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A $2 billion, 10-year research push by Moderna and Flagship Pioneering positioned Noubar Afeyan’s companies to leap into action – just as the world needed an mRNA vaccine for COVID-19. When world first heard about the coronavirus, Moderna’s vaccine was already in human trials. How did they do it?

Afeyan credits this capability to “emergent innovation,” an approach to finding scientific breakthroughs that highlights a risk-reward method over incremental steps. Today these advances are being shared globally through Moderna’s pledge to open up its intellectual property. To Afeyan, that’s just good corporate citizenship at play, rewarding society and shareholders alike.

Learn more about Moderna and Flagship Pioneering’s foray into mRNA vaccines and where Noubar Afeyan sees this platform going next:


John Battelle

Our next guest has leveraged technology and many other business innovations to quite literally change the world. Dr. Noubar Afeyan is founder and CEO of Flagship Pioneering, a company that conceives, creates resources and develops first in category life science platform companies to transform human health and sustainability. An entrepreneur and biochemical engineer, Dr. Afeyan holds more than 100 patents and has co-founded and helped build more than 60 life science and technology startups, during his 33 year career. He is co-founder and chairman of the board of Moderna, the pioneering messenger RNA vaccine company addressing the global COVID 19 pandemic, and he serves on the boards of several private and public companies. Dr. Afeyan, welcome. It’s so good to have

Dr. Noubar Afeyan

Thank you. Thanks for having me.

I’ve really looking forward to this conversation, because I think your work touches almost every single one of the pillars of Signal from technology to commerce, to policy, to corporate citizenship and beyond. So I’m looking forward to getting into this. I know everybody wants to hear about Moderna. I’m sure I mean, if it’s possible, you might even be sick of talking about it. But let’s first talk about the company that helped create Moderna, which is your platform Flagship Pioneering, what is Flagship and what makes it different?

Well, again, thanks for having me. Flagship Pioneering, now in its 21st year of existence, was really an experiment in how to create an institution that can make breakthrough innovations, and also launch companies based on them. And we started with the notion that rather than kind of looking for innovations, and trying to commercialize them, could we actually look for the needs and the big opportunities, and make the innovations needed to have transformative impact? And how could you do that, as a team? How could you do that as a company? So imagine a company whose product is a company, or many companies, each one of them tackling different aspects of human health or sustainability. That’s what we set out to do. Flagship is highly predicated on the notion that breakthrough innovations can in fact, be made systematically, but that they’re not going to be made in the more traditional way where, where you follow the science and you incrementally try to find your way to that. But rather, it involves a whole different way of thinking. And we call this emergent innovation. And using those approaches, and several others, we’ve been able to, over the last 20 years, develop a whole methodology and a platform from which we’re operating.

Can you tell us more about what emergent innovation is?

Sure. So you could believe that breakthrough innovations are made by brilliant people. And there’s no question that brilliant people are needed to make breakthrough innovations. But I would posit that breakthrough innovations are often emergent. And what I mean by that is that they are the result of a long series of iterations that at some point, appear as a major gain of function, gain of capability. And that’s what we deem a breakthrough. If you view it that way, then rather than trying to find these innovations in a fully made fully formed way, you need to create a an environment, a culture in which such emergence can happen. And that’s really what we mean by emergent innovation.

Got it. Is there something about sort of the traditional approach to innovation, say in the pharma and health sciences industry, that make that kind of emergent innovation difficult?

Well, look, I’m I think we need innovations of all types. And so I’m not I’m not here to say one is better than the other, it’s just different. But indeed, traditional innovation is exploring adjacencies. Right? So whatever seems like a reasonable next step, and the next step after that is where people will will try to create a balanced portfolio of investments and projects. Instead, if you want to get beyond those adjacencies, you need to, you’re in a way in a white space. And it’s not clear where you should go and you need different mindsets. I’d say that the traditional pharmaceutical research establishment is rather more focused on the adjacency orientation, because it’s more reliable. You can use risk reward analysis more predictably. Whereas this type of innovation seems a bit more kind of futuristic, but also hard to figure out which one is going to work, which ones not. So I think people tend to avoid it.

Right. Let’s get specific, because I think you’ve got, you know, with Moderna this 10 year overnight success, right, a company that for most of its life, most of the world had never heard of. And then almost within a month, everybody had heard about it. And it was in the news, and has been in the news now, you know, since the beginning of last year, Tell us the story of Moderna. How did it start? What was the technology behind it? And how does it fit into this, you know, pattern of emergent innovation?

Sure, so. So in 2010, where we have kind of been iterating, this model for already a few years, as one of many explorations that we started, one of them basically was focused on whether we could think about a medicine that when delivered to a human subject, could cause that human to make another protein, a protein that could be therapeutic. So the notion is, is can we use a delivered entity that can instruct the human body to make a given therapeutic protein? Now, how you do that, what technology used to do that was a bit open ended. But during this exploration, the molecule class that really caught our interest was messenger RNA. Messenger RNA, it had been already reported in the literature could be delivered into cells, but it causes a very strong immune response right off the bat, which makes it somewhat useless as a drug. And that’s where it’s stood for 15 – 20 years since it was first attempted in the very early days of biotechnology. What had changed over the years, and we researched this to find out what the state of the art was, was that some chemical modifications could begin to tame the immune response, not all the way, not enough to safely deliver it to humans, but a bit of the way. Second, you need to get these into cells. And there was really no technology to get it into cells at the time. But we launched this project, we call this LS 18. For the 18th life science project, we had launched at that point, to ask the question, what if we could deliver medicines that caused humans to make their own drug and started working on, okay, if you can chemically improve, can you do it much more potently? What are the ways you can get it into cells, cells, muscle cells, liver cells. And after a year, plus or minus of search, we found ways to actually in animals show that you could take an mRNA code perfect it in its design, and these are things that we learned by doing, ultimately put it into some packaging, and get it into mice and make a relevant protein. From there, you could look backwards and say it was engineering, meaning the proof of concept eventually would lead us not necessarily to every single protein drug, but some. That’s where we started. Roll the clock forward five years, we for the first time tried this as a vaccine. It turned out we chose a vaccine back then, because it was, it takes one or two shots. And it’s kind of almost the easiest technical challenge to show the proof of concept. And in fact, ironically, we went after two, potentially pandemic flu strains. And I say potentially pandemic, because as you can imagine, in flu, that hyper varies every year. There are some strains that have been known to cause epidemics, and even some that could cause pandemics that have never entered into humans. And we thought that might be the safest thing to try out our technology against, in order to see what kind of immune response we can get. Roll the clock to 2020 beginning of 2020, we had nine vaccine trials that we had already done in humans showing nine different vaccine types all with mRNA. And we were not expecting this this coronavirus, but when it showed up, in hindsight, we were poised to go after it.

Yeah, that’s a very fortunate choice that you made to focus on these areas so that you were ready. When you know when the time came. I’m curious, you know, as I understand it, as soon as the genome of the COVID 19 coronavirus was published, you were ready, at least in terms of a digital model with the vaccine within days. You had the solution, I mean, sitting there on a computer screen and it was like all you needed to do was manufacture it, distribute it, get it, you know, a regulatory approval. Was that frustrating to know that you essentially had the answer but it was locked in a digital version. And now the obstacles were all physical?

I would say, in a sea of frustration we all felt during the pandemic, I’m not sure that incremental frustration could be attributed to that only because we were all overwhelmed trying to find solutions. Instead, it gave us a purpose, which was as rapidly as possible, take that sequence, make it which we did, in days, physically, test it in animals, which we began to do within a week. And then based on data from humans, sorry, from animals, we ended up being ready to go into humans within some 40 days. And in March with the NIH, we began human trials of this vaccine. That timeframe, albeit slower than the one or two days for the digital rendering, if I can call it that of the ultimate vaccine, the 1273 mRNA vaccine. Nevertheless, that timeframe was so so abbreviated, that we felt we were accomplishing something, and it was leveraging this platform, we had spent $2 billion in the prior 10 years developing. Thereafter, we had to test it in humans in much larger trials. And I would say, so you understand the mindset in the biotechnology, pharmaceutical industry, you know, we did not have the vaccine, until the results from our phase three trial were there. Because if you, there, you need to show statistically, that compared to a placebo control, you’re having not only the efficacy, but also the safety needed for it to make sense to be widely deployed. And I would say only at that moment that we know that 10 months earlier, we had the sequence, because until then, we may have had the sequence for nothing. And so think of it as you know that and that discipline exists in biotechnology, development, very, very rigorously. I last year, when I kept hearing about people worrying about cutting corners and all that. I mean, it’s such a, it’s so counter to how everybody that I know in this industry behaves, because, you know, we’re we are dealing with people’s lives. And it is absolutely incumbent on us, first and foremost, to make sure we convince ourselves that this is something that’s safe and efficacious. The regulator’s help us do that. The clinical community helps us do that. But it is in our best interest otherwise, the company’s future is completely affected.

Indeed. I mean, there’s a couple of things that you said there that that strike me is pretty extraordinary. Number one, over 10 years, you spent $2 billion, with no idea how it was going to work out. That that that’s a that’s a lot of money on what feels like something of a moonshot. During those 10 years? Were you certain that that investment was going to pay back? Or is that just part of the calculus of Flagship Pioneering? 

You know, it’s a good question. But I want to make sure that I’m clear about what we did and didn’t know. When you build a platform, and this is to me, among the underappreciated parts of what the advancement in our field looks like. I mean, in tech platforms are well understood, and they’re highly enabling. In biotech platforms are almost non existent. The people think of them as technologies you use in the laboratory, PCR, CRISPR, this and that. But what we mean by platform is a common set of technologies, understanding, that together, allows us to generate product after product of the product in a very reliable, rapid fashion. That platform is what we developed over a long period of time. But the key there is that you don’t develop the platform to have one product. So what we do to mitigate the unknown, if you will, is to have a multitude of products that are simultaneously advancing in clinical trials. So that the ones that actually make it through the clinical testing gauntlet, if I can call it that are the ones that ultimately reinforce the platform and make it valuable. And so when you say, were you uncertain about what would come out, I would say we were not uncertain about the possibility that many, some, of what we were working on would actually have impact. We just couldn’t tell you which one because of the vagaries of the human physiology, and the fact that we don’t have a good computational model yet, of that. So so it’s important to understand that if you develop a technology that has one shot on goal in our industry, something that that I really don’t like very much, there’s this notion of shots on goal. It’s believed that so few things work, that you have to just take a lot of shots. We don’t view it that way. We think the platform’s endow you with multitude of chances. You pursue them all, as many of them as you can afford, and that’s the maximum that’s the best way to maximize an outcome. We couldn’t tell you would have been for coronavirus. We couldn’t tell you if it’s gonna be our next product in CMV or where we’re in heart disease, but we’re working on all of them.

The second thing that you said, that relates to what you just described that I found fascinating is that by March, you had human trials going. Now. That’s March 2020. Correct? 


Now March is when most of us found out that we were in the midst of a pandemic. March was the month everything changed for the whole world, and you were already in human trials. Now, from that point forward, most of us understood that there might be some vaccines, there was sort of this Cheshire Cat grin going on with Dr. Fauci. You know, it seemed like something was up. And and there were various, you know, promises that things might come within a certain timeframe. Depending on which politician you listen to the time frame was further out, or which scientists you listen to. But you were behind the scenes. Take us behind those scenes into that nine month sprint or six month sprint to get to where you could confidently say, we have a vaccine that works, and we’re going to be distributing it, and here’s the plan. What happened in that time in between in 2020?

Well, you know, keep in mind that most of the economy was shut down. And our team at Moderna was was working feverishly, literally 24 hours a day in shifts, to be able to ramp up manufacturing. Keep in mind also that prior to the beginning of last year, we had largely deployed mRNA vaccines in maybe some 2000 human subjects. And here, we were ramping up to be able to make literally hundreds of millions of doses in the first year of, of operation. And so that is a no small feat, probably even a more giant, giant feat than some of the scientific things we were able to do, because it was without any precedent to go from zero to that kind of scale and capability. So that was going on behind the scenes, in front of the scenes. I mean, this was a a mad a kind of dash to do that. It’s remarkable that the manufacturing process stood the stress test, not only in our US manufacturing facility, but also we transplanted it to Switzerland through a partner and set up a capability there. So all of those things were preoccupying a large part of a heroic group of people. At the same time, we needed to design clinical trials, we needed to test some of the kind of key questions about a vaccine and its potential harmful effects so that we can rule them out. You know, very, very specific experiments we wanted to do to assure ourselves that we weren’t, we weren’t taking on extraordinary risks. So all of that was going on. But you’re right in, in capturing the moment that, you know, we were, it’s not that we had confidence that this would work. We just couldn’t figure out why it wouldn’t work. Except everybody told us that it wouldn’t work. And of course, history suggested it wouldn’t work. And worse yet, history suggested that things that have never been tried before, work even less somehow, apparently. And so, ao what we needed to do is, frankly, block some of that out and just do the best science we could do. We didn’t need to win the war of prediction, we just needed to win the war of demonstration. And if we were not successful, frankly, we were hopeful that other people would be successful, so we can benefit from their work. And indeed, it was the case that the two mRNA vaccines that were advanced, basically, using the exact same technology, ultimately did reach the sufficient efficacy and safety goals. But along the way, rightly, the scientific community was highly skeptical that this could be done or done quickly or done definitively or done safely. And the burden was on us to do all of those. And if we were standing at the end, then we had the next race to to enter which was scale, distribution, access around the world. And then variants which we could see coming already in the early days, and how do we prepare for those?

Right, right. We are in the midst of a significant wave based on a particularly potent variant, the Delta variant. Are you working on that?

Well, we’ve been working for several months on both boosters and alternate sequences to our 1273 In order to assess in humans, whether one, a combination, or the other might might give us further protection to to be able to counteract emerging variants. The most recent variant, and it will be supplanted by others, in my view, is definitely more transmissible, therefore more dangerous. And while we have a pretty good stock of immune response in a subset of the population, over time as that antibody response begins to deteriorate, there’s more exposure to a more potent infective virus. And so we need to stay vigilant. And we’re working on that very, very actively. We need to be ready, either with more kind of a booster of the existing vaccine or with some alterations. And by the way, probably, this is going to continue for the foreseeable future, so that we need to be ready again and again. And if we don’t need to use it, then so be it. I mean, the science, we cannot kind of command science to be able to show a safe efficacious vaccine overnight. You can have the design of one, as we’ve discussed, but you still have to do the testing.

You know, I want to ask you this, just because it seems very much in the air right now. What do you say when you encounter people who don’t want to get the vaccine? And who say, well, this is new? I don’t trust it. Maybe they don’t trust the government? Maybe they have other reasons for it. But but do you have a convincing argument as to what what, you know, what might change a person’s mind? And because one of the reasons that Delta variant has spread, is because a large percentage of populations either have not been vaccinated, that’s another issue, or will not get vaccinated. What do you say to that group of people?

Well, I think that there’s probably no one convincing argument. All I can do is to, is to share with people how I would think about it, if I was in their shoes. I would first recognize that, thinking about it, and being initially, at least, doubtful is not a bad starting point. Because it should urge you to collect information. If doubt causes inaction and shutting off, then that’s a bad trait in our brains. If doubt causes you to go seek input and then and then collect input and make your own judgment, then that’s a good instinct to start with. So I don’t have a problem with initial doubt. But then you have to kind of look at who do you trust? Who do you get medical input from? Doctors, public health officials? You know, as you go further and further out, obviously, different people will doubt people as to their motivations in the light. That’s why you need to talk to more than one. But ultimately, what I would say to people is the following. There’s no, there’s no option of opting out without exposing yourself to the risk of infection. That’s not that’s a that’s a fantasy. So you’re basically preferring the possibility of infection, to the possibility of whatever unknown risks there may be in the vaccine. And and given the nature of this virus and the fact that it’s getting more and more transmissible, I think that a choice of not getting vaccinated, at the limit is a choice to get infected. In other words, it’s just a matter of time. And so, then one has to do research, which most people have not done, on the consequences of infection. And, and depending on the age group, depending on the course of the infection, it could be not only fatal, but a long term chronic disease. That’s what we’re seeing in hundreds of thousands, if not millions of people. Now, I think people if they do that analysis, most preponderance of of medical experts would say that, as between the choices, a vaccine gives you a protection against ultimate disease that is far, far more desirable than not. But people have to get there in their own way. And so I try to participate in giving them the line of reasoning, but ultimately, I don’t know how to convince them beyond that. By the way, there’s many things we do in our regular life that could expose us to danger, like we could walk into oncoming traffic. Well, just because we can doesn’t mean that we do as an expression of our freewill, or our political beliefs or whatever. To me, this is not that different. This is not that different. There’s a known danger. And then there’s a known step to avoid the danger. Fortunately, it exists. It involves some perceived danger, nevertheless. But ultimately, people have to act in free will. Yeah.

Good answer. Very quickly, as we’re getting close on time, I’m curious what other disease or diseases do you think this technology or this platform is poised to address?

Ultimately, mRNA medicines, broadly, whether they’re vaccines or drugs, are a form of a code-based molecule, code-based drug. We’ve never had code-based drugs before. We’ve had drugs that were one offs, artisanal kind of undertakings, that one thing kind of ultimately after 10 – 15 years of work works. And then the next one, you start from scratch. Here, we’re starting From a programmable basis. So we have been working already in clinical testing in cancer, in immunological diseases, in cardiovascular diseases. We’ve just begun trials in rare diseases. And those are all just drugs. These are all things that work as a therapeutic once you have a disease. In the vaccine area, we have now over 12 different vaccines in development. We recently announced dosing our first patients, there were we’re looking at using mRNA for seasonal flu. We have programs in RSV, and CMV, which is a very, very major unmet medical need inside of cytomegalovirus virus, of infections and vaccinations. So there’s going to be a few different products that are going to advance. And hopefully this will take its proper place alongside small molecule drugs and proteins that we start from biotechnology, as a third portion of the arsenal to fight back disease.

That’s very exciting. Is there going to be a vaccine for the common cold?

I don’t think that we should rule that out. I know that most healthcare professionals would consider that either not necessary, nor easy to do. And I think that’s a good thing. Because things that are not yet known to be necessary, are worth working on, because sometimes they become necessary. But in any event, I think many of us certainly would think that its an appropriate cost to healthcare system. Being able to fight back the common cold with our own immune system would be a good thing. Promise, it’s hypervariable, it presents in different. Okay, so we have to, we have to do some experiments, and we will over a period of time. We need to prioritize I think and eventually get there. I don’t see why not. Certainly HIV is another important disease in that category where people have almost given up, but where we think new approaches can be tried.

Yeah. Great. Quick question around one of our major themes, which is corporate citizenship. Moderna has now become one of the most spectacular commercial success stories in the history of health science. $18 billion in revenue this year, record breaking IPO last year. How do you balance the imperatives of now being a public company, where you’re beholden to shareholders, with the role that a life science company plays in the broader world with the role of being a good corporate citizen?

Well, I’d start by saying that the essence of life science companies, the privilege of life science companies, that everything we do impacts human life. So we don’t have to have consultants helping us figure out the social impact of successful product development. It’s there and save lives, it’s there in in avoided diseases. And so I think that’s in and of itself, a contribution that we’re making. But beyond that, already, in the pandemic, a lot of what we’ve done, for example, our pledge to not enforce our intellectual property, which we made last October, to allow others to use some of our capabilities and IP to make alternative vaccines, that I think is part of corporate responsibility, but invite others to take similar pledges. And then finally, I’d say much more to come. I mean, the company is only just now entered this phase of its existence. And and, you know, we are surrounded by opportunity to make impact and we will not shy away from balancing. We don’t think that it is not in shareholders interest for corporations to reasonably take steps to ensure that their capabilities are channeled to the good of society, the same society they depend on for their products for their employees, for the culture that they maintain. So I think that kind of in biology symbiosis or mutualism, between being in a corporate world and being a citizen is not in conflict, and in some cases, imminently actionable.

Well, Dr. Afeyan, and thank you for helping us kick off signal this year. And thank you for all the work that you’ve made possible over the past 10 years. And we look forward to seeing what comes next both with Moderna and with Flagship.

Thank you so much. I enjoyed the conversation.