mRNA Hot Takes: Habaneros & Headwinds

Anna Rose Welch: Hello everyone, and welcome to Advancing RNA's mRNA Hot Takes, the show where we talk about serious mRNA things, but with a spicy twist. I'm your host, Anna Rose Welch, the editorial and community director of Advancing RNA, and I'm once again overjoyed to introduce my guest stars, the luminous and brave Sophia Lugo, CEO of Radar Therapeutics, and Michelle Lynn Hall, partner of the VC firm, Entrée Bio. And ladies and gentlemen, we have a surprise guest joining us as well from the Radar headquarters: I'm so excited to introduce Andrew Fraley, founder of Korro Bio, Judo Bio, and Triplet Therapeutics, as well as a score of other things. So, thank you so, so much, Andrew, for being brave enough to join us on this venture, as well as to you, Michelle and Sophia, thank you as well for continuing to come back.

Sophia Lugo: We’d like to be referred to as the “Hot Shots” of the RNA industry.

Welch: Exactly, exactly. Hot shots. That's a great way to refer to you guys. All right, I'm going to steal that for my next script.

We are back to talk about the scientific and business world of mRNA and RNA, but because we are bold and daring, and perhaps slightly overconfident, we are going to try to handle these serious conversations while also setting our mouths on fire by eating hot peppers.

In the past few weeks, we've tackled the jalapeno, the Serrano, and the Thai chili. Now, one of us, not to name names *cough* Michelle *cough* has been crippled by a super spicy jalapeno.

Michelle Lynn Hall: And I'm a Texan. I don't know. I don't know what to tell you.

Welch: And one of us, again, not to name names, *cough* Sophia *cough* has been nearly struck ill by a bird eye chili that was masquerading as a serrano.

Now, not to brag, but I managed to eat four Thai chilies in one sitting, and I had no ill effects, no adverse effects whatsoever. So, I'm feeling very confident that I have a super spicy superpower here. But we'll see if this reign continues this week because this week, we take it another exponential step higher up the Scoville units chart. Here, we are ready to conquer the habanero, which is just a meager 100,000-350,000 Scoville units. Let's take a second and ruminate on how this kind of looks like something out of an evil fairytale, right? Something evil that a sorceress would come up with. I think they're kind of poetic and weird looking.

Alright, you guys ready?

Hall: Yes. No — wait. Does it matter? It doesn't. You're going to do it anyway.

Welch: It doesn't matter. We're going to do it anyway. Alright, now I have a red and an orange, so I feel like I'm going to have to eat a bite of at least both. So, I'm going to start this out with the red and see how this goes.

Lugo: We have to do a seed check.

Welch: I know, the seeds are so high up though. Look, the seeds are all the way hidden up in there. Yeah, we're going to have to keep going with this. This is not bad, although this could come back to bite me.

Yep, yep. It's coming back to bite me. Okay. There it is.

Alright, I'm going to start. Andrew, because you're new here, I would like to start with you. Get your habanero ready.

What has been the biggest misstep our industry has made and is continuing to make today that is making the path forward for RNA harder than it should be or needs to be?

Andrew Fraley: I have to eat and then answer, or answer, then eat?

Welch: Oh, you have to eat then answer.

Fraley: Alright: The biggest misstep.

Welch: Yeah. Make sure you get some seeds in there. Look at how far I am. We're far.

Lugo: He's getting there.

Hall: While Andrew cannot talk, I think it's important to outline some interesting factoids about Andrew. One interesting factoid is that Andrew has a food allergy, and that food allergy is to kale.

Lugo: I did not know that!

Hall: Yeah. Yeah. It's definitely a legit food allergy and not just something he dislikes because it's hippie dippy.

Fraley: That's right. Well, I'm in Berkeley right now, so you know, you got to go with the flow.

Lugo: Yeah. People who know me know that massaged kale is my favorite meal.

Hall: I love massaged kale. This guy is a fascist.

Fraley: Massaged kale? Like it goes to California to a massage place?

Lugo: The better the masseuse, the better the kale!

Welch: Oh my god.

Hall: I'm with her.

Fraley: I'm a fan of collard greens, but not kale.

Welch: Alright, that's a hot take.

Hall: Bacon and collard greens?

Fraley: Vinegar and hot sauce collard greens. Slow cooked.

Hall: You're dead to me.

Lugo: Strange, but we'll forgive you.

Welch: I've just eaten the seeds, and I'm still not impressed. I'm going to end up eating multiple of these.

Alright. Andrew; you’ve had a couple of minutes.

Fraley: What's the biggest misstep we've made in the mRNA or RNA field?

That's a good question.

Lugo: We’ve never made mistakes.

Welch: No, we're perfect.

Fraley: I think maybe not the biggest misstep as a field, but I think it’s a misstep that a lot of people make, and I say this because I'm trained as a chemist. I think we undervalue the chemistry that has to go into how we think about mRNA or RNA recognition and if it's an enzyme or if it's an mRNA interacting with all the translational factors and the ribosome, or if it's the delivery side. I think a great example is a lot of the work that Moderna did back in the day on LNP generation, and really spending time on SAR to find real lipids and understanding how they interact with RNAs to come up with strong products. So, I think that we underestimate the need there. I think a lot of times people now treat mRNA as a software, not as a molecule.

Welch: Interesting. What does that mean to you? Does that mean we're just not investing in the right things? How do we shift the perspective away from that?

Fraley: Well, that's a good question. I think a lot of times we sell the chemistry off too quickly. If you're a company and you don't spend enough time thinking about it and getting it built out, it’ll bite you in the end — just like these peppers.

Welch: Is it burning? Are you on fire?

Fraley: No, I'm fine.

Lugo: Are you fine?

Fraley: I'm good. My lips are on fire, but I'm good.

Welch: The orange is spicier than the red. I'm going to tell you that right now. Also, it looks like it's growing a pepper inside of the pepper.

Hall: Oh, I love it when that happens. Isn't that cool?

Welch: It’s very cool. It's very spicy, but it's good.

Sophia, you were nodding as you listened along. What are you thinking?

Lugo: I'm definitely nodding, and for context, I think we didn't say it yet in the show, but Andrew was the first head of chemistry at Moderna, so he's had a long history of looking at this. But yeah, I do think that a lot of companies right now are looking at mRNA from the molecular biology perspective, and we have a lot of engineers working on it first. So, bioengineers working on it first —

Fraley: You can't answer your question without eating your pepper.

Lugo: I'm not answering yet. I'm commenting.

Welch: She's commenting on you, and then she's going to answer.

Lugo: Exactly. I think that ends up bleeding into a later misstep — this is not my answer, but this is what I was thinking about: The problem with any of the mRNA, RNA, any of the major modalities within RNA, is the CMC question. And I actually think it turns out that, per platform, you probably have 12 to 15 analytical assays you have to do. Every time you make — you add complexity; it becomes very hard to actually verify the identity, the safety, the true action that your molecule is going to have. And I think when companies start with all bioengineers in the room who are willing to engineer anything, it starts to become a CMC morass. I actually think that pharma has been buying those CMC morasses anyway, like conjugating an antibody to an LNP is going to be very difficult, going to be very hard to get a consistent amount of antibodies per LNP and maintain the same potency and then put them in ultra cold storage and not have them aggregate. All that stuff is going to be very hard. And conjugating an antibody to an oligo is going to be very hard. Sometimes I think if there were more chemists at the beginning of the company, people would be thinking about what it's going to take to actually make something. I think chemists are really good at thinking about end-stage formulation and scale up and what each change to your process is going to do for that.

Hall: The chemical engineers are anyway.

Lugo: Yeah, exactly. So, it's a good point.

Welch: Yeah, absolutely. And I think, too, the complications from a CMC standpoint — we really do have yet to see that. I think as a field, we're still very early. There was this one headline that I come back to from the cell and gene space prior to the mRNA awakening in 2020, and there was this headline of this article that I really loved: It was “The year that the FDA ate our CMC for lunch.” I really do think that we are still on the cusp of learning, and we are going to have some pretty big hurdles, especially as our products keep getting bigger and more complicated and we continue to conjugate things to them. It seems like we're still learning the basics, but at the same time we're making it more advanced as we learn the basics.

Fraley: Well, I think the point, too, is don't take the brakes off getting to better products. So, we spend a lot of time thinking about antibody conjugates. If you think about antibody oligo conjugates: Crummy drugs, right?

Lugo: Sold for 12 billion, but…

Fraley: I mean, GalNAc-siRNAs? A great drug; it’s dosed twice a year in the liver. We need more of those in the world.

Lugo: He is sweating now, by the way.

Hall: Oh good. I'm so glad to hear that.

Fraley: Thank you. Yeah, so I think we also need to keep our foot on the gas around how do we get to better products? Things that are going to be better for CMC are going to have better patient profiles. It's a big challenge. I mean, the Avidity story is fantastic, but at the same token, how do we get off of those antibodies and get onto things which are more facile to play with or to move into people and make and have better properties. We still struggle with mRNA as a linear molecule — how clean can we get it versus a cyclic one. There’s the LNP space that we play in, and now we are starting to conjugate stuff onto LNPs. When you think about all those different modalities and they play well, how do we think about the longer game of getting to compounds we really think are going to be very differential while we still prove out the world?

Welch: Well, Sophia, your time has come. Get your pepper ready.

Lugo: Yeah, we forgot to say the first one to go has to last the longest.

Hall: Oh, I'm so glad I'm last.

Welch: I'm two deep here. It's not the most pleasant sensation, but it's not too bad. I'm going to try for number three.

Lugo: These are spicy.

Welch: Yeah, the orange one is definitely spicier than the red. I'm going to ignore the red for the sake of theatrics.

Fraley: I think habaneros have some of the best chili flavor of any pepper.

Welch: It is nice.

Fraley: There’s a nice fruity citrus flavor to them.

Hall: Sophia seems like she’s hanging in there. You look a little more stymied than I'm used to.

Welch: Am I misremembering: Did you say that the habanero is as high as you go? Is that where you top out?

Lugo: Yeah, that’s about the highest I go comfortably.

Fraley: Comfortably. What's next?

Welch: Yeah, well, we have some surprises coming down the pike.

Alright, Sophia, what's our biggest misstep?

Lugo: I'm watching because I'm going to eat mine at the same pace as Andrew.

So, biggest misstep. So, I’m going off of Andrew talking about how mRNA has become software: I think the biggest headwind we clearly see in our industry right now, at least in the US, is perception based. It's political, and it's crazy because it doesn't have to be that way. The US has invested over time about $31 billion into making an mRNA vaccine work. I think about $30 billion of that was during the pandemic and the returns have been immense — Economic and health returns.

[Andrew starts coughing]

Hall: Oh, he's dying. Please don't die. It would be sad for us…mostly.

Lugo: That would be sad. No, Radar would cease. No more Radar.

So, I think that headwinds are political. We just had a massive success. It didn't have to be this way. But I think that one of the issues has been that there's this motto that Moderna has that mRNA is the “software” of life. And “software,” “programmability,” “control,” “platform” — All these words sound very technological; they sound very innovative. But to some people, I think those terms in the public domain could be construed as genetic manipulation, biohacking; exerting control using a technological substance that people broadly don't understand.

There’s a book written by Alvin Toffler in 1970 called Future Shock. It's about how when people experience innovation very quickly, they enter shock. The pace of change is very fast, and it feels very fast in a tight timeline, which happens over and over — He's writing this in 1970. People can feel anxiety or they can feel disoriented and they can feel like they want to go back to how things were before. COVID was that; mRNA entered the scene when family dynamics were changing, social dynamics were changing, people were being told, especially in individualistic societies, to do things by the government, and then the government purchased en masse this vaccine. Over 90% of Americans received the mRNA-based vaccine purchased by the government. So, I think people were receiving an information overload. Misinformation was actually, I think, the majority of that information. I know very smart people, even people in my MBA class in Stanford, who don't remember the central dogma of biology. So, I think that the public was there at a minimal level of understanding of what mRNA was. And, actually, the point of mRNA is to mimic biology to use the same cellular machinery. And I think that mRNA needs to come up with a better slogan and start using it in force. I think we've just doubled down on this programmability and software concept. We do it at Radar, too. I try to avoid using it in public conversation, but so many companies are coming out saying “programmable biology,” “programmable biology,” “programmable biology.” That's very Silicon Valley friendly, tech friendly, VC friendly. But I don't think people actually like the concept of programming their biology without their consent.

Hall: Yeah, I think that's fair.

Welch: That's an interesting point. I would think it would be the opposite to some extent because we are a very technological society, and we are so used to getting new phones and new computers and thinking about programming new things. I would think it would be the opposite. But I like your point that that is perhaps a step too far when we're thinking about our bodies as something that's technological. Maybe that cheapens our biology in some way.

Lugo: There's an ongoing lawsuit against Bill Gates and others that try to prove that he put nanotechnology or chips inside the vaccines. But yeah, it's not a surprise that the anti-vax movement surged from places like whatever beach RFK Junior works out on in LA and Marin County, NSF, which, actually, very wealthy, very liberal communities that are very, you know, like they eat organic food and they —

Fraley: They eat a lot of kale.

Lugo: They eat a lot of kale!

Fraley: True mRNA scientists don't eat kale.

Welch: There's a T-shirt for that now.

Hall: We're going to have to agree to disagree on this.

Lugo: I do think we need to speak past the misinformation. It's really hard to hit it head on or even try to engage with a lot of those arguments. We need to double down on the idea that the reason that we like mRNA as a therapeutic tool is, in my view, safety. Gene therapy’s slogan was a “One-Time Cure” and “Rewriting the Book of Life.” Our slogan, I think, should be around safety and this idea that we actually are trying to mimic biology; that mRNA is transient and gets degraded very quickly by the same cellular machinery that's degrading other mRNAs; that cells are all densely packed with mRNA; and that mRNA doesn't actually change your genome. So yeah, I think there's a lot to be done around this idea that it's safe and mimicking biology.

Welch: It is our biology. I mean literally, we are mRNA. That's the slogan right there. We are mRNA. Andrew, I think I saw you looking like you wanted to say something. You still have some pepper left.

Lugo: He’s really sweating.

Fraley: I’m not that sweaty.

Oh, and then she puts the whole pepper in her mouth.

Hall: She's such a show-off.

Fraley: I think mRNA suffers from its own success, but I think part of it is it just suffers from the fact that it can move so fast now. You think, like, 20 years ago, 30 years ago, and obviously it still holds true today to some extent, but 30 years ago we were making small molecule drugs. That was our aim in life. If you were a scientist, you went to work for Merck or Pfizer, and you were spending 10, 15 years to move that drug through, and you would spend all this time on synthesis, and they were these small discrete molecules, and people understood that. I think that mRNA technology, CRISPR, all these things can move so fast now. You can find a target for an siRNA and have a lead compound in three months. It's crazy. And so, I think that it can move so fast now that society can’t keep up on education. So, we really struggle not just educating people today around what mRNA is and how it works, but just the education process that you learn in school as a kid and the science curriculum. I think it's very hard for people to keep up and continue to understand that. So, we’re kind of in this Catch 22, not just in our current environment politically, but just educationally where the country's been and how it moves so fast. There's so much RNA biology and technology now that I don't even understand, right, because you just can't keep up as a scientist. So, if you're a student or if you're a person in the population, you just have not been along for the ride.

Welch: Yeah, I was going to say, we can't keep up with education, but we can't keep up as well with the amount of information that does keep coming out. Not just in our own field, but the misinformation that can come out. It's released on any platform anywhere.

Hall: Well, most people are getting their news off of TikTok nowadays, so there's a large amount of misinformation that we have to battle, and it's horrifying.

Welch: That was a huge thing at the AMM meeting in September. We were talking about how we should no longer be targeting the New York Times, not the Washington Post. We need to be on TikTok. We need to stop speaking to an echo chamber and actually go to where people are getting their information.

Lugo: Since you said it, a plug for AMM — the Alliance for mRNA medicine.

Welch: Fighting the good fight for us.

Lugo: So, if you're listening and you're an mRNA company that's not involved in the Alliance for mRNA Medicine, check it out. I think they're trying to organize efforts — like what do we do? How do we educate policymakers?

I have met a policymaker who said, “I believe my doctor when they say the mRNA vaccine is okay, but then I get constituents coming with binders of facts about how vaccines are bad for you, and I'm not a doctor. What do I say?”

Fraley: That's a very good point. I think we as a society have forgotten what it was like when measles and polio were around, because when we figured out we could use cowpox for smallpox, our lives changed. Society changed and we realized we could solve and remove all these bad diseases in the world, and they've been gone for so long that people forget, right? People never had to experience them.

Lugo: Even the Spanish flu; my great grandma had Spanish flu as a baby and lost her hearing. We forget those things. Also, if you've seen the show, the Pitt — something I really liked about the show is it just reminded us how bad it actually was during COVID, pre-vaccine.

If you talk to doctors, things were bad. So bad.

Welch: But you didn't always see it. A huge majority of the population might not have necessarily been involved in or seen that. It hasn't impacted them personally. And that's another piece of this that we're missing. We haven't necessarily always seen the effects. If the vaccine's working, you might get sick, but it's not potentially going to be as bad as it might've been.

Fraley: I think this is also another thing that we struggle with in the United States at least: We take a vaccine to protect ourselves. We don't think about vaccines as protecting society, to protect people who can't get them. It’s just like insurance; we get insurance because it protects everybody, not just yourself. So, I think that we as a society have never reached that perspective. So, when you layer that on and then you layer mRNA on top of it, which is a totally new modality that moves super-fast, I think people think: Well, I don't need that; it's super high risk because it’s so new.

Welch: And during a time when everything was an upheaval, right? So, you added a new technology on top of a therapeutic class that's already had its fair share of censure throughout the centuries.

Fraley: Back to the question about what's the biggest misstep: mRNA at some level was its success, but it was also its own downfall.

Welch: It's a double-edged sword.

Fraley: If COVID hadn't happened, Moderna would be down at $10 a share right now, and we would still be just moving mRNA forward like a logical drug discovery paradigm for cancer or for rare disease and have a completely different flavor in society today.

Welch: Absolutely. Michelle, you are much too calm. You are not overly spiced right now. We're going to need to fix this. So, you're going to have to get your pepper ready, because we need to get you into this equation.

Hall: Alright, so as I am wont to do, I would like to introduce my pepper.

Welch: Please introduce your pepper. Did you give it a name?

Hall: No, but we can crowdsource it. So, greetings from the great state of New Mexico, which has dubbed itself the chili pepper capital of the world —

Welch: What a perfect place to film —

Lugo: Let me just say now even the chilies in India are from Mexico, essentially.

Hall: I know. I know. I'm here. So, I'm repeating what I was told. So, this is from the cute little hippie dippy market here in the city. They definitely sell a lot of kale, as well, in case you were curious. Here goes. And I'm weak, so I'm going to do this.

Welch: Do it. Make sure you get some seeds there, sister. You have to do it. Be brave.

Hall: Oh God. I'm dying already.

Lugo: And you have to eat faster because we've been sitting here for a long time.

Welch: I'm on my third one.

Lugo: I’m good by now. Andrew has finally stopped profusely sweating.

Welch: He has. He's not coughing, either.

Hall: There's a little baby pepper in there, too. It's really cute.

Welch: There is. I see it. It's just like mine. Alright, so our biggest misstep?\

Hall: I mean, there's so many missteps to be completely honest with you. So, maybe building on what y'all were saying, I think we've made a couple of mistakes — and I'm super guilty of this: When people came to me during the pandemic and said, “Well, what would you say to people who say that the mRNA vaccine is unsafe and it integrates in your DNA?” I'm not known for my patience, and so I kind of blew them off. And that was a mistake. I think we, myself especially, did not do a good job interacting and interfacing with non-experts in a way where we talked through their concerns. And I think something I really spent a lot of time thinking about is how much nuance people are prepared to understand. So, take for example, my father: Very smart dude, but not a scientist. And when he asks me, Michelle, is it possible it's integrating in your DNA? I'm like, okay. Of course it's possible. I think it's 0.000000001% chance, but of course it's possible. That's a level of nuance I think he can probably understand. And I think probably when we were talking to people who were not mRNA scientists or scientists, I think we were probably like, “Pffft, ridiculous. Of course it's not possible.” And, of course, they reasonably felt blown off. I think we probably didn't do ourselves a favor in the way we engaged. At least I did not.

But other than that, I almost think a misstep we made is reflected in this conversation. We are talking about mRNA and vaccines as if they are interchangeable. mRNA is an approach to vaccines, and vaccines are one application of mRNA. When Moderna was in its infancy, and, Andrew, keep me honest on this, we were not focused on mRNA vaccines. Sure, we were interested in personalized cancer vaccines — now renamed neoantigen therapies. But, really, we were talking about them for rare diseases, for enzyme and protein replacement. And I think now we've sort of gotten in this double bind where we're equating mRNA with vaccines, and I think that's really screwed all of us, because if you think about it, there's so much mRNA can do. We've seen this with Baby KJ.

And so maybe a huge misstep is we got down in the gutter, and we were like, “mRNA of vaccines are amazing” as opposed to just ignoring the trolls — I'm not saying this is the right answer; I’m putting it out there for discussion— ignoring them and being like, well, I guess you're entitled to your opinion; the data disagrees; and then focusing on the things where we knew mRNA would have transformative potential and wouldn't be bogged down by a bunch of politics. I wonder if that's something in hindsight we would've done differently.

Welch: Interesting. Do you guys any knee jerk reactions?

Fraley: Yeah, I agree. There's this notion of splitting vaccines and mRNA because, I mean, you think about the applications for mRNA — it's a vehicle for delivering and making proteins. We forget that, or I think society doesn't necessarily understand that.

Lugo: I've had a few educated people telling me that “I know the vaccine turned my blood; I saw it changing colors as I got the vaccine.” And one on a visit to DC one other mRNA developer commented that they're now dosing in a cancer trial, and they asked the patient if he had been vaccinated, and he said, “No, I'd never get that. I'd never get one of these novel mRNA medicines that kill people.” And they were like, “Sir, do you realize that this is an mRNA treatment? He's like, “Oh, it's okay. It is not a vaccine.”

Hall: See, I think that's a mistake we've made. I think it's as a field where we were so focused on platform — “It's an amazing thing. It's a platform, it can do anything!” And then we were all like, “Oh, just kidding. Platform is dead. Product, product, product.” And I think that is also a mistake that we made, and I don't know how to fix it, if I'm being honest. But I think this jerking around of focus is only going to be to the detriment of the field's advancement writ large.

Welch: Yeah. It's really hard to visualize what platform even means. We can't even do it in this industry, and we're the ones who are working on platforms. We have so many differing definitions.

I do want to jump to a cool down question because we do focus a lot on what isn't working. What are some of the bigger challenges? — Yes, Michelle, get your milk ready, though you actually handled that very admirably. I'm really impressed.

Hall: Thank you. Thank you. I'm working up my tolerance.

Welch: You're doing great. So, we tend to focus on what isn't working right or what we've done wrong, which was the point of this question. But I'm curious to get your sense of what has worked. I mean, besides the promise of more treatments for patients and greater access, some of the benefits of mRNA technology, what is something you think we should be celebrating a little bit more loudly in the mRNA and RNA industry?

So maybe we'll start with you, Andrew. Again, we're going to put you in the hot seat, but you get milk this time, so you get to cool down a little bit.

Fraley: I'm good; I can take the heat — unlike some people in New Mexico.

Hall: Oh, he's so tough. Look, I'm weak. We've established that.

Fraley: I think at some level we've matured the field in the sense that we can use RNA for all these different things now. We understand how to push and pull it around a little bit. There's the one aspect which is therapeutics and where we are today around all that and all those conversations we just had. But I think there's this other point that, if we want to pat ourselves on the back: We have a technology now that is utilized in all these labs all over the world to do all this cool science around everything from being able to use CRISPR to validate new targets for other therapeutics or to understand basic biology and do basic molecular biology that we didn't have 10 years ago. So, on the one hand, the modality, if you will, has matured enough that it's now routine in normal R&D for us to answer problems with. So that's one thing. That then flows into new ideas and ways we can put it to use for new applications that we're just now starting to do. So, as much as we bemoan what's going on publicly in the world of mRNA and vaccines, mRNA scientifically is fantastic. It's wonderful. We're making real strides in biology.

Lugo: To piggyback off what Andrew and Michelle said: Even as VCs have said, “No more platforms, we’re not going to fund these platforms,” I think that, actually, pharma has been betting on RNA platforms this past year. So, July 2024 till last month, there were 76 deals done in the RNA space; $51 billion in deal value, $830 million average deal value. For RNA. Shout out to Piper Sandler who put together a wonderful 200-page holiday read on RNA. I mean we've talked about some of these: Avidity — $12 billion. It was reported they'd only received one term sheet. The CMC is not solved, and yet it sold for $12 billion. To me, that's a platform sale because the product is not ready. Capstan was the same. For Capstan and Orbital — was a product ready? Is it the end state we want it to look like in patients? Is it specific enough? I don't know about that. We don't know. But AbbVie and BMS were willing to make very expensive bets on acquiring a platform. We have Sarepta making a big bet in Arrowhead Pharmaceuticals in the siRNA space. We have so many large deals to point to. siRNA may be more on the mature side, but all the other deals are not mature.

I think what we're seeing is that pharma has to spend dollars this year, next year. The shopping spree is going to continue. It's clear that there are executive level priorities in the RNA space. I actually think it's great; one of the hard things about building a platform is that every component needs to be optimized, and it's really hard to reinvent the wheel; to start again working on the LNP side when another player is working on it. I actually think pharma is a great place to house these RNA platforms and bring together best-in-class ways of manipulating RNAs. So, making them express more, controlling them, getting them to the right tissues. All these questions; pharma is a great place to house all these platforms. They're clearly willing to spend a lot of dollars to do it, and I think that that's great for the space. So, when these companies get acquired, you have talent that comes off of these companies that are like, “You know what? This was the next problem I need to solve. Maybe I'll form a company or a lab around this.”

You know, my co-founder was in a lab that was next door to Moderna and that probably mattered. Why would they be thinking about control in this microRNA lab? Why would they be thinking about control; they had to be next to someone who would even think about that. These are the kinds of communities that then emerge of people breaking off, solving the next challenge. What's the next challenge we need to solve? Things are not great right now for science in the US, but there is a lot of capital still flowing into our sector; talent that knows what the problems are, and is putting initiatives around that, and investors who've tasted the sweet, sweet nectar of the returns of an RNA platform, and hopefully will come back for more

Welch: Sweet, sweet nectar.

Incredible. I love that answer. That is a great answer. And that is one of the things that has been on my radar for the year as well — No pun intended on Radar here. We've got Radar Therapeutics. That’s been on my radar, just given the fact that we had such great deals and big pharma buy-in, which is what we hope to see. And so, I think this past year has been really promising in that regard.

Michelle?

Hall: I am such a huge fan of personalized medicines. I am so darn excited that I don't need one at this juncture of my life —

Welch: Amen.

Speaker 4 (41:39):

I’m just really taken by the number of usually high-net worth individuals, the ones that have the capital that they can outlay who have reached out to me personally on LinkedIn and said, I have this genetic disease. Could you help me coordinate making an mRNA-LNP to do a DNA edit and permanently impact my life? And while I don't want that to be restricted to high net-worth individuals only, I'm just really excited that the customers, the patients, are starting to do outreach and see the potential for this and ask for it. I love the idea that we can have a future where this is the type of therapy we can provide to Baby KJ’s and beyond, and I think that's really, really incredible.

When I first joined Moderna, I remember thinking, “Wait a minute, let me get this straight. So, you're going to encode the gene you want and then deliver it to the patient. That sounds like science fiction — and where do we do this? And I unfortunately had an aunt that passed away of cancer, and I was really keen to see if I could get her into Moderna's cancer vaccine trials. So, I'm just really darn excited that we've opened the lid into what is possible; seeing how quickly we can create these therapies, not only for broad indications like the COVID vaccine for example, but for really, really individualized purposes. And I'm really excited about how we can potentially get those costs down such that this isn't a thing that you have to have some philanthropic donor behind in order to pursue, not just for individualized medicines, but also for vaccines in low and middle income countries. If you think about where these diseases are most likely to originate, treating them at the source as they emerge I think would just be really, really incredible. So maybe the thing that I think we should celebrate more is how much we've learned and how many opportunities it's opening, and I think how much of an exponential growth in opportunity we can see.

Welch: The breadth of the opportunity, I think is what you're hitting on here. There is just a huge breadth, from the personalized to the large scale.

Well, I hate to end the conversation here, but I want to be cognizant of your time. You guys have companies to run, companies to learn about. So, I am going to say: You all have done admirably. We conquered the habanero. What's coming next is going to be somewhat scarier, so, hopefully I see you all back. Andrew, you are welcome to join us again if you're brave enough.

Hall: Negative. Nope —

Welch: Michelle's like, “No; he came on, he espoused his hatred of kale and now we can't have him back.”

Hall: Can we do a kale eating challenge next time? That would be so great.

Welch: I mean, we could do that. We could chop onions and see who cries first. There are a lot of alternatives.

Hall: I'm going to lose that one too.

Lugo: There’s also the inevitable humiliation of having it in your teeth.

Welch: I will say this — the burn, Andrew, I think you were right: The lips were on fire this time around, for whatever reason. My lips are still on fire. That's where I'm feeling the heat.

Fraley: Just don't touch your eyes for the next 24 hours.

Hall: This is why you use a fork, you noobs.

Welch: Oh, that's why you're doing it. Oh, I didn't even put that together. Oh wow. Okay. Alright, so you got genius points.

Fraley: Michelle lost, Michelle loses. That's her takeaway from this experience; she loses.

Welch: Because she was smart and used a fork?

Lugo: Yeah, it was a very nice message about personalized vaccines at the end. But she lost.

Hall: Whatever. See you losers on the flip side.

Welch: Well, thank you all for watching this installment of Advancing RNA’s Hot Takes, the show where the peppers are hot, but the takes are hotter. So, we'll see you next time. Take it easy. Bye.