Noubar Afeyan on the Permission to Leap | Conversations with Tyler

Hello everyone and welcome back to Conversations with Tyler. We are recording on Armenian Christmas Day with Noubar Afeyan. He is founder and CEO of Flagship Pioneering, but these days perhaps best known as co-founder and chairman of the board of Moderna, which has produced one of the two best anti-COVID vaccines in the world. Noubar, welcome.

Welcome. We say Shnoravor Dzununt. That's Merry Christmas in Armenian. And we celebrate this day as our Christmas.

A very simple question to start. Which aspect of entrepreneurship is hardest to teach to other people?

The fact that it is a combination of mindsets and beliefs as opposed to a birthright and connections.

And how did you learn how to teach that?

By putting myself in the shoes of the, of the students and imagining what I would have wanted to know before I launched down a path of, of doing entrepreneurship in as professional of a way as I could fathom. Because I also think that generally the field believes that entrepreneurship is condemned to be a perpetual kind of improvisational, unprofessional act. And I, some 25 years ago, decided that it would be much more productive if we could think about which aspects could be made more professional. And the first way to do that is to figure out that it's neither genetic nor somehow only about these kind of amorphous characteristics than hard work, coming up with, learning ways to do the kind of future backwards planning that we involve. And it turns out those things can be learned by both practice and by hearing about case examples and how people made decisions.

Now, at Flagship, you have a string of successes of what, over 40 companies that you have helped to create? Is that correct?

Yes. In my case, yes. Flagship has a larger number than that, probably closer to 100 now.

Now, how is creating a company as a co-creator a different skill than being either a VC who picks winners or doing all the work yourself and building the company? How would you best describe the nature of that skill that you and Flagship have?

Well, I should say that Flagship is itself an experiment. In a new breed of company that conceives and creates and launches and develops companies. So a company that develops companies is not a traditional way one fathoms what a company does. Our products are effectively platforms that are embodied within companies. So in that regard, if you think of the traditional startup methodology, what one needs to do is to take a scientific breakthrough or an innovation, typically in the life sciences that comes from academia, managerial skills to both initiate and then grow and manage the growth of, and then capital. If all three of those things come in together and coexist harmoniously and the product works and the pricing is right, the excuse, right, then you get a gigantic overnight success. The likelihood of that happening before we get to the product and the pricing and the execution is very low because the sources of innovation, the sources of talent, and the sources of capital have a lot of, let's say, friction among them as to what they think should be done. Contrasted that to what Flagship set out to do, which is to have the innovation capacity, the human capacity to lead, and the capital all as part of one entity, one organization. Such that they are co-deployed in, in pursuit of something that is therefore slightly more risky in the eyes of others because we can persist and we can cooperate because we all share one common objective, and that is the success of that thing that we're creating. So creating a company, having all three of those elements coming from the same source, is a very different act than collecting and optimizing the pieces. It's been my experience. I've done both, obviously. For the first 13 years of my life before 2000, of my professional life, I did it the traditional way. And since then, we've been doing it this way.

And which part of entrepreneurship, biotech entrepreneurship in particular, is hardest to scale? So you don't have 792 companies, right? So something is stopping there from being more companies. What's that scarce factor?

It's a good question because usually the form of the question I get is, what is limiting and why don't you do more? And I'd say the simple answer to that right now for us is kind of not being forced to, let's put it this way. In other words, if there was a need for us to create 20 companies a year instead of the 6 to 8 that we do, I believe the same methodology could do that. And I believe that we would not scratch the surface of the possibilities of transformations that could be going on. But, you know, look, we've been, you know, one of the things you do when you're exploring novelty, in our case, novelty of our life form, if you will, that is Flagship as an entity, is we've been pretty cautious and pretty humble about the notions that what we do can be scaled and could be replicated and can be effective regardless of scale. And that is not something that we can easily kind of defend. And so we've given it some time to ramp up. But your question more specifically, what's rate limiting? It's usually about people more so than capital and innovation. Since we are sourcing a lot of capital, both to start these things but also to scale them. You know, some roughly $5 billion of capital has gone into our collective activities over the last decade, little more than a decade of it, just as we've wrapped up. So, and then on the innovation side, our methodology by which we actually make inventions, which is quite different than the way scientific innovations are usually made, I don't think that that is limited in its potential. There's far more white space out there than there is occupied adjacencies, which is kind of what innovation today is usually focused on. So, long way of saying, I think it's about people,. And it's people who on the one hand need to be kind of trained in this way of thinking about it and be willing to dedicate themselves to a pretty contrarian way of life.

When speed is of the essence, as it was with the Moderna mRNA vaccine, how do management styles have to differ?

Well, Moderna is a company that was already 10 years old by the time the virus appeared. And so unfortunately for the virus, there had been quite a lot of time to get ready with a platform and with a team that was assembled, even though it was still a massive undertaking to do something that had never been done before. So from a managerial standpoint, it's a combination of being able to focus very rapidly on the task at hand, be able to make rapid decisions, which requires a level of pre-alignment around how to do what we do, alignment around values, and then execution with rapid iteration. All of those things are crucial to kind of perform at that type of uncertainty and that type of pace. And fortunately in the Moderna case, they had 9 years of upbringing before the pandemic that was filled with that culture, that those set of principles. And so I think we were somewhat lucky in being poised to take on things that others would consider, well, first of all, they all considered it impossible, but that was not new to Moderna 'cause Moderna has for the last 10 years heard that everything it's doing is impossible and then improbable and then undesirable and then, but now, you know, hopefully we've at least shown that in one case, it can be effective and impactful. And then that opens up a whole lot of new opportunities.

There's a now famous 2-day origin story, right? So you don't even have a physical instance of the vaccine. You just have the code. And in 2 days, you come up with basically the relevant innovation. Now, during those 2 days, what are you doing? Are you peering over someone's shoulder? Are you out by the swimming pool? Are you on Zoom calls all day? How do those 2 days look for you?

You know, actually, for me, My role as a co-founder and chairman has been to work with the leadership team, obviously separate from the board itself, on a variety of strategy issues that required very rapid decision-making. The decision to go down this path is one that involved more than just having a sequence. In fact, there was very little doubt in any of our minds that we could go from the sequence to a vaccine in a short period of time. We've done it many, many, many times before. It's just that that speed wasn't needed or appreciated by anybody. Didn't mean that we took 3 months before and now we did it in 2 days. It always can be done pretty quickly, that step. But the decision-making that preceded it was, were we willing to kind of gear up to go into the clinic in a matter of weeks from having the starting point? And that was the thing that I was mostly working with Stephane and his senior leadership team on. The scientific team that did the conversion of the sequence and optimization frankly did what they do for a living. I should point out, Tyler, one of the things people don't yet realize is that there are— this is, you know, mRNA in addition to being unique in that it's really the first broadly applied code molecule, information molecule, that is used as a medicine. And with all the advantages that come with information versus, you know, kind of digital versus analog, or where you actually have to do everything bespoke the way drugs usually work, the other major advantage that it has is that it is something that is actually taking advantage of nature. And so there was a lot of know-how we had going into this around how the the process could be done. And in fact, let me tell you the parallel that we used. We have a program in cancer vaccines. You might say, what does a cancer vaccine have anything to do with coronavirus? The answer is, the way we work with cancer vaccines is that we take a patient's tumor, sequence it, obtain the information around all the different mutations in that tumor, then design de novo, completely nonexistent before, set of peptides that contain those mutations, make the mRNA for them, and stick them into a lipid nanoparticle and give it back to that patient in a matter of weeks. That is an ongoing, has been ongoing for a couple of years, clinical trial that we're doing. Well, guess what? For every one of those patients, we're doing what we did for the virus over and over and over again. So we get DNA sequence, we convert it into the antigenic part, we make it into an RNA, we put it in a particle. So in an interesting way, we had interesting precedents that allowed us to move pretty quickly. That and the partnership we had with the NIH where for the prior year, year and a half, we'd been actively working on a MERS vaccine, which is a close cousin to the SARS-CoV-2. And therefore we had specific knowledge together with NIH, the NIAID, Dr. Fauci's group on the particular protein that we need to go after. So all of those contributed to being able to go very quickly.

Why is it that right now it seems so many biotech successes are turning into reality? They're not just cool articles in The Atlantic. They're things that are working. We're now stage 3 on a malaria vaccine, CRISPR against sickle cell anemia. Why the sudden concentration? Is that computational techniques?

It's partly computational techniques for sure. Convergence, as people call it, between technology and biology. I'm, you know, I've been working in that space for 33 years, so it seems like an overnight success, 33 years in the making in the sense of, you know, there was no human genome back then. We didn't know even what proteins were existing in the body. And we've come a long way. We know things about, you know, hundreds of millions of bacterial sequences that occupy our gut. We've learned that viruses occupy our body that we could use for therapy. All these things, it's kind of the expanded frontiers coupled with, and this is what I would say, at least that's where we come from, the willingness and the ability to leap, right? So my belief is that we've reached a level of capital, confidence, commitment, community, whatever of those C start, you know, C letter starting words, that it takes to get to a critical mass where people are willing to leap. They're not just incrementally doing, you know, if A, then B, then B prime, and then maybe C. This sequential incremental, uh, and, and then look at the permission to leap. The permission to leap is given either by confidence or need. If you have a pandemic, you have permission and the need to leap. If you have serious diseases that that you can truly cure through editing or gene therapy, you have an obligation. And those things are all converging. But yes, absolutely capability, those needs were there before. Now we have more and more capability, but I'll tell you, 10 years from now, the capability we have will seem like 1% of the capability we will have. I'm very sure of that.

15 years from now, how will CRISPR make people's lives better?

I don't know if CRISPR will be the particular technique that's used 15 years from now, to be honest, because I think CRISPR, like many other things, is a step along a series of innovations that will go beyond that. And by that, I mean the particulars of the enzymes that are bacterially derived that have been repurposed to edit one or two letters. I think that the next step beyond that will be, and you could imagine we're already working on it, we worked on CRISPR, we were one of the founding groups that was involved in the formation of Editas, but We're now moving on to gene writing and basically literally inserting words and sentences into the genome, not just spelling mistakes. But if you think of CRISPR as a metaphoric CRISPR, kind of the ability to do things with the genome, I think 15 years from now we will see multiple rare genetic conditions that are addressed by and corrected by it during somebody's life as opposed to in the conception phase, which is a whole nother ethical issue. But I think that will be done. It'll be more precise. It'll be more pervasive. But I think there'll be plenty of other ways to— that will compete, by the way, with the end result, which often is I need a corrected form of a protein. I don't really care if I get it through my DNA being altered or I get a virus that can safely coexist with my cells so that it keeps making what I need. Or RNA. I mean, you know, one of the things that we gotta realize is that in this field, it's not winner take all at all. It takes too long, it takes too much money to kind of then say, okay, once I've done it, I own the field. It's different than the tech sector where the competition is around execution. And then here, I think there could be multiple approaches that can be taken forward and are being taken forward. And they'll all exist.

When will the mRNA platform repair someone's damaged or bruised heart, for instance?

Look, we have a program, as you probably know, that's in phase 2 trials with AstraZeneca that's going into phase 3 to work on post-myocardial infarction, a heart muscle recovery through stem cells. It's using a molecule called VEGF that in animal studies and in phase 1, we've already shown indications of safety and potential for activity, and we're advancing that with AstraZeneca. I think those programs are probably several years, 2, 3, 4 years in clinical development, still going on, because you've gotta make sure you can show a treatment effect. But I think especially now that the platform is even further blown out and established, we'll be able to pursue not one of these, but 10, 20 of these, and let's see which one makes progress more quickly.

Now, as you well know, some of the early papers on mRNA vaccines, they were rejected repeatedly at academic journals. Katalin Karikó had trouble in her academic career. Now she's highly likely to win a Nobel Prize. So what's wrong with academia and how do we fix it?

Well, I'll just say that is true generally. You know, in their particular case, it was really more about pretty basic mRNA modifications as opposed to vaccines, because Back 20 years ago, people weren't working on vaccines. They were just working on being able to show that mRNA could even get into a human cell. And people were quite resistant to believing that was possible. Look, the scientific method, the scientific community, it works on advances that are predicated on current and prior advances. Incremental advances are the coin of the realm. It is not that they are conservative, it is just that the process, the communal process of accepting truth as that which cannot be negated, causes you to therefore be in every which way questioning everything. So, I learned long ago the expression organized skepticism, that is what science is predicated on. As a result, If you come forward with something that is not fully supported by and connected to the current reality, people don't know what to do with it. Now, what many academic scientists do is to spend the next 5, 10 years putting the connections in place to make what's being proposed kind of a natural extension of what existed before. But in industry, we don't have that need. And the reason we were— Moderna was able to really be the pioneer in the space of establishing a therapeutic platform, even before a vaccine platform, is because for us, the lack of connection between what we were able to do and what had been done before was marginally interesting, but not a— we weren't trying to publish it. We, you know, when you patent something, you don't have to show that it's a natural extension of what people did. You just have to describe something that is novel, that is unobvious. In fact, The less connected, the more unobvious and/or the less connectable. You know, my answer to your question would be a lot of it has to do with the essence of academic scientific pursuit of knowledge, which causes this collectivism, and it has its disadvantages. One of them is if you don't have all the pieces together, people will be skeptical.

How should we improve the biomedical funding cycle?

Well, boy, that's a—

You're in charge. We're going to do what you say. Tell us what to do.

No, no, no.

Yeah.

No, that would be a difficult day for me just because I'd rather do things that people don't think should be done. Look, I think, I hope that the illustration that a vaccine developed in a short period of time with robust, at least early results, hopefully making an impact on the population, should give people a use case from which to think that this is not some artisanal activity that you need a PhD in molecular biology to be able to understand, but rather a set of new tools, the equivalent of a computing infrastructure for other sectors that has been put together. It may not look like a computer, but the assemblage of processing techniques and knowledge gathering and storing techniques has, you know, somewhat digital, somewhat analog, has created a capability. That's why we call these platforms, has created a set of platforms from which we can expect not just slightly better cures and slightly better treatments, but pretty dramatic departures, not once or twice, but over and over and over again. And I think society If that begins to be understood, then biomedical funding should be thought of as an enabler of the underlying science needed to keep making this happen. So I want to make a strong case for what others call basic research, which I'd rather call enabling research because inevitably basic research is enabling to something. And so in a weird way, sometimes academic research frames things as having no purpose whatsoever so that they could keep the purity of it. But actually, they can't even assure that because eventually somebody will come along and use that for good. I think all of it is for good. So enabling research, I understand there can be bad uses of science, by the way, parenthetically, I'm not naive, but we're talking about biomedical now. I think that enabling research, and then followed by applied research where you do the translational work, I would see it's just not about more money. It's about being able to invest in the areas where we're able to have impact and then create the conditions for future impact in the other areas.

Now, some institutions seem to be much more successful than others. So Broad Institute at MIT has had a string of successes. Howard Hughes Medical Institute. Are those successes just luck, or is there something systematic we can learn from the best performers? And if so, what is that? What should we be doing more of?

No, that's an excellent question. First, let me just say that being systematic is an advantage in and of itself, in my view. I know that that's not— doesn't make me popular with, with people who want to believe that exceptional things are by their nature unpredictable and rare and unreproducible. I happen not to believe that. I think that many things we deem exceptional are illusions because we haven't actually gotten around to creating a systematic way to produce the conditions to have them happen. And that's, you know, that's my personal belief. So I would say in and of itself that the HHMI that the Broad or, you know, the cancer, the various cancer institutes that exist have done some amazing things. The Wellcome Trust is a function of their systematic thinking about the job at hand. So that's one. And then of course it's about kind of leadership. It's about the patience inherent in the money. Look, let me say maybe something stark, which we at Flagship believe and embody, but maybe stark in the context I'm saying it in. Which is that we have to be willing to embrace unreasonable propositions and unreasonable people in order to make extraordinary findings. Because the notion that utterly reasonable people doing utterly reasonable things will produce massive breakthroughs doesn't compute to me. Because yes, they can. There's also such a thing as a lottery. So every week somebody will win $100 million and that, But the notion that our, that we should go searching for extraordinary advances amidst what is otherwise kind of pretty reasonable things, each connected to each other by short distances, I think that we need to allow for leaps to coexist with the hard work of filling in the gaps. And so I think that those places you talked about, I mean, HHMI enables very few, but importantly, professors to have capital to do whatever they want to do. And that's kind of, guess what? That's a leaping ability, permission to leap, maybe in the military way. And then it broadened. A lot of what the money that Eli Broad gave and the rest of it that has been assembled has been deployed to doing things that are scientifically kind of with merit, but merit, and I would say, not as dogmatically asserted as one would need if it was gonna go through a whole funding process. So I think some of that, so I'd say encourage leaps, create a culture where leaps are not only permitted, but they're encouraged and they're protected so that if it doesn't work out, that people celebrate that at some level, and then have a systematic way to think about it so that there's learning cycles that come with that.

Now, as you know, Moderna has already issued a no comment statement on the policy idea of first doses first for vaccines. In general, when should companies, whether it's Flagship or Moderna, speak out on policy? Because you all know the most, yet at the same time you have a fiduciary responsibility to the shareholders of the company. And how do you weigh off speaking out on policy issues versus your duties to the company?

That's a, that's a very tough question, and I think it's answered largely on a case-by-case basis, which is inadequate but necessary, particularly given that we're in uncharted territory. There is such a heightened degree of scrutiny on every single word that's uttered and amplification and potentially misdirection that I think that we have to be even more careful. Plus, I think people in a pandemic are vulnerable to believing excesses. And we don't want to kind of play into that by being misconstrued. So the first thing is utmost care. Second is in the right context. So we have the ability to express our views on policy in places where those are relevant, with government colleagues, with certain nonprofits that are focused on issues. But we have to be, as you said, Careful about that because of the way in which the world is processing information on these things. It's not easy. It's not an easy situation for any of us.

Now, when it comes to the Boston-Cambridge area as an innovation center, what is both its greatest underappreciated strength and its least recognized drawback?

Boy, you have— you've thought about the questions a lot more than I've thought about the answers. 'Cause you're asking me, kudos to you, asking me a lot of questions that I don't typically answer. I think that Boston is its own, has its own culture. It's beautifully filled with immigrants that constantly reconstitute that culture. But at the same time, it has roots. It has a history that kind of gives it a, I'd say a rootedness. You can't live in Boston for a long period of time and not feel like you're part of something that has been there and that is this kind of— So the beauty is there are institutions that are world-class. And I think that all of those conditions helped the biotech ecosystem take hold. Frankly, there was no biotech or ecosystem when I started. I remember in 1987, I started my first company And I was quite young, I was 24 years old. And at the time, young people didn't start any companies. And I was interviewed by Inc. magazine, I remember it distinctly. And they pointed out that the office I was in was previously the office of a company that had failed. And how did I feel about that? And my response was that I did not think about whose office I was occupying. I thought about the office of then the most notable iconic non-biotech, but startup success in Boston, which was Lotus. And Lotus was just across the street from where I was. And I said, I choose to look at that office as opposed to looking at who might have had a business card at my desk. And that kind of forward-looking culture has developed, at least in Boston, because Boston I think is a place where you definitely can feel like anything's possible. You have world-class institutions that Educate people and enable them to believe that. And then I think what's happened over the last 30 years, what's really not appreciated is that ecosystems aren't designed or constructed, they emerge. They are a highly kind of ecological concept. And in nature, you've really gotta realize that many, many forces that apply to things through iterative cycles, it cause an emergent kind of form, either whether it's a life form or a community form. And I think that's the best way to understand Boston's ecosystem. So when people kind of talk about reproducing the Boston ecosystem, or for that matter Silicon Valley, more dispersed but similar kind of things, I think that's very, very difficult because you'd have to reproduce the emergent trajectory. That's my view. There's people who publish books that say the opposite. But so I'd say that's less understood maybe is in the category of just how a product of the sequence of events an emerging ecosystem is. And I think what is appreciated is that this is a special moment for Boston, Cambridge, and really the biomedical enterprise, the hospitals, the large pharma companies, the human talent that's been attracted. The key is gonna be how not to necessarily preserve it in the way it is today, but how to make sure you don't mess with the evolutionary experiment. Through policy.

Okay, now here come the easy questions. We have a segment called Overrated vs. Underrated. I toss out a word or an idea. You tell me if it's overrated or underrated. Plant biotech, overrated or underrated?

Let me make sure that you have to say more. Plant biotech as a future potential?

As a future potential, say, to protect against climate change.

Highly underrated.

Tell us why.

Because just like we understood very little about human health, we understand even less about plant health. And plant health is manifested in yield and resilience and drought and in the functionality of plants, which we have, other than feeding ourselves with or animals with, done very little else with. But we— the technological capabilities are now absolutely upon us to be able to harness plants and their own ecosystems to do a lot more than just create food. And I think that that's just beginning. So, you know, plant— and we work in this area, so I'm not saying this as a spectator. I think in the 30 years I've been involved in biotech, where there was an initial kind of excitement but ended up with Monsanto going down a genetic modification route, the understanding of plants as kind of living productive systems that can be harnessed to do things, including in climate, is just beginning. And I think it's got a lot of promise.

Aram Khatchaturian, overrated or underrated?

Hardly known, amazing artist. And I wish everybody— I mean, obviously he's known for one major piece of music, the Sabre Dance, but I would say overlooked in much of the world, but, but a hero to me.

Where should someone start? The piano concerto, the ballet music? What would you say?

Yes.

Yes. Leveronian, overrated or underrated?

Appropriately highly rated.

Jason Tatum, overrated or underrated?

Well, you know, you're of course testing the limits of my my belief versus my hope, and it's really hard to keep them apart. I would, I would like it to be underrated, certainly not overrated.

What is the highlight of Armenian food, in your opinion?

Boy, oh boy. Just one look at me and you'll realize that I'm not very discriminating in that regard. Highlight of Armenian food, you know, well, I mean, Armenian food is largely built around barbecued meat with a lot of barbecued vegetables. So probably this notion of what's called khorovats, which means barbecued, which is the centerpiece of what a lot of the main meals are. There are refined things that Armenians make and eat, but I'd say the, I hate saying it, the meat and potatoes of the cuisine are these kind of combined meat and vegetable dishes that are quite good.

So say I'm on Fountain Avenue in Los Angeles, or I'm in Glendale, and I want to find better rather than worse Armenian food. How should I think about that conceptually? What should I do?

Uh, yeah, well, I mean, go to a place where there's mostly Armenians and relatively less tourists, as a usual algorithm that works beyond just with Armenians. But I, I would say, you know, look, I grew up with Middle Eastern flavored Armenian food, so kind of a fusion between Lebanese food and Armenian food. And because Armenians have been spread all around the world, we have fused our cuisine with wherever we end up. And I'd say probably there's some pretty, pretty interesting Armenian dishes you can get in Glendale that you could probably not get many other places. But I won't profess extreme knowledge. There's a place called Phoenicia, for example, there that, that is quite good. But these are hybrid between Lebanese and Armenian. I just happen to like that.

Why has the city of Montreal fallen into underrated status? It was once the financial capital of Canada, right? Now it feels like a backwater. What happened?

God. Well, you know, first of all, Montreal is where my family escaped to from the civil war in Lebanon at a time when people didn't think it was going to be a long-lasting war. And thanks to my now departed father and his vision, we were among the first to get out. And so Montreal for me has this incredibly special place because that's where I grew up. Your question is a tricky question because one, I'd say in some areas it's certainly fallen a bit behind, but in other areas it's thriving. Canada had a period of time where there was a lot of infighting around language, around laws, around kind of some of those concepts of self. Between a bilingual society. And I think that had some impact on Montreal's vibrancy because there was a big exodus of companies. There was an influx of other ones. And I think a lot of that has largely passed now. And so I think Canada in general is itself, I'd say, underrated because it's got a lot of potential and it's got very progressive values. Maybe a little less kind of at the edge the way the US is able to and willing to be, but that's a choice they make. That's their culture. And so, you know, that would be my answer.

What do you love most in classical music?

Oh boy. What piece, you mean?

Or what composer?

What— Well, let me tell you, I love most, but that's not for cognitive reasons, that my mother was a classical pianist. Trained at the Paris Conservatory. And when we grew up, she played a lot of Chopin. And so there are many Chopin pieces that are kind of embedded into my cells, I would say. But more broadly, I didn't have the ability to continue playing the cello, which I learned growing up, based on the fact that we moved and changed countries. And that was a pretty disruptive event in our lives. But I'm happy to, I enjoy classical music and together with my wife, but I don't have a particular kind of piece or a particular hero in that regard. Obviously the major names, but also once in a while trying to find, I'm very happy that the Boston Symphony Orchestra, which I support and I've been involved with, has a strong commitment to new artists and new classical music intermixed with the older ones.

What is your Armenia-related philanthropic project that right now you are most excited about?

Yeah, there's a bunch of them, but I'll say that, you know, we have a, we created a humanitarian project which was both a prize and a movement called Aurora Humanitarian Initiative that was actually not Armenia-related, but founded upon Armenians' experience with the genocide, because the notion was that at the centennial of the Armenian genocide, which was in 2015, the commemoration, that we needed to kind of look forward by looking back and expressing gratitude to the people who saved my grandparents, for example, back in 1915. But instead of thanking them, because they'd long gone, to step into the shoes of the people who are doing that today and give them the financial means, the recognition, and the worldwide. So Aurora Humanitarian Initiative is a project that I'm quite proud of and involved with. Now, what's happened is that unexpectedly Armenia itself in the last few months has been thrust into a humanitarian disaster by virtue of a war that's been going on with its neighbor, Fortunately, recently they entered into a peace accord, but the resultant damage done to thousands and thousands of families and tens of thousands of lives is immense. So now what's happened is that this Aurora Initiative that was a gift from Armenians to the world to thank people in Africa, in Myanmar, in different places doing humanitarian work has now focused some of its attention in providing help to the very same Armenians that 100 years later are afflicted with this again. The irony is painful, but I'm proud of our ability to contribute to a pretty dire situation.

Now you think about company building in a pretty different way. Do you also think about philanthropy in a different way? And what would you describe as the unity across your approach to companies and your approach to philanthropy?

Well, this is becoming excruciating, Tyler. The parallelism, the parallel between the two has over the years struck me, and it's been kind of almost instructive because I used to keep kind of those two sides of my life quite nicely separated. And what I found was that was that some of the things that we were doing in Flagship with the way we thought about kind of the future backwards approach, kind of what's the destination you want to reach and how do you get there? Seems like a simple idea, quite absent when you're trying to react to people's needs because people's needs are here and now. They're not really forward-looking. Education is meant to be something the government provides because its impact is kind of slowly felt, but so is economic development, so is many things. So I'd say the crossover has been in terms of the relationship with the future. So I, for example, in the philanthropy work that we've done in particular with respect to developing Armenia, which has been going on for 20 years now, the central— I've decided that our customer is a 5-year-old today. I say 5-year-old to make it concrete, but basically somebody that can neither vote nor can express what they wish the future looks like, but for whom we want to try to create a more reasonable life and a more safe existence and sustainable existence. So in terms of that, that's not that different than a startup where you often can't describe your customer but it's somebody that will at some point need it injected into their body to make a vaccine that might save their lives. But nevertheless, describing it future backwards and being anchored in the future as opposed to anchored only in the present or the past, that thinking does affect very much the philanthropy that I've been involved with.

When do you think human beings will start living to age 140 in okay enough shape?

Tricky question. I have— yeah, assuming that that would be a desirable outcome is a big assumption for me. I don't want to guess on that. And I tell you what, I have a— for somebody who has few bounds on what I'm willing to imagine, I think that longevity as a goal versus longevity as a result separate the way in which different people think. I think of longevity as a result. I think that if we can deliver on health security, that is getting people most of their lives to be defended in terms of their health versus treated with their diseases, chances are the result of that will be longer and longer lives. But also longer, healthier lives and presumptively happier lives. The notion that we can come up with disease treatments that keep people alive but are largely just fighting the disease with all the damage that it's already done, that to me is a less desirable future vision.

When do you think we will arrive at the point where dementia and Alzheimer's, they may still be present, but they will not be significant social problems in the wealthiest countries?

I'd like to see a more credible direction there over the last 5, over the next 5 to 10 years. And so that it will have impact in the 10 to 20 year timeframe. I don't see, if I just roll back the clock 20 years, much of what we're doing today, cell therapies, messenger RNA, microbiome, none of those existed or were dreamt of largely And so I think if I just use that yardstick to go forward, that level of both increased knowledge about the pathophysiology coupled with increased tools to address it with, I may be being too conservative, but I'd say over the next 5, 10 years, proof points, clear proof points that that's within reach should emerge.

Here's a very hard question again. What is the most important ethics question you face in your biosciences work?, and how do you handle it or think about it?

You know, we have— being in this space, there's a lot of ethical issues ranging from kind of what you're willing to do in terms of genetic genomic modifications to the ethics of supply and availability of vaccines to What do you do with people who have volunteered for trials and now you know that there's a way to treat them, but that might cause different challenges? It's not the case that ethical issues come up rarely. They come up a lot. And what I do is try to kind of get as many people of different backgrounds and mindsets to talk about it and kind of get external input, but also internal. We're lucky to have a pretty diverse set of folks who have points of view about things and try to arrive at at least a thesis, but be open-minded to revisit it as data emerges. I'm quite, I've long practiced, maybe it's out of my ignorance, the notion that many things there may not be a definite answer for, but you need an answer in order to persist to come up with a better answer, and it may be the opposite answer. And so you're not done answering it, but you still need to proceed. So there are things, you know, I'm not— of course there are things in the ethical realm that are pretty crystal clear, you know, but the more interesting things are not. And they need to be discussed and iterated.

What do you think is the most conceptual or most structural reason why Lebanon has been so politically unstable?

I won't profess expertise in this area other than it's my birthplace, and I lived 13 years of my life enjoying what seemed in hindsight as a Disney ride. It was a an idyllic place. It was a fun place. It had a lot of different cultures, uh, commingled seemingly harmoniously, um, just, you know, mountains and sea and you name it. But it turns out that a lot of the seeming societal, um, kind of stability that I thought we lived within in the decade that I lived there or so was kind of a was a surface on a volatile situation. I think that what happened in the Middle East basically led to displacement of populations, some of which came to Lebanon. Of course, there was a large Palestinian contingent there that kind of was looking for the world to help it and administer its fate or help it with its fate. After the wars that took place. And so it was an unstable place that clearly the way it was put together, post-World War I and the way the governance was decided upon, there were very forward-looking things done, but actually they did not prove stable. That plus used to be the financial capital of the region. And once you have a civil war, a protracted one at that, then that's a fleeting advantage in that it moved to other places like Dubai and other places now. So what single thing contributes to it? It's easier for me to answer how Lebanon has endured despite those things, which is an incomparable degree of optimism about things getting better. I mean, it's really genetic in that country. And I think to some extent, probably it's what makes them survive, it's what might also condemn them to go back there because they may not spend as much time to try to address the underlying conflicts and underlying incompatibilities to so many different factions trying to coexist there as one would like. In order to maybe trade off the short-term optimism for long-term durability. But that's as an outsider, I haven't lived there for some 45 years, but I view Lebanon in the context of my, the prism of Armenia, which has in some ways similar problems in that, you know, when you've, we have a rather optimistic population despite the setbacks. And you gotta ask yourself, is the optimism sometimes hurting you? Or helping you. Sometimes it can hurt you if it doesn't— if it makes you accept the next illusion or the next fiction versus actually dealing with tough problems.

You've described your own approach as a kind of paranoid optimism, and you got that from Lebanon and your Lebanese background, or your Armenian background. You probably didn't get it from Canada. How did you get that?

Probably my Armenian background, and I would say I realized I've viewed paranoid optimism as a mindset that is advantageous in entrepreneurship, particularly when you go to the far edges of what is known, as almost a survivalistic thing. But I never ever associated with my kind of Armenian roots or the history of what Armenians have endured until some 5, 6 years ago. When my worlds kind of collided a bit and I had to— I found myself talking about these kind of survivalistic mindsets in both of the worlds. The world of innovation is very much one of toggling between survival and then thriving. I wish there was a word thrival, but I haven't quite managed to get that word in the dictionary, but that's a good word. But between surviving and thriving in this constant toggle between the two characterizes high-risk, daring startups. And just like it does in a recovering population where they've been afflicted with massive trauma and they have to, on the one hand, survive, but on the other hand, not get trapped in the ghetto of just survival and trying to escape it and trying to thrive. And I think that's probably where the life experiences have at least helped. I cannot draw a connection because it was not conscious at all.

3 final questions all about you. First, what is your most unusual effective work habit?

Unusual effective work habit.

You take notes on everything. You wake up at 4:00 AM in the morning. You have a glass of orange juice before every meeting.

Those are highly, those are highly precedented. I'd say maybe less about a work habit, but rather a Because much of my work is just talking to people effectively. It's kind of the instrument that I play is really just dialogue and discourse. And in that regard, the one thing that I believe in is that— I've said this to you, I've got a strongly evolutionary kind of mindset and this notion of emergence. So I think that if you're doing something that's never been done before, you have to be very humble to recognizing that you don't know what the right thing to do is, but also nobody else does. And in that milieu, you need to create a culture where people are willing to say things and be wrong so that others can say other things, and over time, whatever is right can emerge. So I'd say probably the most unusual thing that I insist on is people's willingness to say things that are not backed up by all the facts that one would typically need, and then to engage them in a dialogue that will eventually get us there. It's tiring, it's not a pleasant activity, but I've developed a sense of that because I think that that gets you to new truths as opposed to repetitions of current dogma.

What book has had the greatest impact on you as a person?

God, I should have a standard answer to that, and I will disappoint you in saying I don't have one. I've had an opportunity to read a number of books growing up. I read books, less books now, and they have often to do with kind of entertainment to me as opposed to kind of content. So I'm going to disappoint myself in not giving you a singular answer.

But tell us an entertaining book, just one that entertains you. Jean La Carré, or what would it be?

No, you know, I read a couple of years ago this book, I think it was called Origins, I want to say by Dan Brown. If it wasn't by Dan Brown, it was probably somebody like Dan Brown because it seemed like that, a kind of series. It was about kind of AI in the context of some mystery novel, and that book, for example, entertained me. I'm just giving a an example of it. There's, yeah, if I thought enough about it, I could give you 2, 3 good answers, but I'll just throw that out. I think it's called Origins. I think it's by Dan Brown.

Last question. How do we attract more people like you to come to America?

Be America.

What does that mean?

What I mean is recognize that the country is itself one giant experiment. It's a melting pot. It has been a melting pot. It should continue to be a melting pot. A melting pot means that people come here to effectively make the country like them and themselves make like the country. And that dissolution is not a source of negative. I know there's lots of people who kind of want to create ethnic differences and all the differences among us. But there's an element to this where I think people have come to this country fully intending to adapt and to contribute, but also to add of themselves to what is considered America today. And I think that that system, that cooperative system between the precedented and the new is what accounts for unimaginable creativity, resilience, resourcefulness that this country has. And I would protect that far greater than any monument or any other national treasure. I think that's— so that's personally, you know, it may seem romantic, but that's what I think is attractive about this country because this country has That has a core advantage. And I think that's a tough thing to pull off. Let me tell you, a lot of other countries that kind of come and go and civilizations who don't have that, who become a bit more homogeneous, more exclusionary, kind of lose their, I'll say it, evolutionary advantage, their competitive advantage to adapt and to respond. And so I think we clearly have a bunch of things to fix as it relates to the way the governance of the country is being executed. There's a level of over-maturation of that and over-stagnation of that that seems very, very troubling. And I don't know how that gets changed. It's beyond my experience base. But I would say whatever happens should— and by the way, I have not said should protect immigrants. Or immigration, but should protect this dynamism that comes from that. I also would say that as a country, there's so many people who have the experience of coming here that that experience can also be transmitted to people who are born here for whom the same mindset of being willing to imagine a better— look, every single person who comes to this country imagines a better future for themselves. That's my belief. Maybe not every single person, 99%. So imagine if all of us were also born imagining a better future for ourselves. Well, we should be, but we got to work to get that. An immigrant who comes here understands that they got to work to get that. They have to adapt. The problem is if you're born here, you may not actually think that you're going to work to get that. You might think you're born into it. And if we're all— this will be kind of a funny thing to say, and I apologize to anybody that I offend. If we were all Americans by choice, we'd have a better America because Americans by choice, of which I'm one, actually have a stronger commitment to whatever it takes to make America be the place I chose to be versus not thinking about that as a core responsibility. So I think that that There's something to be said about that, is to really make a new pact, a compact to say, "What's the America that I really want to be contributing to?" And if that's more equal, less discriminating, different rules and laws, et cetera, we should be open to talk about those things.

Nubar Afeyan, thank you very much.

Thank you.