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Speaker 1: Pushkin. One of the most interesting, most important companies in

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Speaker 1: the world right now is Maderna, this little biotech company

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Speaker 1: that almost nobody had ever heard of until a couple

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Speaker 1: of years ago. This company built on the wild idea

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Speaker 1: of making mRNA and putting it into people's cells. This

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Speaker 1: company has suddenly delivered COVID vaccines to hundreds of millions

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Speaker 1: of people, including full disclosure to me. And maybe the

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Speaker 1: most interesting thing about the story of Maderna is that

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Speaker 1: it doesn't start with the founding of the company back

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Speaker 1: in twenty ten. It starts ten years earlier with the

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Speaker 1: founding of another company, a company called Flagship Pioneering. Flagship

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Speaker 1: Pioneering is a company that makes companies. Flagship has created

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Speaker 1: dozens of companies, several of which have gone public. Pretty

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Speaker 1: much all of them have something to do with biology,

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Speaker 1: and they tend to be pretty out there. Companies using

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Speaker 1: bacteria as medicine, Companies trying to figure out how farms

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Speaker 1: can do more to pull carbon dioxide out of the atmosphere,

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Speaker 1: and of course, companies trying to figure out all the

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Speaker 1: things you can do with RNA, companies like Maderna. I'm

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Speaker 1: Jacob Goldstein and this is What's Your Problem, the show

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Speaker 1: where I talk to entrepreneurs and engineers about how they're

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Speaker 1: going to change the world once they've solved a few problems.

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Speaker 1: My guest today is Nubar Afaan. He is the founder

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Speaker 1: of Flagship Pioneering and the co founder of Maderna. And

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Speaker 1: the problem I wanted to talk with Nubar about is

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Speaker 1: the problem he started Flagship to solve. How do you

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Speaker 1: turn the unstructured, chaotic way that most entrepreneurs start companies

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Speaker 1: into a repeatable, systematic process and what can we learn

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Speaker 1: about that From the story of Maderna, the origins of

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Speaker 1: Flagship Pioneering new Bar's company, the company that started Maderna.

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Speaker 1: They go back to the beginning of his career as

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Speaker 1: an entrepreneur. He saw at the time that venture capitalists

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Speaker 1: had a sort of unfair advantage over entrepreneurs like him

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Speaker 1: because they got to see into so many different companies

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Speaker 1: all getting built at the same time. I was interested

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Speaker 1: in the model that venture capitalists used, and what I

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Speaker 1: observed in the early phase of my career is just

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Speaker 1: how smart all these people seemed. And yet after a

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Speaker 1: while I realized, well, they're two they can't all be

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Speaker 1: that smart. And it occurred to me that they had

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Speaker 1: seen so many attempts at this, with so many different

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Speaker 1: people of different backgrounds, compositions of teams that were only experienced,

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Speaker 1: only inexperienced the science the IP strategy in the markets.

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Speaker 1: So when you take it all together, they were learning

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Speaker 1: at a massive, massive rate that which entrepreneur need to

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Speaker 1: learn but never can learn in one go round. And

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Speaker 1: so I thought, why can't the knowledge assembly practice, experimenting

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Speaker 1: and failing and learning be available to an entrepreneur. So

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Speaker 1: all of those things kind of combined in getting me

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Speaker 1: interested in this notion that what if there was a

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Speaker 1: structure where entrepreneurs such as myself could take experience they

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Speaker 1: had gotten, let's say, in one in one instance, but

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Speaker 1: then started diversifying it and learning in parallel, and then

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Speaker 1: got really good at it. And those are the things

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Speaker 1: that led to the conception of Flagship in two thousand.

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Speaker 1: Starting a company that starts companies almost seems like cheating

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Speaker 1: in a weird way, Like when you get the genie

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Speaker 1: in the bottle and you get three wishes, it's like

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Speaker 1: wishing for more wishes, right, you know, I've never seen

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Speaker 1: a story which starts with you know, some Genie offered

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Speaker 1: somebody three wishes, and the first wish was another Genie bottle. Yeah,

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Speaker 1: it's a little poll have been a smart answer, Yeah, yeah,

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Speaker 1: that would have been a smart answer. So it really

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Speaker 1: is a kind of a curious thing as to why

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Speaker 1: people don't do it. And I can trace it back,

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Speaker 1: especially back in the twenty five years ago, to the

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Speaker 1: fact that the field of entrepreneurship was a relatively young field.

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Speaker 1: Early on, it was this kind of mystical activity, and

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Speaker 1: you had certain personalities that kind of were able to

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Speaker 1: raise money and govern, you know, create teams. There's a

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Speaker 1: whole mythology, right, It's like the like Hero's journey, right

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Speaker 1: where there's this one person who has a vision that

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Speaker 1: nobody else believes in and only they can build the company.

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Speaker 1: I mean, I feel like what you're building is sort

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Speaker 1: of the antithesis of that. Well exactly, entrepreneurship as an

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Speaker 1: activity today is today used to be and hasn't changed

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Speaker 1: so much. Is very much improvisational. There's a lot of

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Speaker 1: kind of almost a romantic side to it. There is chaos,

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Speaker 1: and there is this struggle to survive. And while all

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Speaker 1: of those things are really good, kind of spices in

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Speaker 1: a meal. It is the meal in entrepreneurship. There is

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Speaker 1: nothing else you don't point to, and we're developing products

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Speaker 1: and we're solving on meth needs. Those things almost become

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Speaker 1: kind of the boring part of the story that people

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Speaker 1: want to fast forward through that part of the episode.

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Speaker 1: So it did occur to me, in thinking of parallelyzing this,

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Speaker 1: that actually all those parts can benefit from being more efficient,

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Speaker 1: more effective, more predictable, and more planful. If there's this

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Speaker 1: idea that you can build a system to create companies

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Speaker 1: and that the system maybe ultimately can work better at

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Speaker 1: least better in some settings, let's say, than the sort

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Speaker 1: of visionary entrepreneur. What does that say about you in particular?

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Speaker 1: Like can you build such a good system that you

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Speaker 1: personally become replaceable? Oh? Yeah, that's my goal. So you

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Speaker 1: are set up this company, Flagship Pioneering to solve the

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Speaker 1: entrepreneurship problem. But how does it actually work and how

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Speaker 1: did it lead to the creation of Maderna? That is

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Speaker 1: after the break. Now we're going back to the show.

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Speaker 1: So in the first part of the conversation, Nubar and

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Speaker 1: I were talking abstractly about this problem he set out

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Speaker 1: to solve how do you shift entrepreneurship starting companies from

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Speaker 1: this mythological hero's journey into a repeatable, systematic process. In

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Speaker 1: the next part of the conversation, Nubar gave me an answer.

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Speaker 1: He told me the story of Maderna as a case

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Speaker 1: study for how flagship pioneering his company has started to

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Speaker 1: solve this problem, has started to create a system for

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Speaker 1: creating new companies. The story of Maderna starts in twenty

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Speaker 1: ten when Nubar had a meeting with a Harvard scientist

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Speaker 1: who was studying m RNA. mRNA, by the way, is

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Speaker 1: a molecule that basically tells cells in the body what

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Speaker 1: protein to make. I could researchers had been experimenting with

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Speaker 1: mRNA for a while by this point, but they kept

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Speaker 1: hitting problems when they tried to find clinical applications. And

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Speaker 1: in the middle of this meeting with the Harvard scientist,

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Speaker 1: Newbar thinks if we could make mRNA in the lab

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Speaker 1: and inject it into the body, the results could be incredible.

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Speaker 1: We could use mRNA to tele a patient cells what

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Speaker 1: to make. So I come back from the meeting and

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Speaker 1: I talked to some of the team here and we say, hey,

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Speaker 1: let's launch an exploration, and it starts as an act

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Speaker 1: of imagination. It is not an active reason. And in fact,

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Speaker 1: one of my side i'd say, kind of, I won't

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Speaker 1: call it ran. Yeah. A side rant would be the

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Speaker 1: degree to which our education systematically discourages the use of

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Speaker 1: imagination in creating the world we want to create, versus

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Speaker 1: relying overly on analysis and reason as the only way

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Speaker 1: to make progress. You want to try and be unreasonable

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Speaker 1: to some extent. We need to be unreasonable in order

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Speaker 1: to come up with leaps that eventually seem reasonable. So,

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Speaker 1: in the case of what will become maderna, you have

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Speaker 1: this unreasonable idea, let's use mRNA to get the body

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Speaker 1: to make drugs inside the body. You start this first step,

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Speaker 1: this thing you call an exploration, which means which means

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Speaker 1: what you have this small team studying the state of

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Speaker 1: the art, going out and talking to experts about this idea,

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Speaker 1: and what kind of reactions are you getting from the experts.

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Speaker 1: So the way that you react is to say, the

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Speaker 1: RNA will be washed out of the body in ten minutes,

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Speaker 1: How are you going to make proteins for weeks? How

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Speaker 1: are you going to get into the right cell types

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Speaker 1: by the way, there's all sorts of other immune reactions

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Speaker 1: you're gonna have to deal with, how are you going

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Speaker 1: to make it? Nobody ever designed and made Arnie, And

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Speaker 1: so all those selection pressures causes you, causes us very

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Speaker 1: specifically to go back and try to come up with

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Speaker 1: ways to overcome those let's say, dogumatic objections to based

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Speaker 1: on the present state of the art. And so because

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Speaker 1: you might say, we why don't you just ignore them

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Speaker 1: and just go into lab and do it. And the

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Speaker 1: reason it turns out for us anyways, that we find

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Speaker 1: that these initial hypotheses become refined and refined and refined

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Speaker 1: before we want to go in and spend the money

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Speaker 1: building a company. That's a really important thing. We don't

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Speaker 1: build just any company. We build companies that have gone

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Speaker 1: through a significant upfront set of iterative refinements. That's a

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Speaker 1: process of a couple of months. It's a handful of people,

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Speaker 1: three four people, and it's a couple of months, and

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Speaker 1: we iterate, iterate, iterated internally until we get to a

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Speaker 1: point by the fall where we say, you know what,

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Speaker 1: we're going to make a go of this, because that

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Speaker 1: we think we have a good sense of the range

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Speaker 1: of things that have to be right for this to work.

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Speaker 1: We can test for them, and we don't start the company.

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Speaker 1: We actually start what we call a protocompany. Okay, that's

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Speaker 1: the first phase. Okay, what is a proto company? So

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Speaker 1: a product company is a prototype of a company, just

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Speaker 1: like you make prototypes of every product that you make.

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Speaker 1: But remarkably, there is no such thing as a prototype

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Speaker 1: of a company. People just make companies. And a product

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Speaker 1: type of a company is where, just like in a

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Speaker 1: regular product, you get to beat it up and try

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Speaker 1: to kill it. And that's exactly what we do. And

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Speaker 1: so is it called Maderna Yet you have this idea

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Speaker 1: and it's like proto Maderna. No, it's ls eighteen is

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Speaker 1: the product company? Say it again. LSA teen is the

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Speaker 1: name of the entity that got incorporated to become eventually

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Speaker 1: if things went forward, Maderna. Why light, Oh, it's the

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Speaker 1: eighteenth such thing we did. Okay, it's the eighteenth proto

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Speaker 1: company you had ever made, exactly and today we're at

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Speaker 1: number ninety as an example, why do you do that?

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Speaker 1: Why do you give it just a number at that stage? Oh,

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Speaker 1: you know, when you're trying to create an institution instead

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Speaker 1: of behaviors. One of the things that I knew literally

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Speaker 1: on day one going into creating this whole thing in

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Speaker 1: two thousand was that people hang on to their ideas

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Speaker 1: and emotionally almost romantically connected them and they never can

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Speaker 1: kill them. And I wanted to create a safe zone

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Speaker 1: during which the question was, what is the falsifying experiment

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Speaker 1: that will kill the hypothesis so that we don't go forward. Well,

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Speaker 1: guess what if you give something a name, worse yet,

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Speaker 1: a name you really like, your pet, dog's name, some

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Speaker 1: Greek god's name, whatever, Well you try to kill it.

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Speaker 1: So you give it a number instead of a name

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Speaker 1: to make it easier to kill. Disposable exactly. But anyway,

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Speaker 1: I should say put our companies for us are like

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Speaker 1: a one to two million dollars six months to twelve

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Speaker 1: months plus minus process. It is not a license to

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Speaker 1: hunt for the next three years and ten million dollars.

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Speaker 1: That's a very important discipline. So a key part of

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Speaker 1: doing that is to decide what are the key experiments

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Speaker 1: that you want to do first in order to try

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Speaker 1: to kill it. We needed to convince ourselves that we

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Speaker 1: can actually make things and try them in animals and

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Speaker 1: have them make a protein. There's notion that. Now we

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Speaker 1: go around saying m RNA is the code of life,

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Speaker 1: and we can put it in and we can make

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Speaker 1: any protein we want. Yeah, two billion dollars later we

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Speaker 1: could do that. But on the early days, nobody had

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Speaker 1: shown that you can actually make the correct protein folded

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Speaker 1: the correct way in animal models, not to humans yet,

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Speaker 1: and so we need to convince ourselves of that. We

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Speaker 1: did work on that in small animals mice, and then

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Speaker 1: we had to believe is that we could actually somehow

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Speaker 1: formulate these things so they can get into cells. A

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Speaker 1: year or so nine months, a year of experimental work

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Speaker 1: that we engaged with within the context of LSA teen,

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Speaker 1: which was renamed a couple of months later Maderna. As

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Speaker 1: we started getting ourselves up and running, I just want

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Speaker 1: to I just want to pause. So ls eighteen, I

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Speaker 1: have the number, right, remember number, that's the point, right,

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Speaker 1: LSA teen becomes maderna. But at that time you're not

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Speaker 1: even thinking of vaccines yet, is that right? Well, let

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Speaker 1: me say this thing. We thought of every possible use

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Speaker 1: you could make of every kind of molecule, so vaccines

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Speaker 1: was definitely on tables of things we could do. But

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Speaker 1: by no means did our preliminary analysis suggest that we

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Speaker 1: should do vaccines, let alone only vaccines. And the reason

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Speaker 1: was because our dream, our imagination had us making any

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Speaker 1: protein in the body, and a relatively small subset of

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Speaker 1: the proteins that are made in the body is actually

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Speaker 1: for vaccines, and so we were working on cancer and

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Speaker 1: we were dreaming of cardiovascular disease. So the vaccine part

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Speaker 1: was a transition that started happening three to four years

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Speaker 1: into the development of the company, A long time. A

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Speaker 1: long time into the company, oh for sure, and probably

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Speaker 1: a good billion dollars of capital having gone into it

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Speaker 1: before now. Back in twenty fourteen thirteen, when we started

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Speaker 1: going down this path, of course, it was a pretty crappy,

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Speaker 1: for lack of a better word, marketplace because vaccines were

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Speaker 1: the domain of two or three pharma companies that had

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Speaker 1: a complete monopoly over the space. The development and regulatory

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Speaker 1: approval of them was extremely slow, very very costly, and

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Speaker 1: at the end you couldn't charge much for them. So

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Speaker 1: the reason the biotech industry, I think it'd be hard

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Speaker 1: pressed to find biotech companies that worked on vaccines was that,

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Speaker 1: And so investors, capital providers simply didn't want to go

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Speaker 1: there because it was generally written off as an area

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Speaker 1: for major innovation, but we weren't. We didn't really care

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Speaker 1: as much about that because all we wanted was the

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Speaker 1: proof of principle in humans that this could even be done.

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Speaker 1: You wanted that would work, yeah, in humans, yea. And

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Speaker 1: so in twenty fourteen, going into fifteen, we entered our

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Speaker 1: first clinical trial with two quite ironic people haven't quite

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Speaker 1: realized this yet, ironic in what I would say, two

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Speaker 1: strains of influenza that had not previously been in humans,

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Speaker 1: for which we wanted to make a prophylactic vaccine in

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Speaker 1: case someday they jump from birds or swine into humans. Basically, yeah, exactly.

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Speaker 1: So we just took a very safe road, tried it,

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Speaker 1: and sure enough we showed in the first instance that

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Speaker 1: that first attempt to humans could make neutralizing anybody's to

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Speaker 1: both of those trains, and we felt like, Okay, at

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Speaker 1: least we know we can make proteins and that they

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Speaker 1: do what we say, David, that's five years into it. Great. So,

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Speaker 1: because of all of this, because of the decade you'd

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Speaker 1: spent figuring out how to build a company that builds companies,

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Speaker 1: and then the years after that turning an idea into

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Speaker 1: LS eighteen, into Maderna into a company that makes vaccines.

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Speaker 1: Because of that whole twenty year arc, you're ready, essentially

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Speaker 1: when this new virus emerges at the end of twenty

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Speaker 1: nineteen to very quickly make a COVID vaccine exactly that

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Speaker 1: we worked for many, many years to put this platform

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Speaker 1: into existence. In a minute, the Lightning Round, including new bars,

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Speaker 1: tips for solving hard problems, and one weird trick for

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Speaker 1: knowing when to shut down a company or a proto company. Okay,

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Speaker 1: let's get back to the show. We're going to close

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Speaker 1: with the Lightning Round. What's one piece of advice you'd

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Speaker 1: give to someone who's working on a hard problem. Work

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Speaker 1: both from the present forward, that is, from what you

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Speaker 1: know to solve something, and also work future backwards, which is,

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Speaker 1: imagine the problem already solved and see if you can

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Speaker 1: back trace how you got there. Good. Okay, Two more,

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Speaker 1: do you have any rules of thumb for knowing when

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Speaker 1: to shut down a project? Not uniform rules, but I

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Speaker 1: think that you have to keep the resistance up resistance

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Speaker 1: meaning pressure in order for the team to conclude that

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Speaker 1: they're going through more and more complicated rationalizations using longer

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Speaker 1: and longer sentence is to justify whether its state life

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Speaker 1: sentence length is a good is a good heuristic? I

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Speaker 1: like that. And by the way, that's one of the

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Speaker 1: biggest misunderstood things in the startup world is that more

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Speaker 1: money leads to better companies. Lower money can just as

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Speaker 1: easily lead to worst companies because it causes persistence of

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Speaker 1: companies that don't feel that pressure. And so I think

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Speaker 1: one of the key things is the pressure that comes

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Speaker 1: from raising capital, the pressure that comes from being challenging.

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Speaker 1: I think these are all really really important to produce

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Speaker 1: the end result of deciding not to go forward. I

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Speaker 1: got to add one question, because you talked about money

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Speaker 1: being a problem. You just raised billions of dollars, which,

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Speaker 1: on the one hand, congratulations. On the other hand, is

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Speaker 1: that going to make it harder to do what you do?

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Speaker 1: I mean, there's scale, there's As you've said, having more

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Speaker 1: money can make it harder to keep the pressure on.

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Speaker 1: Is that hard having all that money? Because it took

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Speaker 1: us a long long time to get too larger pools

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Speaker 1: of capital. The process and the discipline and the culture

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Speaker 1: proceeds the capital and all of those are ways to

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Speaker 1: find the capital availability and keep the pressure on. Okay,

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Speaker 1: last one, if everything goes well, what problem will you

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Speaker 1: be working on in say ten years? Honestly unfathomable. I

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Speaker 1: could tell you what problem would be working on today

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Speaker 1: ten years ago. Let me answer it in this way.

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Speaker 1: We don't start with either problem or solution. We try

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Speaker 1: to invent both, make them up, and then we try

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Speaker 1: to match them in that regard. What problems will be

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Speaker 1: visible even at the horizon and what solutions will be

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Speaker 1: imaginable will dictate what we work on. So really the

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Speaker 1: answer to the what problem are you going to be

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Speaker 1: working on in ten years question is like you don't

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Speaker 1: even know the problem yet, And that's sort of the point, Like,

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Speaker 1: on some level your job is to add and discover problems,

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Speaker 1: both problems and imaginable solutions. Number of Fan is founder

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Speaker 1: and CEO of Flagship Pioneering and co founder of Maderna.

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Speaker 1: Today's show was produced by Edith Russelo, edited by Robert Smith,

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Speaker 1: and engine neared by Amanda ka Wong. I'm Jacob Goldstein.

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Speaker 1: We'll be back next week with another episode of What's

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Speaker 1: Your Problem