The Machine that Made the Vaccine

In this special episode, which originally aired the day the FDA authorized the world’s first mRNA vaccine for emergency use, Moderna CEO Stephane Bancel tells the story of the machine that made the vaccine: the platform, the technology, and the moves behind the vaccine’s development.

This episode of Bio Eats World takes us from a world of pipette and lab benches to a world of industrial robots making medicines: We used to grow our vaccines, now we can “print” them, getting them to patients faster and more efficiently than ever before. In conversation with a16z general partner Jorge Conde and Bio Eats World host Hanne Winarsky, Bancel describes the exact moment he realized they might actually be able to make a vaccine for COVID-19; what happened next to go from pathogen to design; how this new technology that uses mRNA works (in a chocolate mousse metaphor!), and what makes it different from “old” vaccines; and how to think about managing both innovation and speed in this world. Why is this such a fundamental shift in the world of drug development? And where will this technology go next?

Show Notes

• What happened when the SARS-CoV-2 virus was discovered, and Moderna’s response [1:44]
• How Moderna’s vaccine was developed digitally [4:02]
• Description of how mRNA drugs work [5:43] and the history of this technology [7:30]
• The advantages of mRNA drugs [11:18]
• How Moderna learned about the positive results from Phase 3 trials [14:41]
• Why mRNA drugs can be produced more rapidly than other processes [19:06]
• How mRNA technology might be used for other diseases, and where it is limited [22:18]
• Details around Moderna’s manufacturing process [27:44]
• How Moderna was founded, their original goals, and challenges faced [32:01]

Transcript

Hi, I’m Lauren.

Hanne: And I’m Hanne, and this is “Bio Eats World”, our show where we talk about all the ways biology is technology.

Lauren: This week, in place of “Journal club,” we have a very special episode featuring Stéphane Bancel, the CEO of Moderna, in conversation with you, Hanne, and a16z general partner Jorge Conde. And we’re talking about the COVID-19 vaccine, right?

Hanne: Yep, that’s exactly right. The conversation is a really incredible dive into how they developed one of the world’s most awaited vaccines. Bancel describes everything from the moment he first realized they could make a COVID-19 vaccine with their technology to the day he heard the first data on how effective it was in humans. In this episode, which is airing just after the Vaccines and Related Biological Products Advisory Committee meeting makes its recommendation to the FDA, Stéphane tells the story of not just how the vaccine got made, but everything about the machine behind this vaccine — the fundamentally new platform and mRNA technology behind the vaccine’s development.

Lauren: This vaccine is really one of the first medicines that is part of a bigger transformation from a world of pipettes and lab benches to a world of industrialized machines making medicines. We used to grow our vaccines, but now we can print them — getting them to patients faster and more efficiently than ever.

Hanne: Bancel describes what it took to go from pathogen to design to clinical grade product; how mRNA works, in a chocolate mousse metaphor; and what makes it different from old vaccine technology — why exactly this is such a transformative shift in the world of drug development, and where this technology will go next.

The discovery of SARS-CoV-2

Jorge: Stéphane, sitting here now, in December of 2020, could you imagine a year ago that mRNA as a concept would be a household name?

Stéphane: No, and we have a lot of things going on in vaccines, in cancer, in autoimmune disease, in cardiology, in viral genetic disease. But I had no idea that 2020 was going to look that way.

Jorge: So, if we flash back to January of 2020, can you talk a little bit about the process that you went through to realize that you potentially had the technology that could be a solution for this emerging pandemic?

Stéphane: Yes, so I’ve been working in infectious diseases all my career, and I’ve developed an eye for outbreaks. So, one of the things I do is I read the Wall Street Journal and the Financial Times every morning as I get up. And between Christmas and New Year of last year, I noticed an article saying that there is a new pathogen agent in China giving pneumonia-like symptoms. That’s all it says. And so, I sent an email to somebody working for Tony Fauci — Barney Graham, who we’ve been collaborating with for years designing several vaccines together. 

And I said, “Barney, have you seen the new pathogen in China? What is it? Is it a bacteria or is it a virus?” And he replied to me a few hours later, and he says, “It’s not a bacteria. It seems to be a virus, but we don’t know which one yet.” And a day or two after, Barney sent me an email and said, “Hey, we learned from our contacts in China, it’s not flu, it’s not RSV. We don’t know what it is yet.” And then another day goes by and he says, “It’s a coronavirus, but it’s not SARS and it’s not MERS. It’s a new coronavirus. Within a day or two the sequence should be put online by the Chinese.”

And so on January 11, the Chinese put the sequence online. And our team at Moderna used the sequence to design a vaccine. In parallel, Barney’s team does the same thing. And when they shared notes after around 48 hours, they had designed exactly the same vaccine.

Creating Moderna’s vaccine digitally

Jorge: A couple of things that are fascinating about this — number one, the fact that the digital copy of this virus came from China before the biological version reached our shores. That’s remarkable in and of itself, that we knew what we were dealing with, at least digitally, in a matter of days thanks to all of the advances with genomic sequencing technology. But the other remarkable advancement in technology here is what you just described — you were able to design a vaccine based on the digital version of the virus, also in a matter of days, is it?

Stéphane: So, you’re right, Jorge. And this is the piece that I think most people in pharma don’t appreciate yet — the power of modern technology is, in 48 hours we designed and locked down the entire chemical structure of a vaccine.

Hanne: Unbelievable.

Stéphane: And we click “order” on the computer — so it all happened in silico, we never had access to a physical virus. And we designed the vaccine. And with, again, the two teams at NIH and Moderna, because we were so worried — to make a mistake in the vaccine design, as you can imagine.

Jorge: Of course.

Stéphane: So, we were super happy when the team literally compared notes after two days and they had exactly the same design for a vaccine, because it was an outbreak and we knew every day mattered. At the same time, we started to make clinical grade products to go into a Phase 1. And that is really remarkable — is the vaccine that is reviewed by the FDA on December 17, it’s exactly the same vaccine that our guys designed in January in silico. We never changed one atom. It’s exactly the same molecule.

Hanne: So, it’s the same vaccine that took 48 hours to design.

Stéphane: That’s going to help hundreds of millions of people next year, yeah.

How mRNA vaccines work

Hanne: Can we take a moment to just get really simple and talk about how you would define this messenger RNA technology, and what you wish the public understood about how mRNA works?

Stéphane: Right. Yeah, so it’s a molecule that exists in every one of your cells that is basically the xerox copy of an instruction of your genome for one gene at a time to make protein in your cells. So the way I would describe it to my two young daughters is — think about DNA like the hard drive of life, where all the instructions of all your 22,000-ish genes are stored. And think about it a bit like this is a recipe book that your grandma gave to you before she passed away. All your favorite recipes, that’s the hard drive, that’s DNA. And when you want to make, let’s say, a chocolate mousse, if you go with your grandma’s precious book into the kitchen, you’re going to damage your book a lot. There’s going to be flour, and eggs, and sugar. And after a few times, you might not be able to read the recipe anymore. So what evolution has done, which is beautiful, is to protect the integrity of the instruction in the hard drive, in the book. When the cells want to make one protein, like let’s say insulin, what it does — it makes a copy of the instruction only of insulin in the book, like my example of chocolate mousse — a xerox copy — and takes it into the kitchen (i.e., the cell) to make for a little machine called the ribosome, that I describe [to] my kids as a little 3D printer that reads the message with the instruction of mRNA, and makes the protein by adding one amino acid at a time. So it’s a natural molecule that basically carries genetic information to make proteins.

History of mRNA technology

Hanne: But using mRNA as a tool in the way you’ve been doing it, that was not always an obvious approach. So can you talk a little bit about where that began, that idea, and what it first looked like?

Stéphane: Yeah, so it’s actually very interesting. When mRNA and DNA were discovered, actually people in a lot of universities tried to make medicines out of mRNA because it was a very logical use of mRNA. Just copy nature — make a synthetic mRNA, inject it into animals before humans, and it should make a protein. Because of what was known about science at the time, including immunology — all the analytical tools that did not exist as part of manufacturing purity and so on — when they would inject mRNA in animals, animals would have flu-like symptoms — a fever, vomiting, diarrhea — because mRNA, if you remember, most viruses in life including COVID-19 is made of mRNA. And so through evolution, mammals have developed mechanisms to recognize foreign mRNAs. And of course, when you inject mRNA as an ID for a drug, that’ll be a foreign mRNA. And so actually people abandoned and just quit on trying to make mRNA as a drug. What happened in the 2010, 2011 timeframe, here in Boston, is you had a set of academics at Harvard and MIT who started to play with mRNA again because there [had] been some new discoveries made in the immune system — that they believed at the time that if you modified uridine, which is one of the four letters of mRNA, you can make an mRNA that’s immuno-silent.

Jorge: In some ways, when you think about it, Moderna doesn’t make therapies, right? You make instructions that the cell uses to make its own therapies.

Stéphane: Yeah, correct. We don’t give you the vaccine. We give you an instruction for the cells of healthy people, in that case — to read the instruction, to make one protein of a virus, to make it as well as if they had been infected by the real virus, to show it to the immune system so the immune system can make a neutralizing antibody and mature it. So that if, later, they get infected by the real virus, the immune system is ready to prevent the virus from [replicating] in their body and getting them sick. But what gets people sick in infectious disease is you have too many copies of a virus.

Jorge: Yeah, and so I think this is a remarkable thing for a couple of reasons. What you’re essentially doing is you’ve looked at the virus’s, you know, genome, and you’ve said, “Okay, if I take certain pieces of code from this virus and encode them in mRNA and deliver them to human cells, I am basically giving the human cells the instructions to make pieces of the virus that the immune system will train itself on, recognize, and eventually neutralize.” And in this particular case, that target was the spike protein in the SARS-CoV-2 virus. Is that accurate?

Stéphane: It sounds correct, Jorge. And the reason that mRNA, in my opinion, is so powerful is that you totally mimic to a human cell the natural biology of an infection without giving the virus at any time. We never give a virus to people — we give, as you said, a piece of the virus. In the case of corona, because it’s a pretty simple virus, we believed — and the clinical data have shown in the Phase 3 that we were correct — that one protein of a virus — a very important one, the spike protein — if you were able to get a high quality of a high quantity of neutralizing antibodies, you should be protecting people if they become infected with the real virus.

Advantages of mRNA vaccines

Hanne: Why is it better to have the cell mimic this natural process than in the old technology?

Stéphane: And that’s a piece that is really unique, because when you think about it, when you get an infection by an mRNA virus in your body, what happens? The virus of mRNA gets in your cell, you use your own cell machinery to make the protein — to basically self replicate inside your cell — and then it escapes your cell. And this is what your immune system sees. And so if you think about it, the old technology of vaccines, where you’re making an E. coli cell or CHO cell — a protein that then you inject in a human, and that just circulates in your blood. That is not mimicking the natural biology. 

In our case, the spike protein — we designed the vaccine, so it’s made inside the cell. So in a human cell, not an E. coli cell, and then we design it to be transmembraning — to stay attached to the cell, and to be presented to the immune system that basically backfalls, you know, in your blood, your body. And we see that thing sticking out of a cell — that is not [itself]. If you think about the 3D configuration of a B cell coming onto that protein, it is exactly like if it was a natural infection — which is why if you look at the data across the nine vaccines we put in the clinic, the antibody level is so high because it’s perfectly mimicking nature.

Hanne: How did you know which protein and that one was enough? How did that process work?

Stéphane: That’s a very good question. And, as Mr. Pasteur would say — and, of course, he has a big role in vaccinology — “only with a prepared mind.” So, one of the things we were doing with Dr. Fauci’s team for the last couple of years, is we [were] collaborating on studying viruses that could become outbreaks. None of us thought we [would] see over our lifetime a global pandemic. The last one we were all aware of as students of infectious disease is, of course, the Spanish flu. And so, one of the things where we got lucky is, we had been working for a few years together with Dr. Fauci’s team as part of that project for outbreak readiness on the MERS vaccine — the Middle East Respiratory Syndrome. 

Which, if I had used those words a year ago, nobody would have known what I was talking about, but today everybody knows it’s another coronavirus. We wanted to provide to them mRNA for research grade — so, animal testing, antigen design, picking the protein that makes sense. Because mRNA is so easy to make once you industrialize it. We were able to send to NIH, to the team working on MERS, all the different vaccine designs they wanted to try in animals. They would vaccinate the animals and then they would challenge them by giving them a high-dose of a virus. The one that was most protective was always the spike protein. They tried a lot of combinations, but spike by itself was always the best.

Jorge: And the theory, I assume, is because you’re essentially putting neutralizing antibodies around the spike and the spike is what the virus uses to get into cells in the first place.

Stéphane: Correct. The full-length spike protein was always the best. Some companies went into a clinic with three, four, five candidates. And there were different hypotheses they were testing. We did not have to do that because we had tried it for a couple of years. We knew that with our mRNA, our best guess was going with the full-length spike protein.

Success of Moderna’s vaccine in trial

Jorge: At a very high-level, you are essentially printing these vaccines versus growing versions of a virus or a denatured virus. So you can design it, you can print it, and then you can, you know, obviously get this into people very quickly as a result. That is a remarkable part of this entire story that is probably somewhat underappreciated, that allowed you, and collectively us, to move so quickly. When did you know, Stéphane, that, all right, this is going to work, this is going to work for COVID?

Stéphane: I had a very high belief that this should work since the beginning, so since January. Because this was the 10th vaccine we were working on. So it’s in the human data of a previous one. And in infectious disease — unlike in oncology, where the animal model tells you nothing — the infectious disease, if you look at a lot of data, there is extremely high translation from animals into humans. I saw MERS data before we started, of course, dosing in humans. So I knew the data in MERS looks great. So because we had done nine vaccines before, I knew it was going to look great in humans, which we learned all of this in May.

Jorge: Can you describe, Stéphane, when you first saw the interim Phase 3 data and what your reaction was?

Stéphane: So, it was a Sunday in November. I knew the independent NIH-led Safety Data Monitoring Board was going to meet at 10 a.m. on Sunday. And so I told my wife and my kids, I’m going to be a wreck the whole morning. I tried to pretend to work, but I was so distracted, I would check my email every two minutes, my phone every two minutes for a text message and so on. Maybe a bit before 1, I got a text from my team saying, “Hey, get on WebEx, we’re going to get the data.” There was not even a slide made. It was just somebody talking, literally reading to us the data.

And so I learned about the close to 95% efficacy. It was already a big N and the p-value was very, very low. Very, very low. So this was real. And the piece that was almost the most exciting to me and my team was the severe case of disease, which there were, I think, eight or nine on the interim data. We have now 30 on the final analysis. And there were zero on the vaccine — they were all on placebo. And you think about what this means, when you connect those two data sets together, it means if you get our vaccine, you have a 95% chance of having zero symptoms if you get infected by the virus. You will not even know you are sick, you’ll just go live your normal life, zero symptoms. And in the 5% case, where you will get disease, it will be mild disease. You will get no severe disease. 

And when you think about what has happened to our society — the elderly, people with high comorbidity, from hospitalization, when it gets bad [it] leads to death, and the total impact on the economy, the loss of jobs in so many industries, and so on — that whole cascade. If you could have a vaccine where most people, 95% get no symptoms, and the 5% who do get mild symptoms — never go and walk into a hospital — that will be a total game changer. So I listened to the data, then we talked to my team [for] a few minutes. No, I don’t think we were processing — and then I left my home office and I called my wife, she was in the house. And I told her, and I just started crying in the house.

Hanne: I think that’s what it felt like for all of us hearing it too. It felt like, you know, normal life could return. It was the promise of something like that.

Stéphane: We are losing, right now, 3,000 people in this country — I think it’s more than 10,000 people a day around the world. And it’s going to be a very tough winter. And that’s only the human toll, which is gigantic, but the piece I don’t think is talked about enough is the mental health toll happening to, you know, people at every age. All the young in, especially, you know, more disfavored communities where, you know, people are living in the small apartment, where Mom is trying to work. And kids trying — without a computer, without a good internet line, to learn remotely — the impact this will have in terms of equality. 

And then, of course, so many industries have been totally destroyed. I mean, look, they are closing indoor dining again, which I think is the right thing to do. Because I think the most dangerous thing right now is to have dinner indoors. I have not walked into a restaurant indoors since March, and I won’t go until I’m vaccinated.

Rapid manufacturing process

Jorge: So, as amazing as I think the COVID vaccine story is, I think it’s also worth talking about the machine that made the vaccine — the technology platform that you have built over the course of 10 years that allowed you, in January of 2020, to say like, “Hey, we need to develop a COVID vaccine.” I remember coming to visit Moderna on Kendall Square, that first facility you had. And what was interesting about it is you walked in, it didn’t look like your typical biotech company. It was a row of machines, a row of printers, a row of robots. And that’s very different than what your traditional biotech company looks like. And it looked a lot more like an assembly line, in some ways. Where you can order something up and out the other end would come the mRNA medicine that you had ordered.

Stéphane: Yes, and this goes back to this incredible property of mRNA, which I’m surprised that so many have missed — is that this is a disease and information-carrying molecule that you can industrialize. When you are in an analog business — which is what I think all pharma and all biotech is, in my book — it’s because every molecule is a different chemical entity, you cannot industrialize the making of a lot of it at the research grade. You have to literally have chemists, and pipettes, and so on. You know, doing like we all did in chemistry class, writing the synthetic route to get to a molecule that they want to do the biological effect they want. 

And then they have to design that chemical equation, and then all the pipettes and test tubes to do that. And when it’s another molecule, they have to invent another synthetic route. So it’s very — an analog world where you invent everything once at a time for one product. Because if every product is different, you have to re-optimize every time, and sometimes it’s very complicated because of very complex biological systems. So sometimes it will take you 6 months, 12 months, 18 months to get ready from preclinical data to be making clinical grade product that you need to file to FDA so that they give you the green light to go into testing this in humans. It’s highly regulated — as it should be processed to protect people’s safety. But in our case, it’s always the same thing, because mRNA is always made of [the] four same letters — the four letters of life, like zeros and ones in software. It’s the same manufacturing process. 

This is like software or LEGO, this is an engineering problem. It’s an engineering technology, it’s a platform. The only difference between all Zika vaccines, or all CMV vaccines, and the COVID vaccine — it’s only the order of the letter; the zeroes and ones  of life. The manufacturing process is the same, the equipment is the same, with the same operators. It’s the same thing. And so this is why we could go so fast. It took us 60 days to go from a sequence of a virus presented by the Chinese to dosing a human. The first SARS — SARS-CoV-, or as it was known before SARS — it took the NIH 20 months <Mmhmm.> to go from sequence to starting the Phase 1 study. So, you went from 20 months to 2 months.

Possible future uses for mRNA drugs

Jorge: Which is remarkable. Are we in the plug-and-play future for vaccines?

Stéphane: Oh, 100%. We’re going after making a seasonal flu vaccine — because, as we all know, still 10,000 Americans die every year, on average, of seasonal flu. We believe that we should be able to make a big dent [on] flu. And today we have six vaccines in development. We’re going to have many more soon, because for 10 years, you know, Jorge, we hoped that mRNA vaccines were going to work. We believed scientifically they were going to work — but until you have a Phase 3, randomized, placebo-controlled study where you test for the prevention of disease, you don’t know. Now we know.

Hanne: Are there limits right now to how sophisticated these instructions can get, or can we essentially give them as sophisticated instructions as the human body is capable of?

Stéphane: It’s — when the mechanism of a disease is not well understood. So we spoke about vaccines, and we said, “Look, coronavirus,” as I said, “is actually a simple virus.” We, as a society, got lucky. Think about HIV. HIV [was] discovered 40 years ago. There is still to this day no approved vaccine against HIV. Think about the awful world we would be in right now if Dr. Fauci had been standing on the presidential podium back in spring, and told them, “Folks, I’m sorry to tell you, but this is an awfully complex virus. We have no idea when we might have a vaccine.” Think about the state of mind we would all be in now. The biology of viral genetic disease is very well understood. Why? Because kids got two biogenetic information from their parents that they cannot make a correct protein, and that is what causes their disease. They have a wrong instruction in their DNA. 

You can give them an mRNA from our technology, coming in their cells with the right instructions — then they will have the right protein and they won’t get sick. If you think about cancer, on the other hand of the spectrum, or Alzheimer’s now, if the disease mechanism is not understood, we cannot drug it easily. We can try things, of course. We could make an mRNA behind that hypothesis, go try it in a clinic — but a lot of things will fail because we are guessing. And so the piece where I think we have an incredible tailwind — basically overlaps doing academic biology work around the world are helping us. Because if tomorrow there is a paper published by our lab in the U.S., or in China, or anywhere in the world that says protein X, Y, Z is the root cause of that disease, or those five proteins in this ratio are the root cause of that disease, then we can literally turn on the computer and, you know, design a drug to go test that hypothesis in an animal.

Jorge: Basically, the power of this approach works when you know what you want to make and then you just need to deliver the instructions to make that. Where it doesn’t work as well is when you’re not quite sure what it is that you need to make.

Stéphane: This is basically biology complexity or biology risk. The other dimension for us is the ability to deliver the mRNA in the right cell. We actually have become a “delivery of nucleic acid” company. We realized that what would allow us to maximize the impact we could have on disease, or helping as many people as we can over the next 5, 10, 20 years, is the ability to bring up mRNA to different cell types. So a good example today is, if you say, look, there is this university that published the mechanism of Alzheimer’s disease. If it happens in the brain and we don’t know how to bring mRNA [to] the brain safely, we cannot drug it. So the biology will be understood, but the delivery technology will not be there.

An example where we’re making a lot of progress right now is the lung. <Mmhmm.> We have been working with Vertex around how to deliver mRNA via an aerosol via your mouth into your lung, because they know the biology very well. And we work together to develop a delivery system to bring mRNA safely into your lungs, and to bring enough mRNA at a safe dose to get the biological effect. And we’re getting very close now. Once we can prove in the clinic that that delivery system works, then the next morning you can make any other drug you want that you need to get into the lung, because it’s getting another set of zeros and ones coded differently, with the same delivery system into the lung. And that’s the power of the technology — which is why with vaccines we’re able to go so fast.

Jorge: Yeah, the instructions have gotten so sophisticated over time that now the next sort of horizon is, you’ve got to get the vehicle for delivery equally sophisticated.

Stéphane: We’re adding vertical, after vertical, after vertical — then we bring mRNA into a new cell type. So the vaccine is one vertical. Getting mRNA into a tumor is another vertical. We have a very cool drug, where we inject mRNA in people’s hearts after a heart attack — and here we code for a protein called VEGF, for the biology geeks on the podcast, V-E-G-F. That is a protein that we all have the instruction in our DNA, which basically tells your body to make a new blood vessel.

Hanne: Amazing.

Stéphane: You use that protein every time you cut yourself.

Using robotics to manufacture drugs

Hanne: Stéphane, you’ve mentioned, you know, kind of the fast design of the vaccine, and then you mentioned even robots printing medicines. Can we get your version of what that machine assembly line looks like?

Stéphane: So, the robotics farm we have in our factory is basically just an assembly of robots that get instruction coming directly from computers. There’s no human interaction. And basically, you start from a piece of DNA. That is basically your template. You put that in a reactor with water. There is no cell — it’s a cell-free manufacturing process, which is why it’s so fast. And you put enzymes. And basically, what the enzymes do, they attach to the DNA, and they read the DNA template. And they quickly tell pieces of nucleic acid — i.e, the zeros and ones, the four letters of life — they bind them next to each other to make an mRNA molecule. Then the robot goes to the next step, which is you add a cap. 

Think about it like the nose of a molecule, that you add again with another enzyme. Then what you do, you purify the mRNA. So basically, you pick the mRNA from all that water, enzyme, and nucleotide, nucleic acid, and so on. And then when you have a pure mRNA molecule, after purification, you mix it with a lipid, i.e, fat. And that fat basically goes around and packages, like in a little bowl, the mRNA to protect the mRNA in your blood, and to get the mRNA inside your cells. When it’s inside your cells, the lipid — the fat — falls apart, the mRNA is released inside the cell, and the little ribosome — the little 3D printer of your cell — is going to read that message, make the protein on demand, and here you go — the patient, the human is making his or her own medicine.

Jorge: I remember from the earliest days you were obsessed with the operations. You were obsessed with turnaround time, with throughput, with, you know, cost per output. And the benefit of that approach is that it obviously just compounded over time. The benefit of the technology, as you’re describing it, is that you have a machine that prints the instructions that go into the cell — that uses the cell’s machine to make the medicine, or to make the vaccine. And that’s this incredibly powerful paradigm, you know, to taking therapeutics or vaccines from being very bespoke efforts to being truly industrialized, designed efforts.

Stéphane: That’s what is really so powerful is that the whole drug process is all about information. The piece that is remarkable is you have this very modular technology, because what happens in our cells is actually extremely logical. We start from the sequence information of a virus, like in the case of a COVID vaccine, or we use the human genome. We put [it] into a technology genetic-based cassette, and then you click “order” on the computer and you go again. And that’s the vision I always had since day one. And a lot even of my scientists thought I was crazy, because this industrialized, engineer-driven approach to drug discovery has never happened [before].

Hanne: So, Stéphane, you’ve described this process which is, you know, much more efficient, industrialized in nature, incredibly fast compared to the old process. Is there a world in which that gets even faster? Are there other things — you know, other increases in technology that would speed this up even more?

Stéphane: Yes, so it took us 42 days to go from sequence to shipping the human grade vials to Dr. Fauci’s team. The big bottleneck is sterility testing — a very important quality control test that is done for any injectable pharmaceutical to make sure that there’s no bacteria in the product. That test takes two weeks, because what basically you do, you take a sample of your vaccine and you wait enough time. If there’s only one copy of a bacteria, by that time you have enough multiplication of bacteria, through the detection of the assay of a test that you will see it, you will not miss it. It’s very important for people’s safety. Well, if there was a technology developed where you could do sterility testing in one day with high sensitivity, then you could take our process down to two weeks.

The history of Moderna and its approach

Jorge: So, we’ve talked about the vaccine. We’ve talked about the machine that made the vaccine. I’d love to take a second to talk about the company that built the machine. So from the moment that you started this company, you took a very different approach. And you’ve described it as having an engineer’s mindset. Can you talk a little bit about what you did, and how you thought about the early company build?

Stéphane: I had never built a company in hypergrowth. You know, I worked at Eli Lilly, I ran bioMérieux, which is a big diagnostic company. But I have never built myself a company building very, very quickly. We decided to do something very atypical, because most biotech companies are one-drug company at a time. What was very clear to us, because mRNA is an information molecule, is it made no scientific sense that this will be a one-drug company. It will be either zero, because we run out of money before we can safely get the drug approved, or it’ll be a company with thousands and thousands and thousands of drugs because of the platform.

And so, once we realized that, in the first hours of talking about Moderna, we started to become very worried and paranoid about, “Geez, we don’t know what we don’t know about this technology because it’s new. It has never been approved.” And, “Geez, if we pick one drug, if we are wrong and it doesn’t work in the clinic, everybody will believe what people have believed for 50-plus years” — which is, mRNA will never be a drug. And we most probably are going to go bankrupt. But if mRNA could’ve worked, we will have failed society. Because if we find a way to make this work, this will [mean] thousands and thousands of drugs that are undoable using existing technology — like the VEGF in hearts — and we will shortchange societies, shortchange patients. And that was just unbearable.

And so we spent a lot of time thinking about, okay, what are all the things that could make us fail? We ended up zooming [in] on four risks that we say — if we can manage and reduce those risks, we will have [the]  best chance to be the best version of Moderna. Those risks — we’ve talked about very publicly, especially when we went public. It’s technology risk around the mRNA technology. So, of course, if you do a new technology you don’t know what you don’t know. There’s going to be a lot of risk there of things not working as you expect. Two is the biology risk. You can have incredible risk that your scientific hypothesis on the biology is incorrect and the drug will fail — not because the technology wasn’t working, but because the scientific hypothesis on the biology is incorrect. Then there was going to be a lot of execution risk. And then, of course, financing risk. Because we said, like, you know, asset managers build a portfolio — we said “Picking one drug is crazy, it’s like buying only one stock.” And so we said, “Let’s build a full portfolio of drugs.”

And after many, many months of discussion, we designed basically a pipeline of 20 drugs that we said we’re going to take all those drugs in parallel to the clinic, so there would not be a binary event that the company makes it or not on one drug. So we diversified the technology risk around six different technology applications, from vaccines, to [a] drug in the heart, to a drug in the liver for a genetic disease. And then for every application, we took several drugs to diversify the biology risk. And we launched that crazy experiment with, you know, 17 drugs in the clinic so far — which was going to create incredible execution risk because it’s harder to do 17 at the same time than 1. And incredible financing risk because we needed a lot of capital. But we traded those risks with our eyes wide open, because the other risk could kill us with much higher probability — the technology and the biology risk.

Jorge: It’s very difficult in this industry to take that balance, platform versus programs. And, you know, what tends to be the case very quickly is most companies when they have to choose where to put an incremental dollar, or an incremental head, they put it on the programs because those are the golden eggs and they want to move those forwards to create value inflection. And as a result, the platform ends up getting starved. <Yes.> You started the other way around. You actually fed the platform, and you fed the goose, and then let the goose lay its eggs.

Stéphane: Yeah, exactly. The goose is more valuable than any egg. If you really believe you have a goose that’s going to be making thousands and thousands and thousands of eggs, you don’t want to kill the goose on the first or second egg.

Jorge: Although most geese are not that fertile in biotech. Yours… <crosstalk, laughter>

Stéphane: And that’s why I told you both that I was not interested [in going] public early because the capital markets were going to force me to not invest in the goose. Because biotech firms like to bet on eggs, not on [the] goose, because there has not been a lot of geese before in this industry. So we’re not used to it.

Jorge: I mean the record will show that you did a lot of things right. As you built the company over the last 10 years, can you talk a little bit about the things you did wrong, that if you could get them back you would do it over?

Stéphane: Well, [the] easiest one, given the COVID situation is — it took us three years to start working on vaccines. So think about how the world would be different and Moderna would be different if we started working on vaccines from day one. We might have been able to go even faster for COVID. So that’s a thing I regret, and that’s on me. I made quite a lot of mistakes hiring people, because I underestimated how intense our company is because I live it every day. I thought initially that it was obvious that this is a small company fighting for its life, so people are going to work hard. It’s brand-new, cutting-edge science, so it’s going to be complicated because every other thing is not going to work. 

So, being able to manage uncertainty — people having a lot of grit. Collaboration, because making a drug is a team sport. A drug is a system of so many capabilities — the biologists, the [toxicology] people, the chemists, the engineers to make the drug. And a lot of times, people coming from big pharma are used to working in silos. And people who come from academia don’t know how to develop drugs. It’s a system. And like any system, you get the best outcome if you really optimize the system working together.

Jorge: So, last question I would ask you — what advice would you give to the engineer that wants to get into biotech?

Stéphane: So, first he needs to learn a bit about biology. I mean, I had a chance, as I spent my entire career in biology, so I’ve learned a lot on the go — I’ve learned a lot by reading. I’m a curious guy, so I read a lot. You can get biology books and learn. And I think it’s understanding enough of biology so that you can be part of a conversation, so that you can have an impact on decisions and scientific choices that happen. And then you can go from there.

Hanne: That’s wonderful. Thank you so much for joining us on “Bio Eats World,” Stéphane. We’re so grateful for your time.

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