Noubar Afeyan on the Permission to Leap (Ep. 113)

How Moderna’s overnight vaccine success was 33 years in the making

“The world of innovation is very much one of toggling between survival and then thriving,” says Noubar Afeyan. Co-founder of Moderna and CEO of Flagship Pioneering, the biomedical innovator, philanthropist, and entrepreneur credits his successes to his “paranoid optimism” shaped by his experiences as an Armenian-American. Exceptional achievements like the rapid development of the COVID-19 vaccine, he believes, aren’t usually unpredictable but rather the result of systematic processes that include embracing unreasonable propositions and even unreasonable people.

He joined Tyler to discuss which aspect of entrepreneurship is hardest to teach, his predictions on the future of gene editing and CRISPR technology, why the pharmaceutical field can’t be winner takes all, why “basic research” is a poor term, the secret to Boston’s culture of innovation, the potential of plant biotech, why Montreal is (still) a special place to him, how his classical pianist mother influenced his musical tastes, his discussion-based approach to ethical dilemmas, how thinking future-backward shapes his approach to business and philanthropy, the blessing and curse of Lebanese optimism, the importance of creating a culture where people can say things that are wrong, what we can all learn by being an American by choice, and more.

Watch the full conversation

Recorded January 6th, 2021

Read the full transcript

TYLER COWEN: 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.

NOUBAR AFEYAN: Welcome. We say Shnorhavor Amanor yev Surb Tznund. That’s Merry Christmas in Armenian, and we celebrate this day as our Christmas.

COWEN: A very simple question to start: which aspect of entrepreneurship is hardest to teach to other people?

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

COWEN: How did you learn how to teach that?

AFEYAN: By putting myself in the shoes of the students and imagining what I would have wanted to know before I launched down a path of doing entrepreneurship in as professional a way as I could fathom because I also think that, generally, the field believes that entrepreneurship is condemned to be a perpetual, improvisational, unprofessional act.

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. The first way to do that is to figure out that it’s neither genetic nor somehow only about these amorphous characteristics than hard work, learning ways to do the future-backwards planning that we’re involved in.

It turns out those things can be learned by both practice and by hearing about case examples and how people make decisions.

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

AFEYAN: Yes. In my case, yes. The Flagship has a larger number than that, probably closer to a hundred now.

COWEN: 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 in building the company? How would you best describe the nature of that skill that you and Flagship have?

AFEYAN: 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. 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.

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, and the execution is 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.

Contrast 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 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.

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, has 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.

COWEN: Which part of entrepreneurship — biotech entrepreneurship in particular — is hardest to scale? You don’t have 792 companies, right? Something is stopping there from being more companies. What’s that scarce factor?

AFEYAN: 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? I’d say the simple answer to that right now, for us, is not being forced to . . . Let’s put it this way. If there was a need for us to create 20 companies a year instead of the six to eight 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.

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.

That is not something that we can easily defend. 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’re sourcing a lot of capital, both to start these things but also to scale them. 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 ramped up.

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 what innovation today is usually focused on. One way of saying, I think it’s about people, and it’s people who, on the one hand, need to be trained in this way of thinking about it and be willing to dedicate themselves to a pretty contrarian way of life.

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

AFEYAN: Well, Moderna is a company that was already 10 years old by the time the virus appeared. Unfortunately for the virus, there has 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.

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 — alignment around how to do what we do, alignment around values — and then execution with rapid iteration. All of those things are crucial to perform at that type of uncertainty and that type of pace.

Fortunately, in the Moderna case, they have nine years of upbringing before the pandemic that was filled with that culture, that set of principles. So, 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 because Moderna has, for the last 10 years, heard that everything it’s doing is impossible, and then improbable, and then undesirable, and then . . .

Now, 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.

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

AFEYAN: 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 three months before and now we did it in two days. It always can be done pretty quickly — that step, but the decision-making that preceded it was, were we willing to gear up to go into the clinic in a matter of weeks from having the starting point?

That was the thing that I was mostly working with Stéphane [Bancel] 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, what these people don’t yet realize is that 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 — 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. There was a lot of know-how we had going into this around how the process could be done. 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 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 — a 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 has been an 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. We get DNA sequence. We convert it into the antigenic part. We make it into an RNA. We put it in a particle. In an interesting way, we had interesting precedents that allowed us to move pretty quickly.

That and the partnership we had with 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. Therefore, we have specific knowledge — together with NIH and the NIAID, Dr. Fauci’s group — on the particular protein that we needed to go after. All of those contributed to being able to go very quickly.

On convergence in biotech

COWEN: 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 three on a malaria vaccine, CRISPR against sickle cell anemia. Why the sudden concentration? Is that computational techniques?

AFEYAN: It’s partly computational techniques, for sure. Convergence, as people call it, between technology and biology. 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 there was no human genome back then. We didn’t know even what proteins were existing in the body.

We’ve come a long way. We know things about 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 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.

My belief is that we’ve reached a level of capital, confidence, commitment, community, whatever of those 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 “If A, then B, then B-prime, and then maybe C.” This sequential, incremental . . .

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 you can truly cure through editing or gene therapy or whatever, you have an obligation.

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 percent of the capability we will have. I’m very sure of that.

COWEN: Fifteen years from now, how will CRISPR make people’s lives better?

AFEYAN: 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. 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 literally inserting words and sentences into the genome, not just spelling mistakes.

If you think of CRISPR as a metaphoric CRISPR — 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 all another ethical issue.

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 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 from 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 . . .

One of the things that we’ve got to realize is that in this field, it’s not winner take all, at all. It takes too long. It takes too much money to then say, “and once I’ve done it, I own the field.” It’s different than the tech sector where the competition is around execution and . . . Here, I think there could be multiple approaches that can be taken forward and are being taken forward, and they’ll all exist.

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

AFEYAN: Look, we have a program, as you probably know, that’s in phase-two trials for AstraZeneca, that’s going into phase three 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 one, we’ve already shown indications of safety and potential for activity. We’re advancing that with AstraZeneca.

I think those programs are probably several years — two, three, four years — in clinical development, still going on because you’ve got to make sure you can show an adequate number of people a treatment effect. 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.

COWEN: 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. What’s wrong with academia? And how do we fix it?

AFEYAN: I’ll just say, Tyler, that is true generally. 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. 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’s not that they’re conservative. It’s just that the process, the communal process of accepting truth as that which can’t be negated, causes you to therefore be, in every which way, questioning everything.

I learned long ago the expression organized skepticism. That’s 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. What many academic scientists do is to spend the next 5, 10 years putting the connections in place to make what’s being proposed a natural extension of what existed before.

In industry, we don’t have that need, and the reason 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 we weren’t trying to publish it.

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 connectible.

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.

COWEN: How should we improve the biomedical funding cycle?

AFEYAN: Well, boy, that’s a —

COWEN: You’re in charge. We’re going to do what you say. Tell us what to do.

AFEYAN: No, no, no [laughs]. That would be a difficult day for me just because I’d rather do things that people don’t think should be done.

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 — somewhat digital, somewhat analog — has created a capability — that’s what 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.

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.

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. Enabling research — I understand it can be bad uses of science, by the way. Parenthetically, I’m not naïve, but we’re talking about biomedical now. I think that enabling research, followed by applied research, where you do translational work — 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.

COWEN: Some institutions seem to be much more successful than others. 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 should we be doing more of?

AFEYAN: 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 doesn’t make me popular 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. That’s my personal belief.

I would say, in and of itself, that the HHMI, that the Broad or the various cancer institutes that exist, have done some amazing things. The Wellcome Trust. It’s a function of their systematic thinking about the job at hand. That’s one.

Then, of course, it’s about leadership. It’s about the patience inherent in the money.

Let me say maybe something stark, which we at Flagship believe and embody, but may be stark in the context of saying it, 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.

Yes, they can. There’s also such a thing as a lottery. Every week, somebody will win $100 million, but the notion that we should go searching for extraordinary advances amidst what is otherwise pretty reasonable things, each connected to each other by short distances — we need to allow for leaps to coexist with the hard work of filling in the gaps.

I think that those places you talked about — HHMI enables a very few, but importantly, professors to have capital to do whatever they want to do, and that’s, guess what? That’s a leaping ability, permission to leap, maybe in a military way.

Then, at Broad, a lot of the money that Eli Broad gave, and the rest of it that has been assembled, has been deployed to doing things that are scientifically with merit, but merit, I would say, not as dogmatically asserted as one would need if it was going to go through a whole funding process.

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.

COWEN: Now, as you know, Moderna has already issued a no-comment statement on the policy idea of “First Doses First” for extra 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. How do you weigh speaking out on policy issues versus your duties to the company?

AFEYAN: 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 play into that by being misconstrued.

The first thing is utmost care. Second is in the right context. 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.

COWEN: 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?

AFEYAN: Boy, you’ve thought about the questions a lot more than I’ve thought about the answers because you’re asking me — kudos to you — asking me a lot of questions that I don’t typically answer.

I think that Boston 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 gives it, 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. 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. At the time, young people didn’t start any companies, and I was interviewed by Inc. Magazine. I remember it distinctly. 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?

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 — a non-biotech — but startup success in Boston, which was Lotus. Lotus was just across the street from where I was. I said, “I choose to look at that office as opposed to looking at who might’ve had a business card in my desk.”

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.

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 ecological concept, and in nature, you’ve really got to realize that many, many forces that apply to things through iterative cycles — it causes an emergent form. Either way, 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 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 . . .

What’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 going to be not how 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.

COWEN: Here come the easy questions. We have the segment called overrated versus underrated. I toss out a word or an idea. You tell me if it’s overrated or underrated.

AFEYAN: Oh, got you.

COWEN: Plant biotech — overrated or underrated?

AFEYAN: Let me make sure. Say more. Plant biotech as a future potential?

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

AFEYAN: Highly underrated.

COWEN: Tell us why.

AFEYAN: Just like we understood very little about human health, we understand even less about plant health. 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. 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.

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 excitement but ended up with Monsanto going down a genetic modification route, that the understanding of plants as living productive systems that can be harnessed to do things, including in climate, is just beginning. I think it’s got a lot of promise.

COWEN: Aram Khachaturian — overrated or underrated?

AFEYAN: [laughs] A hardly known, amazing artist. Obviously, he’s known for one major piece of music, the Sabre Dance. I would say overlooked in much of the world, but a hero to me.

COWEN: Where should someone start? The piano concerto? The ballet music? What would you say?


COWEN: Yes. Levon Aronian — overrated or underrated?

AFEYAN: Appropriately, highly rated.

COWEN: Jayson Tatum — overrated or underrated?

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

COWEN: What is the highlight of Armenian food in your opinion?

AFEYAN: Boy, oh, boy, just one look at me and you’ll realize that I’m not very discriminant in that regard. Highlight of Armenian food? Well, Armenian food is largely built around barbecued meat with a lot of barbecued vegetables — 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 hate saying it — the meat and potatoes of the cuisine are these combined meat and vegetable dishes that are quite good.

COWEN: 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?

AFEYAN: Well, go to a place that is mostly Armenians and relatively less tourists. As a usual algorithm, that works beyond just with Armenians. I grew up with Middle Eastern–flavored Armenian food, so kind of a fusion between Lebanese food and Armenian food. 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 interesting Armenian dishes you can get in Glendale that you could probably not get in any other places.

But I won’t profess extreme knowledge. There’s a place called Phoenicia, for example, there that is quite good, but these are hybrid between Lebanese and Armenia. I just happen to like that.

COWEN: 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?

AFEYAN: Oh, God. Well, 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. So Montreal, for me, is 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 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. I think a lot of that has largely passed now.

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 and maybe a little less at the edge the way the US is able to and willing to be, but that’s the choice they make. That’s their culture, so that would be my answer.

COWEN: What do you love most in classical music?

AFEYAN: Oh boy, what piece you mean?

COWEN: Or what composer?

AFEYAN: Let me tell you, I love most but not for cognitive reasons. My mother was a classical pianist, trained at the Paris Conservatory, and when we grew up, she played a lot of Chopin, so there are many Chopin pieces that are embedded into my cells, I would say. 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. That was a pretty disruptive event in our lives.

I enjoy classical music together with my wife, but I don’t have a particular 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.

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

AFEYAN: There’s a bunch of them, but I’ll say that 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 genocide.

The notion was that at the centennial of the Armenian genocide, which was in 2015 — the commemoration — that we needed to look forward by looking back and expressing gratitude to the people who saved my grandparents, for example, back in 1915. Instead of thanking them — because they were long gone — to step into the shoes of the people who are doing that today and give them the financial needs, the recognition, and all the rest. 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.

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, and different places doing humanitarian work — has now focused some of its attention in providing help to the very same Armenians that a hundred 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.

COWEN: You think about company building in a pretty different way. Do you also think about philanthropy in a different way? What would you describe as the unity across your approach to companies and your approach to philanthropy?

AFEYAN: This is becoming excruciating, Tyler. The parallel between the two has, over the years, struck me. It’s been almost instructive because I used to keep those two sides of my life quite nicely separated.

What I found was that some of the things that we were doing in Flagship, with the way we thought about the future-backwards approach — 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 are not really forward-looking. Education is meant to be something the government provides because its impact is slowly felt, but so is economic development, so is many things.

I’d say that the crossover has been in terms of the relationship with the future. 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 — I’ve decided that our star customer is a five-year-old today.

I say “five-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 sustained existence.

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 an injection into their body to make a vaccine that might save their lives. Nevertheless, describing its future backwards and being anchored in the future, as opposed to anchor it only in the present or the past — that thinking does affect very much the philanthropy that I’ve been involved with.

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

AFEYAN: Tricky question. Assuming that that would be a desirable outcome is a big assumption for me. I don’t want to guess on that. I’ll tell you why. 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 the less desirable future vision.

COWEN: 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?

AFEYAN: I’d like to see a more credible direction there over the next 5 to 10 years so that it will have impact in the 10- to 20-year time frame. 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.

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.

COWEN: 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?

AFEYAN: Being in this space, there’s a lot of ethical issues, ranging from 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. What I do is try to get as many people of different backgrounds and mindsets to talk about it and 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’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. You’re not done answering it, but you still need to proceed. Of course, there are things in the ethical realm that are pretty crystal clear, but the more interesting things are not. They need to be discussed and iterated.

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

AFEYAN: 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 an idyllic place. It was a fun place. It had a lot of different cultures, commingled seemingly harmoniously, just mountains and sea and you name it.

But it turns out that a lot of the seeming societal stability that I thought we lived within in the decade that I lived there or so was a surface on a volatile situation. I think that what happened in the Middle East basically led to displacement of population, some of which came to Lebanon. Of course, there was a large Palestinian contingent there that was looking for the world to help it and administer its fate, or help it with its fate after the wars that took place.

So it was an unstable place that, clearly, the way it was put together in a 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 it used to be the financial capital of the region. 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.

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. It’s really genetic in that country, 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 trying 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 a long-term durability.

As an outsider, I haven’t lived there for some 45 years, but I view Lebanon in the context of the prism of Armenia, which has, in some ways, similar problems, in that we have a rather optimistic population despite the setbacks. You’ve got to ask yourself, is the optimism sometimes hurting you or helping you? Sometimes it can hurt you if it makes you accept the next illusion or the next fiction, versus actually dealing with tough problems.

COWEN: You’ve described your own approach as a kind of paranoid optimism. 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?

AFEYAN: [laughs] Probably my Armenian background. 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 it with my Armenian roots, or in the history of what Armenians have endured, until some five, six years ago, when my worlds collided a bit, and I found myself talking about these survivalistic mindsets in both of the worlds.

The world of innovation is very much one of toggling between survival and thriving. I wish there was a word thrival. I haven’t quite managed to get that word in the dictionary, but that’s a good word. Between surviving and thriving, and this constant toggle between the two characterizes high-risk, daring startups, 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 try to thrive.

I think that’s probably where the life experiences have at least helped, but I cannot draw a connection because it was not conscious at all.

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

AFEYAN: Unusual effective work habit. You got me there.

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

AFEYAN: Those are highly precedented. I’d say maybe less about a work habit because much of my work is just talking to people effectively. The instrument that I play is really just dialogue and discourse. In that regard, the one thing that I believe in is that — I’ve said this to you — I’ve got a strongly evolutionary mindset and this notion of emergence. I think that if you’re doing something that’s never been done before, you have to be very humble, recognizing that you don’t know what the right thing to do is, but also nobody else does.

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 gets you to new truths, as opposed to repetitions of current dogma.

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

AFEYAN: God, I should have a standard answer to that. 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 entertainment to me as opposed to content, so I’m going to disappoint myself in not giving you a singular answer.

COWEN: Tell us an entertaining book. Just one that entertains you — John le Carré or what would it be?

AFEYAN: I read a couple years ago, this book, I think it was called Origin, 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 AI in the context of some mystery novel. That book, for example, entertained me. I’m just giving an example of it. If I thought enough about it, I’d give you two, three good answers, but I’ll just throw that out. I think it’s called Origin. I think it’s by Dan Brown.

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

AFEYAN: Be America.

COWEN: What does that mean?

AFEYAN: 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 make themselves like the country. That disillusion is not a source of negative.

I know there’s lots of people who want to create ethnic differences and all the differences among us, but there’s an element of 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.

I think that that cooperative system between the precedented and the new is what accounts for unimaginable creativity, resilience, resourcefulness that this country has. I would protect that far greater than any monument or any other national treasure. Personally, it may seem romantic, but that’s what I think is attractive about this country. This country has that as a core advantage.

I think that’s a tough thing to pull off, let me tell you. A lot of other countries that come and go, and civilizations who don’t have that, who become a bit more homogeneous, more exclusionary lose their — I’ll say it — evolutionary advantage, their competitive advantage to adapt and to respond.

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 overmaturation of that and overstagnation of that that seems very, very troubling. I don’t know how that gets changed. It’s beyond my experience base, but I would say whatever happens should . . . 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 . . . If you 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 percent.

Imagine if all of us were also born imagining a better future for ourselves. Well, we should be, but we’ve got to work to get that. An immigrant who comes here understands that they’ve 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’ve got to work to get that. You might think you’re born into it.

This will be 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.

I think there’s some things 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?” If that’s more equal, less discriminating, different rules and laws, et cetera, then we should be open to talk about those things.

COWEN: Noubar Afeyan, thank you very much.

AFEYAN: Thank you.