Founder Stories: Noubar Afeyan, Flagship Pioneering

Welcome to Director's Dialogue, a series of virtual conversations with visionary leaders of science, education, and the biotech industry. I'm Ruth Lehmann, and I'm going to be your host today. Our goal in these dialogues is to offer an inside perspective on the new opportunities and emerging challenges and trends in biomedical science and technology. We'll ask our guests to share their most meaningful experiences and observations, to tell us what excites and concerns them most about the present and future in biosciences, and to tell us about innovations that could dramatically affect the future of human health. In a moment, I will be introducing today's guests, and we'll have what I think will be a compelling conversation. But I'd like you to be able to participate as well. And so at the end of the conversation, we'll reserve about 10 minutes to respond to questions that you submit. So during our conversation, please use the question and answer box at the bottom of the screen. And I should also note that this talk will be recorded and distributed later. Tonight, we continue the series by speaking with one of global biotech industry's most effective inventor, entrepreneur, and corporate leader, Noubar Afeyan. Noubar is the founder and CEO of the life sciences platform company Flexure Pioneering, which has developed more than 100 scientific ventures over the last 20 years, most of them here in Cambridge. The economic and clinical impact of those companies is remarkable. Together, they have generated more than $30 billion in value and developed scores of new drugs, including one particular noteworthy vaccine platform, Moderna's messenger RNA platform, pioneered and nurtured within Flagship as LS-18, its 18th company, before spinning out and eventually going public. This platform has provided an incredibly important weapon in the fight against COVID-19 and may herald a new class of medicines. Nubar was born in Beirut to Armenian parents, did his undergraduate work at McGill University in Montreal, and in 1987 completed his PhD in biochemical engineering at MIT. Since then, he has been responsible for more than 100 patents and has co-founded and helped build many companies. Some of them we can actually see from the roof of the Whitehead, including Indigo, KSQ, Omega, and Cirrus. During tonight's discussion, we'll touch on some of his key experiences and hear his perspectives of the— on the challenges facing science, biotechnology, research and development, and if time permits, the world in general. Noubar, welcome to our dialogue. Much of today's conversation will be future-focused, but I must begin with two questions about the past 15 months. What have been your key experiences as chairman of Moderna Therapeutics as it raced to create, produce, and distribute one of the first vaccines for COVID-19?

Well, thank you for having me on, and it's a great, great occasion to be back with colleagues at the Whitehead. I've had the great pleasure of working with many, many of the faculty and staff there for 3 decades now, and it's a great pleasure to be here. Well, the last 15 months have been quite memorable for all of us in different ways. In my case tonight, I'll tell you a little bit about what it's been like as a founder and chairman of Moderna. For me, the story began back on January 21st, 2020, where I was sitting literally a few blocks from where you are, where the institute is, at Pammy's in Central Square celebrating my daughter's birthday when I got a text followed by a call from Europe where the CEO of Moderna, Stéphane Bancel, was actually in the middle of the night up at Davos having just had a set of meetings with the folks at CEPI and several of the other vaccine-focused organizations who had begun to realize that what was thought to be some kind of a pneumonia/potentially a coronavirus-related disease was quickly showing signs of a potential epidemic eventually pandemic. And, and Stefan called basically to say, you know, people are asking us to kind of jump into this and use mRNA, but it's going to be partly a distraction, partly an untested territory. And he was leaning into for us to do this. And the question was, can we do this as a public company and what are the consequences? We quickly concluded that while it wasn't clear it was a big issue in the US back then, that our platform was ideally suited for this type of a challenge and that we couldn't not do it, both for global health considerations, but also as pioneers in the space to really see whether the platform could respond in a very short timeframe and offer a possible solution. And in fact, that's when we started very quickly to advance our program. We were fortunate to have a relationship with the NIH, with Tony Fauci's group at NIAID, and in particular have been working on the development of a very related vaccine of another coronavirus class. And from that moment to delivering the first dose into human by March 16th of that year to getting phase 1 results in May of that year and then Phase 3 results ultimately on November 30th is a blur, I'll say. And but what ensued in the meantime was this incredibly heroic activity by a company of probably 800, 900 people when we started, already with more than a dozen programs in clinical development independent of this vaccine. So that was on top of And how to operate in the middle of a pandemic with all the restrictions to lab work and still be able to do this really is a great tribute. And much has been said about this and more will be, but the team, the leadership just did an amazing job. Now, as from a chairman standpoint, I'll tell you a couple of other interesting noteworthy things. When we started, there was no government contract to fund the kind of work we plan to do. So we have to literally go to our investors and explain to them that as a company which have never had product revenues or an approved drug or a vaccine, we wanted to raise half a billion dollars initially and eventually another billion dollars to fund this work. Eventually the government's program came in in a big way and supported our work as well. The OWS entity was created. One of our board members, Master Slowy, who's probably the foremost expert in the world, left our board, joined the W.S., and started developing multiple vaccines for the country to benefit from, as we've seen these days. So many, many points along the way, scaling up something that had only ever been produced at the level of grams to tens of grams suddenly needed to be produced at the level of kilograms and beyond. We had only ever tested our mRNA across all our programs in probably less than 2,000 people. Suddenly we tested it on 30,000, and now it's been on more than 50 million people, perhaps closer to 60 million now. All of those things to scale up the production, the FDA regulatory process, quite unprecedented for a vaccine to receive emergency use authorization, the shipments all of a sudden of the scarcest resource on the planet, and making sure that we can robustly get this, all the collaboration with the military through OWS. It just has been a remarkable journey. And say that the one takeaway is most of my life I've dealt with startups, and inevitably in every startup you learn Murphy's Law is alive and well. That is anything that can go wrong will go wrong. And once in a while Murphy gives way. And I would say, I am very, very thankful that Murphy perhaps has also been in quarantine up until now, knock on wood, in that many, many, many, many things that could have gone wrong so far have not, they could still go wrong. But I think the brilliance, the hard work, and the absence of Murphy have contributed to where we are today.

Yeah, yeah, yeah. We all benefit from Murphy not going wrong. Yeah. So let's go even further back. So can you tell us sort of what were your goals in founding Flagship 21 years ago? So clearly you are not risk-averse.

Well, you know, back 21 years ago, if you remember, it was kind of in the, era of both the internet and the Human Genome Project. We forget that there was this coincidence of a couple of shocks for society in that our connectivity was about to reach an unparalleled level and our understanding of the nature of human cells and just biology in general would undergo a major leap. Comparable to the initial understanding of the structure of DNA. And much of that work started at the Whitehead Institute, I might add, as you and your colleagues know all too well. And so, you know, back 21 years ago, the idea that got me and a few of us hooked was the notion that we would no longer think about biology and innovation as this kind of artisinal, almost amateur kind of activity, but rather in terms of commercialization, but rather could we think about the very process of making big innovations, breakthrough innovations, and the process of converting them into companies, entities that would seriously take those forward into products and medicines that impact society, that these could be somehow institutional activities as opposed to individual activities. And having spent the prior 12 years being involved in a number of startups already in the old-fashioned way, I was very intrigued by the challenge that has been occupying us for the last 20 years of trying to find a way to make the activity of innovation and startups less improvisational, less speculative, less probabilistic, and the opposite of those words. And 20 years later, we think we've got at least a good start on how one could do that. And the reason it's important to do that, in my opinion, is that the understandings in science and the development of complementary technologies is such that we can do so much more provided we do it in a more predictable way. And that's what we think is possible today. And Moderna is a great example of the outcome of that belief. If we thought that we needed to kind of wait for science and discovery to be just ready for these things, we would probably be waiting until now. We needed to jump in and really start doing the innovation work even while we have a lot more to learn.

So what's the secret sauce to make innovation predictable? It seems almost contradictory.

Oh, it is contradictory. But I would say that there's a few things that I'll ask the audience to think about. I know that they are not— they are counterintuitive. And ultimately, we may be wrong. But we've been doing this for a long time. And across almost 100 companies now, we've learned a few things. One of them is that ironically, particularly those of us in the life sciences, we tend to forget that perhaps some of the most impressive complex machines that exist on the planet have not been made by humans. They've actually evolved. And yet we think that the human activity is going to do somehow more marvelous things than already exist within us and all around us. And yet the process that nature uses for the very act of innovation is not setting goals, following schedules, under-promising, over-delivering, and all the things we've learned how to do in a kind of an organized innovation setting, but which I think doesn't actually necessarily produce the kind of marvel and the kind of leaps that you see in nature. And instead in nature, and I don't have to tell you, but just to remind folks, a simple process of variation, selection, and iteration yields emergent superiority. In other words, the process of emergence, you can't a priori detect what will be the winner, but you can certainly create the conditions for this process to lead to emergent advances and over time, what seems like a remarkable breakthrough. I happen to think having been doing this for now 33 years, that most breakthrough innovation, if not all, is just that process. Simply that usually what happens is that when ultimately there's a gain of function, ultimately there's some punctuated form of evolution, the people who are there describe it as some other act, some kind of, superhuman act, but I actually think it's a continuum. And the reason that's important to us is that we set out our process to allow this to happen. In other words, we didn't think, for example, that we will find fully baked breakthroughs by looking for them, that we would have to let them emerge. And that the parents of really good innovations are pretty ugly ancestors. In other words, you shouldn't be looking for the best idea to give rise to the most impactful innovation. So these are things that if you relax some of the constraints in the way we've been taught to think that great begets greater, begets even greater, but rather sometimes these things come from quite unexpected places. These are things that we have implemented in the way we've created a scientific environment. Our team today of nearly 70 scientists 75 PhDs, MDs, engineers who work on this way of doing innovation, emergent innovation, you know, we have to iterate and learn how to do it. So one of the things we've learned is that. And the second thing is to think about how far away you want to make an innovation from what is the present dogma, the present belief. And I would argue that, you know, in the way a lot of science is done, and of course Whitehead, is a good example of trying to overcome that limitation, is very much driven by whatever ideas can get funded. And the ideas that get funded are typically the most reasonable ideas. And so if you have the most reasonable ideas be the only ones that get funded, then they cannot give unreasonable ideas that could have given rise to these, won't ever get funded. And one has to think about, Can you allow for the process to accept the fact that sometimes you have to leap forward and then come back and connect things to the current reality? These are all things that I'm saying this as though kind of these are ideologies. These are things that are implemented in the way we've set up our culture, we reward our teams. And the result of that are the companies that you see all over Cambridge. There's some 41 of them that exist and operate now, all of them basically came about through this type of thinking future backwards and thinking emergent advantage versus predefined advantage.

I love the idea of hybrid vigor in terms of research innovation. So looking forward, Flagship is increasingly focusing on the challenge of health security. And that term, you know, means different things to different people, and it's a term that you have been using. And can you explain what you mean by that and how Flagship is actually pursuing this idea of health security?

Sure. So let me just— so this is a direction that we've started going down for the last 3 years or so. So this preceded the pandemic, and the pandemic has only made us more convinced, and we hope society more open to the need for this. And let me explain what we mean by health security. First of all, health security is sometimes meant as securing our healthcare. So we want access to vaccines, access to healthcare. And if that's threatened somehow, that's how people think about health security. I think of it a little bit differently. And let me kind of lay out the thesis at least. I would observe that what we mean by healthcare today with all of its impact, but all of its limitations well known to us, whether that's the dramatic and rising costs, the relatively ineffective solutions in many, many disease areas that we can't yet deal with, and also kind of the general kind of malaise about who's gonna pay for it. Is it society, the government, private? All of these things we think are describing healthcare. But I would argue just for you to create an alternate reality that all of what we're getting today is a form of sick care. And the reason that's a more apt description is that you generally have to get sick to get any of it. And so you don't actually generally exist in the healthcare system. And I can for a minute exclude vaccines and I'll come back to it. But generally, your entree, you deserve to get it once you are diagnosed. And the whole point of diagnosing is to enter that system. Now, you might say, well, what's the big deal? Well, I would, I would suggest that the more we learn about the science of underneath the pathologies that afflict us and ways in which we could perturb it, we clearly realize that disease doesn't— it doesn't have this instant onset. And of course in medicine there's this idea of early stage disease. But I would ask the audience to think about, okay, so what comes before early stage disease? The answer is not a genetic predisposition. We don't go from when we're born to early stage disease either. There are many stages before that. So park that thought and now let's look at how we think about our physical security, our physical well-being. Well, we expect our government to, on the one hand, have all sorts of countermeasures to surveillance. They invade our privacy, but we expect them to protect us from all manners of threat locally, globally, you name it. And the way they do that is a whole lot of things upstream of wars. And then when it comes to wars, trying to get the best weapons and the best fighters to be able to wage a war. Now contrast that to our health security, securing our health. We have a lot of money spent on the final weapons and treatments and detection of, but upstream relatively little. We looked 3 years ago at the numbers and at least back then in the UK where they keep close numbers, the published numbers were that some 2.5% of all healthcare expenditure goes upstream of disease? 2.5%. That means 97.5% is going to disease and after. Now what if that number was 10%? Just 10%. Well, of course that would be a fairly large opportunity. So by saying health security, what we have in mind is what if the brightest graduates from Whitehead and the faculty started saying, you know what? It's too late by the time we get to disease. We need to understand the molecular basis of what comes before disease. Sometimes people call this pre-disease. We need to develop not treatments, but interventions, not diagnostics, but detection. And we need to find ways to defer, delay, deter, derail all sorts of things upstream of entering the cell. Sick care system in which I would suspect that if we did all these things well, we could afford to spend a lot of money on those very expensive weapons, but use them more sparingly. Now, this sounds like an ideal and I'm sure you'll say, well, there's lots of books that have been written and the CDC is not just CDC, it's CDC, Centers for Disease Control and Prevention. But really how much of that do we do? And the answer is you ask any entrepreneur like me or an innovator and they'll tell you there's no money in that. Just none. There's no reward. There's no— the society does not treat that as a serious activity. The regulator doesn't allow you to develop generally upstream solutions, and there's no reimbursement. So I would say, what if we changed all that? If anything, as a tribute to what happened to us in the pandemic, where clearly we were caught unprepared and had to deal with the actual disease by the time it hit us. And so this is not just about vaccines. This is about a whole rethinking of how you apply science technology and how you reward innovation in order to be able to treat the continuum that leads to disease in ways that will actually take the burden of disease down. That's the goal, and we're well on our way with multiple projects and lots of collaborators to start seeing if we can do this seriously.

Yeah, I guess, you know, the role of basic science is often seen as being interested in the underlying mechanisms, right? So I feel like I study mutants to actually understand what's the wild type, and that seems like what you're talking about. Last month in our first Director's Dialogue, we spoke with Susan Hockfield, and she was talking about the age of convergence, where biology and the physical science really come together to create novel solutions. And so what do you think is that convergence playing? What role does that play in the biomedical discoveries and development now going forward? So how could you see also having other disciplines really entering the field of biomedical research?

Well, Ruth, if you'll permit me, because you said in the beginning a little bit about basic science, let me just address that a bit because I've long wondered since my graduate school days at MIT about the seeming tension between the two and when I ultimately became kind of more on the industrial side, an entrepreneur and innovator, I always wondered why it's framed that way. I would say as a beneficiary of basic science that basic science is enabling science. Enables innovation. Without that, you don't have any innovation. And so by casting it as basic, sometimes I feel like people mean to imply some purity and also a goallessness to the activity. It's almost like fiercely protected as if it has a goal, somehow it loses its meaning. But I would just remind everybody who does basic research and basic science, that there is a goal. It is to enable people that come after them to have societal impact. And if you just frame it that way, then it is extremely useful, without which we can't do anything. So I just, I always find that basic science, I argue, is enabling science, and enabling science is a prerequisite, both in terms of the people and the expertise and the knowledge that comes from it. So that would be my two cents comment on this. I don't view it as a choice. I view it as a real continuum as well. As it relates to Susan's comments about convergence, she has been for many years, and I completely agree with the view, talking about the power of convergence in advancing, propelling, accelerating the advancement of life science, biomedical science. She's used it both in terms of convergence between the physical and life sciences, but also what you see technology bringing in, in allowing us to do things. I'd say among the most recent examples of this would have to be artificial intelligence and what it can do for life sciences. So these points of convergence, in my view, are absolutely think about crossover versus mutations, absolutely a part of how ideas are going to evolve and new capabilities are going to be enabled that we could not within any given kind of space potentially find solutions. And we'd have to look at the interfaces. So indeed, one of the things that I've always admired and loved about MIT is the fearlessness of the collaboration between disciplines. Look, I'll propose to you in a center of global expertise in everything that among the best ideas come from people who actually are experts in one area but dare to think about another area with a collaborator. And it's that magic in between the two or three or four. That I think creates what we think is astonishing novelty. But actually it's simply that people dare to ask questions that if they were just inside their field, they would have likely talked themselves out of. And if they didn't, then the grant reviewers would have talked themselves out of because it was viewed to be not realistic, not reasonable, not proximal. And so yes to convergence and yes to educating bilingual, trilingual graduates and postdocs who have a degree of humility about the areas they're not experienced in, but still go into and realize that they could learn and they could actually perhaps do some innovation.

Do you think there are enough opportunities to create that juxtaposition, or could we actually do better in doing that to kind of, um, accelerate the next generation of innovators?

Look, I think it comes from, first of all, your position and the position of leaders in academia to, in a way, expose this topic. I always have to be a little bit careful in what I'm saying, but let me say it in a slightly less careful way. I believe much of innovation happens outside people's own areas of expertise. And so how do you get people who are rewarded and advanced and given a kind of recognition within their area to feel comfortable going out of their area and seeing just how creative they can be? I think it's cultural. I think it's about celebrating those things, which by bringing it up today, you're doing a bit, and I know Susan does a lot of. And then actually encouraging, whenever I talk to students and I have been at the Sloan School for 16 years teaching innovation entrepreneurship courses in the last few years at Harvard Business School. And whenever I meet students who wanna get into science-based commercialization, I tell them either go to the extreme frontier of what you're doing or go to adjacencies to what you know. And get out of your comfort zone. In fact, this is a big part of what I think prevents innovation is actually being in your comfort zone. Because if you can't, if you're not willing to look embarrassed with your ideas, you will not espouse ideas that later might become breakthroughs. I am a firm believer that the more people make peace with the fact that it's okay to start out saying things that are not necessarily knowably correct, but then to iterate, iterate, iterate, and find a way to make them, if they are in fact come about as being correct, then that's a very different culture and mindset. So yes, I think more opportunities, more recognition, and sending out a new generation of students who just aren't about narrow expertise.

Yeah, talking about out of comfort zone, we both share the experience of having to come out of comfort zone when we— because we were born and raised outside of the U.S. and then found ourselves here, and so how would you characterize the importance of immigrants in the U.S. for the scientific enterprise and What do you think, you know, foreign talent could play in American science coming forward? So how can we encourage that despite some of the backlash?

Well, yeah, we can— this— the discussion today is a little bit more kind of less, perhaps, charged than it would have been a few months ago. But it could also revert because a lot of the policies I don't think were, you know, you need not only one person to espouse a policy, you need a receptive community to actually make it policy. And so I am quite concerned about the degree to which this thought that somehow immigrants are a net negative for the country, take jobs away, etc., etc., was pervasively accepted and espoused. And I'm not saying that because I'm an immigrant myself, but I can bear witness to what that's all about. Look, I think, first of all, I remember fondly, very, very fondly coming to Boston in 1983, having first immigrated to Canada and then coming here to do my PhD, walking along the Infinite Corridor, which in the fall of 1983, my first semester, I remember had in one of the vitrines, the kind of the glass showcase, whatever, post where people put up posters, had this big poster of a Native Indian chief. And it had a finger pointed out saying, who are you calling foreigner, pilgrim? And I went by that every day looking at it thinking, that's right. Who are you calling foreigner? Because this is a country of foreigners. That's in fact the essence of the country. It's a melting pot. And that melting pot notion has become an interesting exclusive act because everybody who's melted now wants to exclude what is yet to be melted into it in order to excel and improve. So I, look, I think I'm not the first or the last person to make this case, but I think immigrants, first of all themselves, are an important part of how this country regenerates. And, but secondly, I would also just offer for the audience to think about for a minute just how much innovation actually resembles immigration. Just think for a minute that true innovation, leaving your comfort zone and doing something completely new, is literally just an act of intellectual immigration, right? So what happens if you're an immigrant? You go to a new place because you think it's better there, or you get chased out of the space you came from. By the way, that happens in innovation. And you initially make a fool of yourself because the locals don't quite understand why you're saying what you're saying. You have to adapt, you have to get your ideas to be somewhat, you know, kind of acceptable and conformist even though you actually want to change things. And eventually, you kind of start creating a new reality. And it could be a new product, it could be a new platform, or it could be a person who's now kind of adding to the place where they're living. I really do think that the reason a lot of immigrants get drawn to this, but also a lot of— this is not about where you're born, this is about a mindset. It's having an immigrant mindset of figuring out that nobody owes you anything. Your expertise does not entitle you to some special treatment. Those concepts, in my view, have very interesting parallels. And especially policymakers should think long and hard about what it means to cut out immigration as it relates to what drives innovation both physically and intellectually.

Yeah. Yeah. No, I think this is the biggest weapon the US has is its immigrants and the possibilities. So we touched politics a little bit. So we have now our colleague Eric Lander serving as the science advisor to President Biden. And I was wondering what you think he should be discussing with the president and what kind of policy recommendations you would be giving. So you already kind of alluded to it a little bit with actually caring for health rather than sickness. But I would be very curious.

Well, you know, look, there's a lot of things there. And I've had the great pleasure of knowing Eric and considering him a colleague in a different sense of the word than a pure academic colleague for 2, 2 and a half decades back in the human genome sequencing days. We worked on a number of things. And so, well, first of all, I couldn't be happier that somebody like him is near a position of having really transformative effect on the standing of science and technology and its impact on society. We continue to think that these big challenges we face, whether it's poverty or climate change or food shortages or any number of things, let alone health, are going to be impacted by human ingenuity. And then we do everything we can to prevent or discourage that human ingenuity in the way we fund it, in the consistency, in its relative standing in society, on and on and on. So I think we're increasingly a field of almost miracle workers, which we cannot be. I'd rather it be a reliable part of our arsenal of really bringing about societal impact. So I think first of all Eric can, can bring that to life through examples, through his own work. Certainly President Biden is no stranger to that because he spent the last few years out of office actually focusing on transforming many aspects of cancer research and funding, etc. Himself very touched by this. So I really think that this is the time to leap. And I believe we need to think like the Hamilton line, kind of we need to leap more, increment less. And the system is designed to support some version of egalitarian accessible incrementalism. And yeah, I think that's fine, but we need to be able to figure out the areas where leaps are needed And we need to figure out how to support those, support the people who make the leaps. Those people will generally not be reasonable seeming people, and we need to find a way to provide them the funding, the support, and the encouraging environment to make giant leaps. That's what we need as a society. And yes, we need all sorts of work thereafter to actually then make it useful. And almost I view this as colonizable. So you, you can do pioneering work and then you can colonize the space. You need all of that. But I think that with Eric and you said kind of like what, what one thing they should do, you know, a lot of this moonshot kind of talk is out there, but I just think we need to embrace the fact that we can do things from the present forward. We can also do things from the future backward and we need to deploy significant resources to both of those. That's of course health security, the role of vaccines. Look, one of the things we all learned in the last 15 months is that something that experts and everybody considered impossible in a very serious way, hundreds of hours of television broadcasts espoused to the absolute recklessness of aspiring to having any kind of vaccine developed in a timeframe of less than a year. It's not the people who tried to do it, whether it's Moderna or Pfizer-BioNTech or now J&J, AstraZeneca, Novavax, and on and on. It's not that these people did not realize the risk, but the notion that what they were doing was viewed with certainty as reckless, I find worth people going back and reflecting on what they've said. And I'm talking about the majority of the experts in vaccinology and epidemiology and health, global health, et cetera, and just say, what else don't we think we can do in a timeframe and in a cost structure that is absolutely attainable, which is now causing us to lose lives? So I think that's one of the biggest kind of things that will happen in this pandemic era as a force for good is for us to all challenge all the things we've taken as gospel truths about what can and can't happen and aspire more and take calculated steps to see if they can happen and let science and data dictate whether it can or not, not speculation or expert opinion.

Yeah, so what do you— what would you— what advice would you give for, you know, young and mid-career researchers who are interested in basic science? So with that in mind, what you were just saying.

Look, I think that people follow their— do things that hopefully move them. And that could be just following the pursuit of knowledge and adding to the body of knowledge that humanity has. I think that's a super noble pursuit, knowing full well that somebody will then come along and want to use that knowledge for societal good. And that could be a different person at a different time or maybe at the same time. All that for me is good. I think that everybody in biomedical science should realize— and I'm saying this literally 33 years after having stepped foot into the outside of MIT world— that there just is a massive opportunity of using this science to come up with new solutions in health, many aspects of health, as we discussed ahead of disease, after disease, in agriculture, nutrition, sustainability, many, many other areas, related areas. There's a world around us that is affecting our lives There's a world of living systems that we can harness for new solutions. So the tools that are being developed today— and let me also emphasize, Ruth, particularly because of MIT's recent heavy foray into machine learning as a main connector, AI as a main connector between the sciences, I fundamentally believe that We're living at a time when downstream versions of what artificial intelligence will allow us to do will be particularly enabling to life science. And I'll make a small case for that. And anybody who listened to me, I usually tell them that if I was in graduate school or if I was a postdoc, I would not miss a chance to avail myself of these techniques and technologies just the way I have to learn how to use a personal computer or for that matter, a large supercomputer when I was an undergraduate. And here's why. I would say that since we deal with evolved systems, they embody a level of complexity and a level of parts that interact in the thousands, in hundreds of ways. And these are just numbers I'm making up to create a kind of this incredible symphony that we call life, that is not going to likely be disintegratable in the way that physics has tried to disintegrate things at an atomic level to explain everything. That's my view. We have complexity at a level where our own minds, our own ways of describing mechanisms of action simply do so by ignoring most of what's going on and focusing on one small aspect. But machine learning algorithms that can actually use the totality of the data available across hundreds of thousands of experiments or people across time is just not something that a human is going to on their own be able to match. And yet they may actually reveal a very different way of harnessing complexity in life science than we've ever been able to do. And I really look forward to how what people consider the artificial intelligence becomes a form of augmented human intelligence as it relates to the way life science is done. Yet another instance of convergence that Susan talks about.

Yeah, yeah, I agree. So let's turn to some of the questions. Some of the questions are very closely related to what we were just sort of talking about. And then there are some very concrete vaccine questions. Let's just keep with the science-industry-academia-industry interface for a moment. Kevin Little asks, what do you see as the most significant opportunity for large industry and academia to work together to create these breakthrough innovations?

Well, look, there's a lot of collaboration that already exists between both large companies and smaller companies. And academia. And I think that we can always do better. There are barriers to that, rightly predicated on concerns about conflicts of interest and disclosure, et cetera. But to me, none of those are things that cannot be bounded, made transparent, and safeguarded against if the actual result of such a collaboration is far greater than the risk taken by some of the things that make us concerned. I would argue that just like in a vaccine where you make a risk-reward calculation, and if the reward far outweighs the risk of side effects, you go forward even if there are some side effects. I'd call it the same thing in industrial collaboration. So I think we just need to get better at that. And then look, I mean, in my post-MIT lifetime, I've gone from seeing a few professors at most be involved in startups to a few professors not involved in startups, or at least not involved in seeing their science in some way, those who want to, applied to have societal impact. And that journey is only going to get further developed, enhanced in the next generation. So I think we can do a lot, but we're already doing a very, very good job of this interface becoming more productive.

Yeah, and so Namita sort of follows up on that question in terms of how do we actually support that, the basic research. So do you think there's a role for industry biotech VC to fund the leaps in academic research, especially given that industry biotech VC profits largely from the innovations generated in academia? So this comes back to the funding question we were talking about, the shortcomings at NIH and how do we, how do we really promote science? How could that work?

Yeah, it's a tricky question because I think that funding leaps is a very difficult thing before they're made and a very expensive thing after they're made. And so people generally don't believe Ruth, I would say that leaps can be made. And they think that leaps are kind of some chance event that results from— I mean, the expression I dislike the most in the pharmaceutical industry is called shots on goal. As far as I'm concerned, wrong sport. The notion that you just sit there far off of a net whether it's in soccer or hockey and take shots on goal is just in my view, not reality. And yet if you believe that, then nobody's gonna fund leaps because they're gonna just think it's just about a lot of trying things, all of which may be equally valid or not, and then finding the thing that is most rewarding. So do I think that, Funding for leaps is going to be possible from industry? Probably not. Is it going to be possible if academic funding— oh, so government funding makes room for such possibilities? Some of you in the audience might be thinking, well, isn't that what DARPA does? Isn't that what's— but I would say, how about 100 times more of that? And Alongside kind of a lot more of the building and blocking and tackling. So I think this is a good question. I don't have a good answer, but I just want to make the case that thinking carefully about the possibility of people attempting, daring, and having resources to make leaps is an important part of the solution.

I want to read to you A question by a high school junior here. Here we have the future scientist. And this is Victoria Lee, and she asked, you redefined healthcare as sick care, describing its tendency to function once a diagnosis is made. You also mentioned that the more we learn about pathology, the more we realize that disease doesn't have an instant onset, emphasizing the need to seek interventions before the need to seek treatments With this in mind, what is your perspective on disease detection and prevention in regard to CRISPR-Cas9, and how do we as a society determine what diseases or even attributes should be prevented, altered, in terms of ethics, such as societies that have strong cultural preference for boys, the widespread assumption of ableism, etc.? Very, very interesting question by Victoria here. Well, yeah. Very broad. We could probably have another hour on this topic.

Yeah, yeah. And look, I mean, Victoria, it's good to be thinking about this, and you should be thinking about this for every technology that's been developed. You know, social media is now being used, as we know, for disrupting our elections and many, many other quite negative things that are happening to people. We're living in it in the past days with what we're seeing happening with, with Asian Americans, and you realize that a lot of technology that was supposed to be good is being used as a source of bad. And that's the case in life sciences as well. I think that CRISPR is something that we need to be very, very careful in how it applies in, in a reproductive setting. And yet there are cases where it's difficult for some people in society to say fear for it being misused, you can, you have to now suffer because something that could have been done should not be allowed. And so these are things that our societies, I think, have a way to have discussions around, careful safeguards in, and then in that case, incremental progress, giving us a better and better sense that we can actually provide the kind of risk mitigation before we go chasing the hope for rewards. I do think that in the detection area, we've seen already in the COVID-19 disease detection area, the application of CRISPR-based methods by Feng Zhang's lab as well as Jennifer Doudna's efforts. We're seeing some work being done on using CRISPR in some even antiviral therapeutic kind of strategies. We certainly have been working most recently and even much future generations of what CRISPR is today through gene writing technologies that, that aren't based on those. So there's just going to be a lot of both improvements, which improvements by the way might embody certain safeguards by the nature of what's being done that could address some of these concerns. So for the longest time that I've been around the space, I remember these arguments when the human genome sequence was being thought about being published and whether people would be discriminated against based on their genetic dispositions. As long as you're in science, you have a responsibility because you need to understand the science to put a human context around it and not simply say, well, that's not what I do. I'm going to rely on humanists to do that and now dictate what science can and should do. I think we need a collaboration there.

So let's turn to some very concrete vaccine questions. Two questions I have here. Phil Sharp asks, what is the importance of the emerging SARS-CoV-2 variants? Will the vaccine keep abreast of their emergence? So that's obviously something directly related to what, what's probably going on at Moderna right now.

Sure. And, and, you know, since I remember Phil as a professor when I was at MIT, and he was a towering figure then as well. I always have to be careful when I get a question from him. Look, I think that the vaccine, especially since it's an RNA vaccine, is undergoing seeming mutations. I'll say seeming only because it's really rather more undergoing selection than just mutations. And that's why we're seeing some of these strains take hold. It shouldn't surprise anybody. And the rate at which it's happening also shouldn't surprise anybody in my view because it's not like we have a population model of immune compromised people versus ineffectively kind of treated, et cetera, that we can fully understand the laboratories that have been set up for this virus to mutate in within. But what we can do and what we are doing certainly with messenger RNA approaches which are ideally or among the ideally suited ways to do this, is to on the one hand do a lot of surveillance and detection work on whether sera that are derived from either convalescent patients or vaccinated people can show neutralizing properties against the variants, which we are doing with great vigilance and will continue to do. Obviously those are limited by how representative they are in the real-world situation, but that's certainly being done. And we've reported our results there and we'll continue to do so as new variants emerge. And then the second is to actually preemptively start working on another set of sequences that are rather more geared towards the South African strain, which we announced we've already started doing. And I've started going into testing in humans because that will be an example, even if it's not needed ultimately, of how we could quickly respond if this really becomes a global need. We just don't know yet, but instead of waiting to find out before starting, we're starting and we will develop, again, if the need arises, all the way through to emergency use authorization in other another form of vaccine. We are simultaneously testing it on younger folks because the answer to this is as well the most rapid way to get the vaccinations to happen so that the conditions for this rampant variation are somewhat counteracted.

Are you doing direct experiments for the evolution of the virus? Because you could do this instead of having, you know, waiting for it to turn up.

So I know that there are many labs that are working in this area. Internal to Moderna, we collaborate with folks who do that work and we use the information to guide our design activity. I can tell you at Flagship, we have an ongoing project that's doing this with machine learning techniques quite actively in trying to create a sense of the cloud of potential viral variants that already exist and that could exist based on reported sequences and computationally then juxtaposing against hundreds of both computationally derived antibodies that should and could bind to the spike protein and the RBD as well as actual proteins that are in the market through Regeneron, Lilly, and others. So we have actually an interesting project to try to foresee what variants might exist in computer-based evolutionary simulations fed by data from any number of folks that are actually trying to do these experiments.

So were they— did they predict the variants which came up?

They did not predict the variants which came up. They have though predicted, including very recently with this new California strain, which antibodies will not work against them purely computationally. Yeah. But it's too early to tell because, you know, the prediction business, you're only as good as the number of cases you can point to. But certainly it is a learning system. So we are getting more and more comfortable that the more data we can generate, and we will, by the way, so just so you know, in that case, we're generating huge libraries of antibodies against RBD, I mean, using high-throughput techniques. And then using the binding information to inform what variants could escape and how. So that's being done based on generating lab-based antibodies even while the variants are being sourced from outside.

So maybe kind of ending here, which is the last question that, you know, a lot of us think about because it is so important probably for really ending this pandemic, and that is, if we can ever do that, what in your view is the path to vaccination of, you know, the third world or maybe just the rest of the world?

Because I think that's definitely a shared responsibility. I have, as much as I can, advocated for the U.S. to play a leadership role in that. I really do think that the approach that had to be taken certainly in the past year, which was everybody on their own, should be somewhat counteracted with a leadership role. I think that the US certainly has contributed to the solution here in a way that, and has the resources, and I'd argue has the sheer, forget altruistic value, but that the sheer resources to do this. And you're seeing a couple of reports in the last just 2, 3 days where people are beginning to write thought pieces arguing that the US should and can source the vaccines to be able to vaccinate everyone in the world. If you just do the math here and look at how much money has been spent on testing, repeatedly testing, testing, testing, each test at $25 or $125 depending on where you are, the incremental cost of vaccination is trivial. And yet, as you saw in New York Times just a day or two ago, there's a big report on how the slowness in the uptake of the European vaccine orders had everything to do with shaving a few dollars here and there. And I just think that that is, remnants of the way people thought about vaccines in the past, which was just how little can I pay since I'm giving it to all sorts of people who may not need it. And I believe in a health security world, that's exactly the wrong idea. Because if the consequence of not using it is to test and test and test people who may not otherwise need the test, and that far exceeds the cost, I think people should really do the math I think you're talking about maybe $70, maybe $100 billion. And these are not huge sums of money when you're passing trillions of dollars of bills one after the other. So now nobody will listen to me, but if they were, that's what I think the solution is. As opposed to trying to figure out how 50 different companies can make this around the world, and then we need to get them regulatorily approved. I think there are now 5, 6, 7 sources that if we just scale them up, we can get enough doses and boosters for everybody.

Thank you so much. I've really found this conversation today incredibly insightful, interesting, and also very powerful to talk about both the side of biotech and the side of innovation and basic research. And I hope everyone who is listening felt the same way and enjoyed this conversation. And I thank you very much. Very much, and we look forward to having another conversation with you in the near future. And good evening, everybody.

Thank you.

Mm-hmm.