Pod Insights a16z Podcast The Machine That Made the Vaccine: Company, Platform, Innovation About this episode Moderna CEO Stephane Bancel tells the story of not just the vaccine’s development, but the machine that made the vaccine: the platform, the technology, and the moves behind the vaccine’s development. Aired on Bio Eats World right after FDA EUA.
Transcript Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.
0:00 Sonal? Hi, everyone. I'm sharing our most recent BioEats World episode here because it covers the topic of vaccines, a theme we've covered here since January of this year in our early and ongoing pandemic coverage as part of our mission to continue bringing you everything you need to know about this crisis, as well as how tech changes our future. You can find our past coverage, including early discussions of plug and play vaccines, to breaking news and what we still need to know, to how vaccines in general are made and what was done process-wise to accelerate development, as well as the politics of who gets it first, at a16z.com/vaccines. But in the discussion that follows, our BioEats World show, be sure to subscribe if you haven't already, interviews the
0:43 Sonal? Moderna CEO, which aired right after the FDA authorized their vaccine for emergency use. And it goes into the machine that made the vaccine, including the machine inside the company and the platform itself. More details in the intro that follows.
0:59 Speaker 01 Hi, I'm Lauren.
1:00 Hanne Tidnam? And I'm Hannah, and this is BioEats World, our show where we talk about all the ways biology is technology.
1:07 Speaker 01 This week, in place of Journal Club, we have a very special episode featuring Stephane Bancel, CEO of Moderna, in conversation with you, Hannah, and A16Z general partner Jorge Conde. And we're talking about the COVID-19 vaccine, right?
1:21 Hanne Tidnam? 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, Stephane 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.
2:03 Speaker 01 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.
2:21 Hanne Tidnam? 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?
2:42 Speaker 03 Stefan, sitting here now in December of 2020, could you have imagined a year ago that mRNA as a concept would be a household name?
2:52 Speaker 04 No, and we had a lot of things going on in vaccines, in cancer, in autoimmune disease, in cardiology, in regenerative disease, but I had no idea that 2020 was going to look that way.
3:06 Speaker 03 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?
3:22 Speaker 04 Yes, so I've been working in infectious disease 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 phenomena like symptoms. That's all it says.
3:55 Speaker 04 And so I sent an email to somebody working for Tony Fauci, Barney Graham, who we have been collaborating with for years, designing several vaccines together. And I say, Barney, have you seen the new pathogen in China? What is it? Is it the bacteria? 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 say, 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.
4:41 Speaker 04 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 note after around 48 hours, they had designed exactly the same vaccine.
5:00 Speaker 03 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 of genomic sequencing technology. But the other remarkable advancement in technology here is that, for 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?
5:28 Speaker 04 So you're right, Rory, and this is a piece that I think most people in pharma don't appreciate yet, the power of our modern technology is, in 48 hours, we designed and locked down the entire chemical structure of a vaccine.
5:44 Hanne Tidnam? Unbelievable.
5:46 Speaker 04 And we click order on the computer. So it all happened in silicon. We never had access to a physical virus. And we designed the vaccine. And we had 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.
6:01 Speaker 03 Of course.
6:02 Speaker 04 So we're super happy when the team literally compared note after two days and 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 one. And that's the piece 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.
6:34 Hanne Tidnam? So it's the same vaccine that took 48 hours to design.
6:38 Speaker 04 That's going to help hundreds of millions of people next year.
6:41 Hanne Tidnam? 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?
6:54 Speaker 04 Right, yes, 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 will 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, chocolate mousse,
7:35 Speaker 04 if you go with your grandma's precious book into the kitchen, you're going to damage the 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 have a cell, to make through a little machine called the ribosome, that I describe as my kid, as a little 3D printer, that reads the message, read the instruction of mRNA,
8:19 Speaker 04 and makes a protein by adding one amino acid at a time. So it's a natural molecule that basically carries genetic information to make proteins.
8:28 Hanne Tidnam? 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?
8:41 Speaker 04 Yes, 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 will have flu-like symptoms, a fever, vomiting, diarrhea.
9:21 Speaker 04 Because mRNA, if we remember, most viruses in life, including COVID-19, is made of mRNA. And so through evolution, mammals have developed mechanisms to recognize foreign mRNA. And of course, when you inject mRNA as an ID for a drug, that would be a foreign mRNA. And so actually, people abandon 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's been some new discoveries made in the immune system. They believed at the time that if you modify uridine,
10:06 Speaker 04 which is one of the four letters of mRNA, you can make an mRNA that's immunosilent.
10:12 Speaker 03 In some ways, when you think about it, Moderna doesn't make therapies. You make instructions that the cell uses to make its own therapies.
10:21 Speaker 04 Yeah, correct. We don't give you a vaccine. We give you an instruction for the sales 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 multiplying in their body and getting them sick. What gets people sick in infectious disease is you have too many copies of a virus.
10:57 Speaker 03 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 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?
11:34 Speaker 04 That's 100% correct, Roy. 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 we said, a piece of a virus. In the case of Corona, because it's a pretty simple virus, we believed, and the clinical data have shown in the phase three 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 a real virus.
12:15 Hanne Tidnam? Why is it better to have the cell mimic this natural process than in the old technology?
12:20 Speaker 04 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. So if you think about it, the old technology of vaccine, where you make in an E. coli cell or a true 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 in an E. coli cell, and then we designed it to be transmembrane,
13:05 Speaker 04 meaning to stay attached to the cell and to be presented to the immune system that basically patrols, you know, in your blood, your body, and we'll see that thing sticking out of a cell that is not self. 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 vaccine we put in the clinic, the antibody level is so high because it's perfectly mimicking nature.
13:35 Hanne Tidnam? How did you know which protein and that one was enough? How did that process work?
13:41 Speaker 04 That's a very good question. And as Mr. Pasteur would say, and of course he has a big role in immunology, only the prepared mind. So one of the things we were doing with Dr. Fauci's team for the last couple of years is we are collaborating on studying viruses that could become outbreaks. None of us thought we will see over a lifetime a global pandemic. The last one we are all aware of, a student 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,
14:24 Speaker 04 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 will vaccinate the animals and then they will challenge them by giving them, you know, high dose of a virus. The one that was the most protective was always a spike protein. They tried a lot of combination, but spike by itself was always the best.
15:08 Speaker 03 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?
15:16 Speaker 04 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 didn't have to do that because we had tried it for a couple of years. We knew that with Imani, our best guess was going after full length spike protein.
15:39 Speaker 03 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, Stefan, that, all right, this is going to work? This is going to work for COVID?
16:11 Speaker 04 I had a very high beliefs that this should work since the beginning. So since January, because this was the 10th vaccine we were working on. So I'd seen the human data of a previous one. And infectious disease, unlike in oncology where the animal model tells you nothing, infectious disease, if you look at a lot of data, there's extremely high translation from animals into humans. I saw mouse data before we started, of course, dosing in human. So I knew the data in mice looks great. So because we had done nine vaccines before, I know it was going to look great in human, which we learned all of us in May.
16:52 Speaker 03 Can you describe, Stefan, when you first saw the interim phase three data and what your reaction was?
16:58 Speaker 04 So it was a Sunday in November. I knew the independent NIH-led safety data monitoring board was going to meet at 10:00 AM on Sunday. And so I told my wife and my kids, I'm going to be awake the one 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 one. I got a text from my team saying, hey, get on a WebEx, we're going to get the data. There was not even a slide made. It was just somebody talking and 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.
17:43 Speaker 04 So this was real. And the piece that was 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 was 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 a vaccine, you have a 95% chance of having zero symptom if you get infected by the virus. You will not even know you are sick. You just go live your normal life, zero symptom. And in the 5% case where you will get disease, you will be mild disease. You will get no severe disease. And when you think about what has happened to our society, the elderly, people who have
18:28 Speaker 04 comorbidity from hospitalization, when it gets back, 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 would be a total game changer. So I listened to the data and we talked to my team a few minutes. 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.
19:03 Hanne Tidnam? 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.
19:12 Speaker 04 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 people at every age, all the young in especially, you know, more disadvantaged communities, where, you know, people are living in a small apartment, where mommy is trying to work, and kids trying without a computer, without a good internet line to learn remotely.
19:44 Speaker 04 The impact this will going to have in terms of equality. And then, of course, so many industries have been totally destroyed. I mean, look, they are closing, you know, 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 indoor. I've not walked into a restaurant indoor since March, and I won't go until I'm vaccinated.
20:04 Speaker 03 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 2020 to say like, hey, we need to develop a COVID vaccine. I remember coming to visit Moderna and Kendall Square, that first facility you had. And what was interesting about it is when 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,
20:44 Speaker 03 where you can order something up and out the other end would come the mRNA medicine that you had ordered.
20:50 Speaker 04 Yes, and this goes back to this incredible property of mRNA, which I'm surprised that so many have missed, is that this is an information-carrying molecule that you can industrialize. When you are in an analog business, which is what I think old pharma and old biotech is in my book, is 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 in pipettes and so on, you know, doing like we all did in chemistry class, you know, 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,
21:35 Speaker 04 and then all the pipette and test tubes to do that. And when it's another molecule, they have to invent another synthetic route. So it's really 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 a very complex biological system. So sometimes it will take you six months, 12 months, 18 months to get ready from pre-clinical 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 a highly regulated, as it should be, process to protect people's safety. But in our case, it's always the same thing.
22:21 Speaker 04 Because mRNA is always made of 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 Legos. This is an engineering problem. It's an engineering technology. It's a platform. The only difference between all Zika vaccine or CMV vaccine and the COVID vaccine, it's only the order of a letter, the zeros 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 caused only by the Chinese to dosing a human. The first SARS, SARS-CoV-1, or as it was known before SARS,
23:06 Speaker 04 it took the NIH 20 months to go from sequence to starting a phase one study. So you went from 20 months to two months.
23:15 Speaker 03 Which is remarkable. Are we in the plug-and-play future for vaccines?
23:20 Speaker 04 Oh, 100%. We're going after making a seasonal flu vaccine. Because as we all know, still, you know, 10,000 Americans die every year on average of seasonal flu. We believe that we should be able to make a big debt on to flu. And today, we know we have six vaccines in development. We're gonna have many more soon. Because for 10 years, you know, we hoped that mRNA vaccines were gonna work. We believe scientifically they are going to work, but until you have a phase three randomized placebo-controlled study, where you test really prevention of disease, you don't know. Now we know.
23:59 Hanne Tidnam? Are there limits right now to how sophisticated these instructions can get? Or can we essentially give them as sophisticated instructions as, you know, the human body is capable of?
24:10 Speaker 04 It's when the mechanism of a disease is not well understood. So we spoke about vaccine and we said, look, coronavirus, as I said, is actually a simple virus. We, as a society, got lucky. Think about HIV. HIV has been discovered 40 years ago. There is still, to this day, no approved vaccine against HIV. But think about the awful world we will be in right now. If Dr. Fauci had to be standing on the presidential podium back in the 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 will all be in now. The biology of rare genetic disease is very well understood. Why?
24:54 Speaker 04 Because kids got too bad genetic information from their parents that they cannot make a correct protein. And that is what caused their disease. They have a wrong instruction in their DNA. If you can get them an mRNA from our technology coming in their cells with the right instruction, then they will have the right protein and they won't get sick. If you think about cancer, on the other hand of a spectrum, or Alzheimer 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 the clinic. But a lot of things will fail because you are guessing. And so the piece where I think we have incredible tailwind,
25:38 Speaker 04 basically overlaps doing academic biology work around the world, are helping us. Because if tomorrow there is a paper published by a lab in the US or in China or anywhere in the world. That says protein XYZ 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 in an hour, design a drug to go test that hypothesis in an animal.
26:07 Speaker 03 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.
26:20 Speaker 04 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 realize 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 five, 10, 20 years is the ability to bring mRNA to different cell type. 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 in the brain safely,
27:03 Speaker 04 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. 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 to save those to get the biological effect. And we're getting very close now. Once we can prove in the clinic that that delivery system work, then the next morning you can make any other drug you want that you need to get into the lung.
27:47 Speaker 04 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 a technology, which is why with vaccines, we're able to go so fast.
27:58 Speaker 03 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.
28:07 Speaker 04 We're adding vertical after vertical after vertical. They bring mRNA into a new cell type. So a 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 heart after a heart attack. And here we code for a protein called VEGF, for Biologic Geek on the podcast, V E G F. That is a protein that we all have instruction in our DNA, which basically tells your body to make a new blood vessel.
28:38 Hanne Tidnam? Amazing.
28:39 Speaker 04 You use that protein every time you cut yourself.
28:41 Hanne Tidnam? Stefan, 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?
28:55 Speaker 04 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 put little pieces of nucleic acid, either 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.
29:41 Speaker 04 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 packaged like in a little ball, 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 foodie 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.
30:24 Speaker 03 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 has 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.
31:07 Speaker 04 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 happened in our cells is actually extremely logical. We start from the sequence information of a virus, like in the case of our COVID vaccine. Or we use the human genome we put into a technology genetic-based cassette.
31:32 Speaker 04 And then you click the order on the computer and you go again. And that's the vision I always had since the day one. And a lot even of my scientists at the beginning thought I was crazy. Because this industrialized, engineer-driven approach to drug discovery has never happened.
31:49 Hanne Tidnam? So Stefan, 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, other, you know, increases in technology that would speed this up even more?
32:08 Speaker 04 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 is no bacteria in the product. That test takes two weeks because basically you do, you take a sample of your vaccine and you wait enough time. If there is only one copy of bacteria, by the time you have enough multiplication of bacteria to the detection of the assay of a test, that you will see it, I 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
32:52 Speaker 04 with high sensitivity, then you could take our process down to two weeks.
32:59 Speaker 03 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?
33:22 Speaker 04 I had never built a company in hypergrowth. You know, I worked at Ilaly, I run Biomeario, which is a big diagnostic company. But I had 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 would be either zero, because we run out of money before we can safely get a drug approved, or it would be a company with dozens and dozens and dozens of drugs because of a platform. And so, once we realized that in the first hours of talking about Moderna,
34:06 Speaker 04 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 fifty plus years, which is mRNA will never be a drug. And we most probably are going to go bankrupt. But if mRNA could have worked, we will have failed society. Because if we find a way to make this work, this would be dozens and dozens of drugs that are undoable using existing technology like the VJF in the heart. And we will shortchange society, shortchange patients. And that was just unbearable. And so, we spent a lot of time thinking about, okay,
34:49 Speaker 04 what are all the things that could make us fail? We ended up zooming on four risks. That we say if we can manage and reduce those risks, we will have a 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, the biology risk. You're going to 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.
35:34 Speaker 04 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 say, let's build a portfolio of drugs. And after many, many months of discussion, we designed basically a pipeline of twenty drugs that we said we're going to take all those drugs in parallel to the clinic. So, there will not be a binary event that the company makes it or not on one drug. So, we diversified technology risk around six different technology application. From vaccine to 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.
36:15 Speaker 04 And we launched a crazy experiment with, you know, seventeen drugs in the clinic so far, which was going to create incredible execution risk because it's harder to do seventeen at the same time than one. And incredible financing risk because you need a lot of capital. But we traded those risks with our eyes wide open.
36:35 Speaker 04 Because the other risk could kill us with much higher probability, the technology and the biology risk.
36:40 Speaker 03 It's very difficult in this industry to take that balance on 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 forward to create value inflection. And as a result, the platform ends up getting starved.
37:03 Speaker 04 Yes.
37:04 Speaker 03 You started the other way around. You actually fed the platform and you fed the goose and then let the goose lay its eggs.
37:10 Speaker 04 Yeah, exactly. The goose is morally evolved 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.
37:19 Speaker 03 Although most geese are not that fertile in biotech.
37:21 Speaker 04 You're a great goose. And that's why I told the board that I was not interested to go public early because the capital markets were going to force me to not invest in a goose.
37:30 Speaker 03 Right.
37:31 Speaker 04 Because biotech funds like to bet on eggs, not on goose, because there's not been a lot of geese before in this industry. So we're not used to it.
37:40 Speaker 03 I mean, the record will show that you did a lot of things right. As you've built the company over the last ten 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.
37:50 Speaker 04 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 what I would be different. If we started working on vaccine from day one, we might have been able to go even faster for COVID. So that's the 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.
38:34 Speaker 04 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, a biologist, the tox people, the chemist, the engineers to make the drug. And a lot of time, people coming from Big Pharma are used to work 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.
39:05 Speaker 03 So last question I would ask you, what advice would you give to the engineer that wants to get into biotech?
39:11 Speaker 04 So first, you need to learn a bit about biology. I mean, I have a chance that 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 he's understanding enough of biology so that you can be part of a conversation, so that you can, you know, have an impact on decisions and scientific choices that happen, and then you can go from there.
39:35 Hanne Tidnam? That's wonderful. Thank you so much for joining us on BioEats World. Stefan, we're so grateful for your time. Thanks so much for joining us on BioEats World. If you'd like to hear more about all the ways biology is technology, please go subscribe to the A16Z Bio Newsletter at A16Z.com/newsletter. And of course, subscribe to BioEats World anywhere you listen to podcasts.
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