quite as a professional shop as as you may be running with Strand, but nevertheless, because of.... the commoditization of some of the equipment, that techniques, the fact that now we can take any sort of living organism or a virus, which is sort of like a zombie state entity, and be able to digitize its constitution, like what it is, and then easily share that around the world? What do you feel about the work of these groups? So I'm very pro, open source open source science, open source publications. I believe that science should be accessible to more people, I believe we should have more community oriented science centers. But where biohacking kind of runs up against this... You know, a lot of times the today's current biotech industry and the current genetics revolution is juxtaposed with the technology revolutions of the late 20th century, the computer clubs and the hacking clubs that birthed Steve Wozniak and Steve Jobs running off with Apple computers out of kind of one of these hacking groups, that hacked together something that could... I think the story of Apple is, that was the hack and jobs built this chip that you could plug onto a phone, and it would allow you to make long distance phone calls. And I think Jobs like called the Vatican, from the San Francisco area, and called all the way to the Vatican. This was in the 70s, when that costs hundreds of dollars. And it's a very funny story, right? And a lot of the early hacking, people were able to pull pranks in computer science, people were pulling pranks and the most damage you could do.... I mean there are stories of people trying to attack like AT&T's infrastructure, or mess with those mega corporations. But the most damage you could do was limited to what technology was relied upon at that time. And then as technology got more advanced, and we became more reliant on technology, the hacking obviously got better. But the defenses against hacking got better. And now when you know everyone's life and personal data, and health data and banking data, and pretty much everything you have is online and there are hackers and nation states and such that are attacking that.... there's also a lot more defense, we've matured in the way that we can defend against this hacking, and you don't see nearly as many at least, of these sorts of bad things that happen. And again, that's because the hacker culture that started in the early tech industry could only hack into whatever we were using technology for. And here's the problem with complete open-source, unregulated biohacking, is that we're dealing with the end system, right? Like the biohacking is hacking of the body, right? So whatever sorts of problems or oversteps that biohacking may cause could immediately impact people's lives. If you're messing around with making some sort of therapeutic that's going to give someone like ... you're just you're doing something that you think is going to be funny, and then ends up causing a huge problem that will immediately impact people's lives. It's not like it's the '70s and the only thing I have on the computer is like a game of Tetris, right? It's a lot more serious now. So I think we have to be careful how we juxtapose the two revolutions and understand that while science should be more accessible and should always strive to be completely open, we also have to think about what is responsible. So do you think in the future, there's gonna be biohacking security companies that evolve out of this? Like virus scan and an encryption...? Well, I mean, so right now, we already have a number of these defenses in place, right? So for example, if you order synthesize DNA from any supplier in the United States, and you go onto the IDT website, integrated DNA technology, one of the main suppliers of synthesize DNA, and you enter a sequence, that sequence immediately gets run through a number of algorithms that try to pin it down to whether or not it is a viral or pathogenic origin immediately. And if it is, it will flag it and they'll ask for a number of different credentials, you know, where are you ordering from? Are you ordering from a trusted company or ordering from a university and even when you're at the university you have to go in and sign waivers and say exactly what you're using this sequence for. So that exists today. I think that in the future, we're definitely going to have to get way more serious about biosecurity, and thwarting bio hacking, because as fun as biohacking is in a trailer in the Cambridge, Massachusetts neighborhood or someone sets up a trailer, and does some biohacking to turn some bacteria green. That same technology can now be used by someone with more nefarious purposes, to create engineered super COVID. And while the technology is not there yet, we need to take that threat seriously today, because again, if we look back at the technology sector and this juxtaposition between biotech and technology, we clearly are behind the gun on cybersecurity, right? I said, we have great defenses but you know, people are trying to hack our elections, people are trying to hack into everyone's systems constantly. And Equifax is losing everyone's social security information. So we're not there. We weren't there on technology... the hackers were able to stay in front of us. In biotech, we don't have that luxury. Again, it's much more serious. And we need to take that biosecurity threat seriously from day one. So it sounds like we absolutely then would benefit by having a national defense policy on synthetic biology, right? On cyber biosecurity... I'll read a brief passage from a proposition that's on a national defense strategy around this. And it says that, for the listeners and viewers who are interested in this is that in in 2017, researchers at the University of Washington were able to encode malicious software into a string of DNA, that when sequenced allowed them to take control of the underlying computer system. And this vulnerability provides a sophisticated attack vector into academic and commercial operating systems enabling traditional cyber threats, such as data exfiltration, or industrial sabotage. So could you both of you react to that? Yeah, I mean, I think the points that have been made are absolutely spot on. We want to strike the right balance between having access to these tools and making sure there's open science, open communication, but also balancing of the fact that we need that oversight. And I absolutely agree that there needs to be more done on the federal level to have a security program that's really making sure that these tools are being genuinely used for scientific research or innovation or creating things that are actually going to be useful. I mean, I think definitely we need this now. And I think a lot of what Jake has also been writing about in his advocacy on the side outside of Strand is getting at that to really making sure we have a national defense biosecurity program that's not just being reactive to potential threats but proactive in detecting them or making sure we have an arsenal of tools to go after anything that could come our way. So absolutely agree that we need something like this. It's true. For instance, when Andrew Yang ran for president now in 2020, he talked about creating a cabinet position for technology right? Secretary of Technology, and that was this revolutionary idea, right? It's like oh my God, this forward thinking guy. And we've been on this technological war path for 50 years, right? Since the 70s, we've been trucking up in technology to where today, you interact with a number of technology devices, and your entire life, again, is contained inside of that. And we're only just now starting to talk about a cabinet level position for technology. Luckily, the current administration of the last couple of weeks, has already prioritized genetics and synthetic biology as a key interest area, and elevated Eric Lander who is a professor at at Malvika and my alma mater, at MIT, Eric has been not only made the a Director of the Office of Science and Technology Policy, they have then elevated that scientific advisor level from an advisory level to a cabinet level position. That shows great promise, I think that that is the first of many steps in the correct direction. What we really need is a full encompassing department, right? And I feel like the federal government or the executive branch of the government has not added a new department since a lot of us were a lot younger when we added the Department of Homeland Security. And in the wake of 9-11, but we can't really be reactionary anymore, we need to both prioritize technology, because clearly hacking and social media influences and things like Cambridge Analytica, and Facebook influences and fake news are having a real negative impact, a real, measurable, toxic impact on the culture and the stability of American society. And much the same, we need to be in front of that curve on biotech. Because again, the risks are just that much more compounded. And there's a thought that I hear, you know, to some people to take the Luddite kind of approach to biotech, where we say, well this is dangerous or this is complicated so we should just cease all research. And of course, that's insane because even if America chooses to cease all research, because it's scary, China won't, Russia won't... these other global superpowers won't be stopping their research. And so we have to find a way to continue to not only push research, but really accelerate our research, but at the same time, accelerate all sorts of different mitigation and planning strategies, and my advocacy, what you're mentioning, and some of the things I've written specifically on pandemic responses, but should be taken into an all encompassing view of how we think about biotechnology is to view things through a defense lens. For whatever reason, human beings, and Americans especially view things through a defensive lens and through a preservation-of-self lens that lends itself to thinking of preparation, right? When we think about, preventative health, we don't do so well. But when we think about preventative defense, and how do we build... building aircraft and aircraft carriers and different sorts of missile systems, we devote over half of our federal budget to that sort of a thing. So I think that we should start thinking about that in terms of biotech. So now that we have Space Force maybe the next thing we need is Bioforce. Yeah. 100%, that's it... President Biden if you're listening, call me up, let's make Bioforce. Bioforce join today, enlist. I would totally sign up that sounds interesting and definitely would be helping prepare us for the future. We already have the uniforms if we just look to the Captain Planet cartoon we already know. There we go. Perfect. One one thing I really wanted to hear and give our viewers a little view into the founding of your company. Talk to us a little bit about this process as you're at MIT and thinking about starting an awesome new venture and what that journey has been like so far. An "awesome new venture," yes that's what I told myself every day. I was like, "I'm gonna do an awesome new venture." No, so the way that I think great companies get started in the science realm or in the deep tech realm is from a point of inquiry first. And that's why I think academia can be so powerful and why I think that allowing or creating roadmaps for graduate students or postdocs are really researchers at the academic level or at the research lab level, to spin that technology into into companies or even into nonprofits is really what we should be enabling. And so I say that because of how my company came about. So when Moderna first started becoming more of a mainstream company and I say"mainstream" not on CNN like they are today, but really just as they achieved more publications in the trade presses of biotech, as more people became aware that there were people like Moderna and BioNTech and such working on mRNA. This is 2012, let's say, what we were doing at MIT in my synthetic biology lab, we're thinking about all right, this is a new area of scientific research, a new area of therapeutics. And we know that, other types of gene therapy from engineered cell therapies to oncolytic viruses, all of those genetic based therapies, at the time were starting to... synthetic biology was starting to innovate on them. It was starting to program higher specificities into cell therapies and into engineered viruses. But mRNA didn't have any of the tools that DNA-based approaches like viruses and cell therapies have. So for a decade before this even happened, synthetic biology had been building all of these tools to program the DNA of anything you wanted. And those tools were able to be ported into these viral engineered gene therapies. mRNA didn't have any of those tools. And so it was a 2012... mRNA is more complicated or like higher hanging fruit? Why was mRNA lesser served? Yeah, there are a number of reasons, one of which is that no one saw the reason, right? So with DNA, most of the genetic circuits in your body that we're at least aware of right now are based on DNA. They're based on these proteins called transcription factors, they bind to the DNA, they turn genes on and off. And it makes it a lot easier to build synthetic systems, when you already have that sort of technology. From what we know of how mRNA is regulated, mRNA is a very transient molecule, it degrades pretty fast once it's into the body. And that also limited its ability, early on as a gene therapy platform, because it is so short lived, it's very hard to build a robust gene therapy platform around a number of innovations that have been covered by the press now such as Catalin Carico, Andrew Weissman, at UPenn, their breakthroughs with engineering messenger RNAs to get us to where we are today, changed that thought process a little bit. But again, there were both no natural systems to build off of for mRNA regulation and there was also no reason to build them because unless you are delivering your gene therapy on a messenger RNA, you are delivering it via DNA. And so there's no real reason to build all of this genetic circuitry to work at the mRNA level, if you have DNA there, and you have a whole toolbox to play from, but in 2012, with the legitimization of the mRNA companies like Moderna and BioNTech, we were able to take an academic approach because again, we were academics, we were at MIT, Ron Weiss is the director of the Synthetic Biology Center and one of the pioneers of synthetic biology, one of the people who really created the field of synthetic biology. And Ron and I and my co-founder of Strand, Tasuku Kitada, along with a number of other scientists at the time, got to sit and perform this academic exercise, which was if this technology is successful, if mRNA is as impactful as Moderna and BioNTech and these other companies claim that it's going to be, what will we need to take it to the next level, what will be the next step of hurdles that will impact the technology and the ones we identified were specificity and duration of expression and all of these things that required synthetic biology to add this next layer of expertise on top of it. So you found some opportunity by just thinking two steps ahead? There's this new thing, what's the new thing for the new thing? Yeah, exactly. Malvika, with your perspective on synthetic biology and some of the shared colleagues on this could you outline some of the challenges that will need to be addressed, perhaps for the industry overall, but also that Strand and Jacob maybe facing down the road, and we can talk through... establishing of priorities to address some of those challenges? Sure, Jake, might be the best on that. But I'll definitely take a stab at taking the bird's eye view of synthetic biology as a whole. Jake hit on a few of those points... it comes down to some of the transient nature of mRNA, specifically for the field he's working on. And like he's saying, making sure that this mRNA molecule is... it comes down to like, it's at the right place, right time. And so that's some of the core pillars that are going to have to be overcome. I mean, on a broader level, there's a lot of regulatory challenges. This is a new therapeutic technology that would have to go through the FDA, and I'm sure he can tell you about some of the clinical trials that they're planning to run, but as with any new molecule, there are many hurdles, and it could take somewhere between five to ten years to even get approval to get into the clinic. So that's like that's one notable thing. And I mean, as he's probably already building... working towards making sure this is a platform technology. And so with that word "platform," what that means is that there are many different indications that this technology could be used for, but picking the first one to start with is something that is probably on top of many people's minds in this space how do we prove that our synthetic biology technology works? What is that first sort of indication that we should go after where there's a sizable unmet need from a clinical perspective, but also that you can actually get paid for it. So someone's going to be actually willing to pay for this therapy down the line, whether it's insurance, company hospital... just understanding that whole ecosystem. And so that's something that I'd love to hear more about from Jake is how he thought about planning what is that first market? I mean, it sounds like oncology. What, specifically? And how did you select that as the first sort of indication to go after given that what you're working on can apply to so many different areas? It seems disorienting, yeah. Yeah, how did you do that Jake? It's a challenge to prioritize. So where do you start? Yeah, Malvika is completely correct on all of those points really. I think, from a regulatory perspective, it's interesting, because when I started the company, we knew that mRNA was going to be this new frontier of medicine. And there were, a number of phase one trials that were ongoing, with Moderna, and with BioNTech, and CureVac as well. mRNA companies had been around for a decade at that point, doing early stage clinical trials and trying to get the science to a level that it would be acceptable. Where we're at now is actually in a little bit different arena, because mRNA has now become a, much more widely used therapeutic modality. And by the end of 2021, my company strand will enter the clinic in 2022. But by the end of 2021, there will be billions of people that have been injected with messenger RNA, at least as a vaccine and that's very powerful I think... to talk about the coming frontier of a drug. When you get to the levels of hundreds of millions or billions of people that have been administered a drug that lowers the bar, of what's acceptable, or at least it raises... the rising tide raises all ships and whatnot... because the FDA now will be less looking at the fact that it is messenger RNA, in my opinion; they'll be looking less at the fact that it's messenger RNA, and more at what are you doing specifically and how are you different? How have you changed this molecule? What are you delivering with the molecule? What is it encoding? So those are all classic drug hang-ups that you need to get through with the FDA, but now that we're past the novelty of the platform itself the novelty of the messenger RNA in that hundreds of millions of people and potentially billions worldwide are going to receive mRNA. You know, we're at kind of a different perspective there. Malvika, you brought up clinical indication selection... We mapped out where the highest unmet medical need was and what our technology could do in the quickest amount of time because if anyone has ever spoken to me before, they know my number one goal is to make medicine move faster. And that doesn't mean irresponsibly... it doesn't mean that the FDA should not do its due diligence. But we've seen in 2020 that medical innovation and regulation and clinical trials and such can move faster when people are motivated, when we deploy resources and when agencies are incentivized to move with time as a deciding variable. And with COVID, it was because with time picking up more people were dying every day, the economy was at least for small businesses, maybe not the public markets, but for small businesses... was getting crushed. And we understood that time was the most important factor. And my argument is that time will always be an important factor for someone, for that mom who's just gotten diagnosed with breast cancer, right? Time is a critical factor, and if you advance your drug a year faster, and that drug is the drug that would have cured or put her into complete remissionwith that breast cancer as opposed to succumbing to it within two years, then that year that you could have advanced that drug is incredibly, incredibly important. And so I believe that medicine needs to move faster, we need to innovate in the FDA, and the FDA has been incredibly innovative with new gene therapies, they are on track. But I believe that our research infrastructure, our clinical trial infrastructure, and our regulatory infrastructure can all move faster. Because the medical technology, the messenger RNAs, and other engineered platforms that are coming to the market now allow us to move faster in the drug discovery and the drug development realm, which has historically been the longest process that we need to move through. And so we chose our cancer as a first indication... well the specific cancers that we're looking at one of which is breast cancer, because we knew we could move very quickly and provide real value to patients in the fastest amount of time, and also provide value to the company. We'd be able to move quickly and that allows the company to demonstrate its technology, which allows us to build value, and be able to raise more capital, which we can then put back into... all of the capital we raise goes right back into our our Research and Development division, which is working on building the platform for new and exciting areas, which may have a longer research time horizon. We're trying to innovate on all sorts of different areas now and so that's kind of the the strategic outlook that we took as a I think those are really good points. And I want to share company. something that Malvika shared with me before recording the episode, a post by a colleague that was saying how we celebrate... the iPhone 11 was released, and then a year later, Apple releases the iPhone 12. And that's celebrated as a super innovative company, an amazing product. And consumer tech is celebrated for that speed, though now we're starting to see, on the biotech side of things, where... about a year and a half is when we have go from the beginning of a pandemic to having potentially widely distributed vaccines for that.... I want to just sort of bring up the point is that we may celebrate the innovation of consumer tech, one year from an amazing device to an amazing device, year after year and sustaining that. With medical land, it's a little bit different, that there are concerns of the safety or the integrity of it... that there's a perception that this isn't safe. And so... The main issue being people are reacting to the fact that they think things were rushed... that it's easy to make an an iPhone version. People are like, "Wow, that's amazing, new features." And now of course everyone's super impressed with the speed at which mRNA vaccines got into the clinic and ultimately are now all over the world. But there's also that skeptical nature... "Oh no, this was rushed." How could we possibly do it and that dichotomy of the consumer tech versus the biotech speed? How do we...? What would you say to folks that think like that that things are rushed? I mean, there's this huge backlash that it's going to be difficult to overcome that. That is a fantastic point. And one thing it does is it illustrates what I was saying earlier, which is why biotech and technology while similar, while you can talk about them in the same vein, and you can talk about the revolutions in technology in the same vein why they need to be handled differently, why we need to be in front of bio threats earlier than we were in front of cyber threats. That being said, I think everyone should, should have just the utmost faith in our regulatory agencies. And it's a hard thing to do in today's society of mass information, of social media, and, frankly, of fake news, right? Because what ends up happening is that folks who aren't familiar with the regulatory agencies, they aren't familiar with the FDA and how they operate and how clinical trials work are now very laser focused on clinical trials. And very laser focused on vaccine development and all this different technology, that in a normal time, people outside of the industry aren't really paying that much attention to. And so now that people kind of have lasered in on it, they've said things like, "well, the vaccine development was rushed." I can tell you that, if we wanted to rush the drug through, we could have had the drug ready in March. The vaccine that we have today was designed actually at the beginning of 2020. We spent the entire year of 2020, validating the safety of the drug. And we spent the entire 10 years before that validating the safety and the efficacy of this type of drug working with messenger RNA as a platform. So we have a whole wealth of data and a whole lot of science, that underlies exactly what this sort of thing can do. And it should be said that while drugs directly go into your body and they're designed to make some sort of change, it's really the most amount of scrutiny that any product that's consumed is put under, because we have we have no shortage of examples of where a new a food company or an oil company or anything starts augmenting their product and gets it out to the market. And it has real health consequences, because they're never really looked at, but at the drug level, we look at these things, we look at these things so incredibly intensely and with armies of people whose only job is to really be skeptical, and to know exactly how to review and pay incredibly close attention. I think that what we're facing right now is when it comes to getting the vaccine, I advocate 100% everyone should get the vaccines. They are incredibly safe. They're very much in line with what we would expect from any sort of a vaccine. And we should trust the FDA to have done their due diligence, right? Because there's a reason that we have an FDA and we don't put all drug reviews to a popular vote, because it takes an incredible amount of expertise to determine these sorts of things like drug safety and drug efficacy. So we need to take a step back and know that even though this drug development is in the center line of the media, we really need to have faith in the agencies that we've built on the FDA being one of the most effectively run organizations despite my qualms about the speed at which... drug regulation happens outside of the Coronavirus vaccine. FDA is one of the most fantastically run organizations in the federal government. And it's been incredibly effective at managing this sort of case. And I would love to give everyone a masterclass in the ins and outs of drug regulations and how we should determine the safety of these drugs, but that isn't what people are necessarily interested in. They're just interested in knee-jerk reactions and believing that something has come to market quickly. So we'll have to do another episode on the masterclass for drug regulations. It'll be a special Tough Tech Today episode. Educational. So Jake I know one of your personal motivations... as you've mentioned many times now is to make medicines move faster. I also wanted to make sure viewers of Tough Tech Today also heard a little bit about the advocacy side on the proactive pieces you've been pushing for: the Manhattan Project for vaccines. Could you explain what that is? And why you think that's really critical? Yeah. Love to talk about this. So one of the things that the mRNA vaccines enable us to do... so the reason that the mRNA vaccine was able to move so fast is.... mRNA is what's known as a platform therapeutic. We've mentioned this a little bit on this, this podcast so far. A platform therapeutic is really where you have a given molecule, so mRNA that is encapsulated in a lipid nanoparticle. And all of the molecular species are kind of known. And the only thing that you're changing with messenger RNA is the sequence of the... welll people are familiar with ATGC. But in the case of mRNA, it's actually AUGC, because thymine is switched to uracil. And so with the AUGC sequence of the messenger RNA, you can change that to be any sequence and that sequence can match any viral protein. That sequence will code for a viral protein through classic genetics and you can then switch in the sequence of any viral threat that exists out there. And so what I've been advocating for is that, again, we take this defensive look this idea of vaccines for the national defense knowing that one of the greatest threats that we face as a nation and as a species is that of the biological. Throughout history, biology and the microscopic and the basically invisible to us, has been shaping our lives. It changed how the Americas were founded.... when the settlers came and interacted with the natives that lived here in this country, how that proceeded had to do with disease, infectious disease that was that was brought along with those with those settlers. So we've always been shaped by this piece of biology. And it's always been a threat, though for the past 100 years, we've enjoyed an unbelievable period of peace time. Since Spanish influenza to the current pandemic, we've had our trials and tribulations, we've had polio, we've had HIV, we've had a number of different diseases come out, but we haven't had anything on the level of COVID. And so we have to think about how do we prevent this from happening? And the way we prevent this from happening is by taking these platform therapeutics, now that we know that this formulation works as a vaccine; this particle with a messenger RNA inside of it can be injected into the body and form immunity. And it's very easy to now recode, that mRNA rather than what it would take to say build a traditional vaccine, for every virus, which would create, you'd have to make a new process, it'd take multiple years for every single sort of virus and understanding it and building it, everything would have to be very niche. With platform technologies, we can just start encoding every viral antigen sequence that we can possibly think of. And so what I believe we should do is take the proactive step, where we create prototype vaccines against every known infectious virus, starting with the most high risk viruses. And then we create, even further vaccines, against other sorts of known antigens that could emerge, we create a monitoring system where we're constantly sequencing the viromes, the viral genomes that are found in wild animal species that are close to humans, such as bats and pangolins, which is where coronaviruses mostly come from. Sequencing these viruses, identifying new viruses and making new vaccines in a proactive way, and taking each one of these vaccines through what we call early safety trials. So the first six months of 2020, the first nine months of 2020 even, were spent proving out that the vaccine was safe, and you can do safety trials without an ongoing pandemic. You need a number of volunteers. You need money to spend on that, but it's a small amount of money. It's single digit millions of dollars to go from the mRNA technology we have today to a fully executed phase one safety trial. And we could do that for every single vaccine that we could possibly develop. And so what this allows us to do is, at the time of a new emerging pandemic, we can take this arsenal of already de-risked vaccines and begin right at the phase three level, which the phase three is that efficacy trial that was in the news in November and December, that has to do with 95% of efficacy, that was all over every headline... we can begin those trials, not in the fall, as we did in 2020; but on the same timeline, we can begin those in January, we can start deploying vaccines and be ready to roll out vaccines. By the time we get to the spring or the early summer, if we're looking at a 2020 roadmap, we can be ready to roll these out and really take this proactive defense, of course right now, our health, our public health defenses are so reactionary. To put it in context of the Defense Department, imagine if we waited until there was an attack on US soil until we made any tanks or any aircraft... we just waited and then the moment someone attacked us, we tried to spin up the manufacturer of fighter jets and aircraft carriers and build them all and deploy them then. Imagine how bad things would get in that interim time where we were we were waiting. So with defense, we take a very proactive role, and since infectious diseases is clearly one of the largest threats looming, we live in a time of unprecedented global peace for the most part, so how do we now talk about the these new threats, such as biological...? Both natural biological threats and biological warfare, which could also emerge in the future, we need to be prepared. So, Jake, who do you think you need to convince? Who's gonna pay for it? I mean, the protector of the public health is the public. And so I believe that at the national level, it needs to be the country, right? The country has to pay for this, just like we pay for our national defense. I also think and dream of a more global coalition. We have the World Health Organization, we have these large scale global cooperation treaties that people come together... the Paris agreement to fight climate change, we could have similar agreements of countries that come together and agree to fight pandemics, to do environmental monitoring, to do global task forces to have unified rules to what happens when we identify a novel virus. When COVID broke out and they locked down Wuhan, China, that actually took an amount of time before that lockdown happened, and a number of people left the city in that time, because they knew that this lockdown was coming. We need to have more unified sorts of ways of cooperating if we're going to live in a global society, if we're going to live in a world where you can walk down to the airport, pay, get on a plane and be on the other side of the world in less than 24 hours. That's the society we live in today. And it's beautiful. But if we're going to live there, then we have to have global cooperation, we have to have a way that the entirety of the human species, or at least the vast majority, comes together to say, these are our priorities, this is how we're going to move forward, and this is what we're going to build to make sure that something as catastrophic to the our way of life as a species like COVID never happens again. Thank you very much for joining today. Thank you guys for having me. I really appreciate this conversation. This is a ton of fun. Hi, I'm Jake Becraft, CEO and Co-Founder of Strand Therapeutics. Stay tough. We hope you enjoyed the discussion with Jacob Becraft and Malvika Miller. If you learned something from this episode, I invite you to say so in the comments, to ask a follow up question, and we invite you to leave a five-star review or like. Our next episode features Emily King, a global mining expert. This is really important because mining enables us to get minerals, and there's a world of minerals in every single electronic gadget. Click subscribe to be the first to hear when the new episode drops. Until then, stay tough!

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