Q&A with Jason Park on Sourcing Drugs from the Human Body

Liz Pavone: Hello, I'm Liz Pavone, manager of content and science communications at Flagship. I'll be talking with Jason Park, Flagship operating partner and Empress founding CEO to learn more about Jason and Flagship-founded Empress Therapeutics. Welcome, Jason. Can you tell us a little bit more about yourself and your role here at Flagship?

Jason Park: Hi, Liz, thank you for having me on. So I'm the CEO of Empress Therapeutics, and I'm an operating partner here at Flagship Pioneering, where over the last eight years, I've been helping conceive, build, and launch a number of companies.

Liz Pavone: Thanks, Jason, it's great to have you here. Let's kick this off by learning a little bit more about Empress. I understand that Empress is looking for drugs inside the human body. What does that mean?

Jason Park: Yeah, so, Liz, I saw this article in The Economist just the other day, and one of our companies, our sister companies, Indigo Agriculture, was featured in it. And it was talking about this concept that they called the holobiont, which is this idea that if you look at an organism like the human body, there's 60 trillion, over 60 trillion cells that comprise us. And here's the surprising part: only about 30 trillion of those are what we would have considered human. And so, it turns out there are all these cells, all these organisms, and they came together through evolution, through coevolution they're conserved. And the idea here is that there is chemistry produced by those cells. They may be human cells, maybe bacterial cells or other sources that we think are really important to human physiology and represent an untapped source of really privileged starting points for making great medicines.

Liz Pavone: So you're saying that we have drugs floating around our bodies, and we maybe know of some of them, but not all of them?

Jason Park: So let me give you a couple of examples of this, or a couple things to, a couple of flagpoles to help better understand. One is, let's start with biologic medicines, which you probably know of and you've heard of, you've read of, and we tend to think of those as proteins, as DNA or RNA, or even cells themselves as a basis for making medicines. Well, it started with the realization that you had these molecules inside the body that played a really important role in health or disease. For example, EPO and insulin. One of the ways we figured it out was if you're missing those compounds, those molecules from inside your body, you get a certain type of disease. And the other insight that might be helpful is that if you think about chemistry, small molecules, it turns out that something like 70% of the chemical drugs that we think of, and these are things that most people tend to think of as medicines. When you say medicine, someone often pictures a pill. Well, most cases that's actually chemistry inside that pill, 70% of those were found out in nature. They were made by a plant or a fungus or a microbe somewhere. And we either took those compounds, that chemistry out of the environment or used it as a starting point for designing better chemistry to turn into medicines. And so take those two ideas that there are bioactive molecules that are ultimately encoded in genes, DNA, RNA, proteins, and then you've got chemistry that make for great drugs. Nobody, to our knowledge, had combined those two insights to look for chemistry made by these cells inside of us, whether it's human cells or bacterial cells, using genetics to find that chemistry.

Liz Pavone: So when you say using genetics, I understand that biologics are proteins, for example, are coded in our DNA. How is that similar to these small molecules?

Jason Park: It's a great question, Liz. The central dogma obviously goes from DNA to RNA to proteins. Well, it turns out that a number of really important chemistries are actually made by proteins, and they're made by specific proteins called biosynthetic enzymes. And what do enzymes do? They take a substrate and they make a chemical change to it, and they hand it off to perhaps another enzyme, which makes a different chemical change to that same compound. So all of a sudden, what you can do is you can go from DNA to RNA to proteins now to specific small molecules or chemical compounds made by certain proteins. It's sort of like an extension of the central dogma. And that is the core insight behind Empress that it's now possible to look at genetic data from a patient. And again, that genetic data can come from the human cells, it can come from the bacterial cells, and can really come from anywhere, ultimately, because it's just about biosynthetic DNA. You can look at that biosynthetic DNA, read it like a language, read it like an instruction booklet or a program, if you will, for producing specific chemistry. And that's what we do.

Liz Pavone: And so how are you doing that? This Chemilogics™ platform, how does it work and how is it accelerating small molecule drug development?

Jason Park: To put it in context, in the traditional or conventional way of small molecule drug discovery, what we do is we often start with a target. We say, here's a target, it's got genetic evidence, it looks like it's important in disease X, and let's try and make a chemical compound to drug that target. And one of the things that makes it such a long, unpredictable, and frankly haphazard process is that we don't know what the chemistry should behave like, we don't know what the properties are. And what do I mean by that? Well, to make a medicine, you need certain properties: You need it to be potent, you need it to be selective. That is a basis for thinking about how to think about efficacy and safety windows when you actually ultimately go into humans. And so what Empress does is it actually flips that equation. We say there must be chemistry if it's encoded in genetics, there must be chemistry that has a genetic association. The same way that we've long thought about biology having genetic associations, maybe there's chemistry that has a genetic association. And why is that powerful? Well, we know that genetics is a really powerful tool for focusing on what's important. And because of this concept of the holobiont, the idea that there are these cells that are conserved that coevolved with us, we also get the added benefit of knowing that the chemistry we're looking at was conserved through evolution, which is another powerful clue for telling you that something's really important. So we use those concepts to very quickly generate chemistry. It only takes us months. And then what we do is we prioritize the chemistry that already looks like drugs, that already looks potent, that already looks selective, that already looks like it's compatible with the human body. And so we've been able to compress what is something that usually takes years, many years, anywhere from four to seven years, often, down to a process that looks like it takes us months, twelve months, 24 months.

Liz Pavone: So in your role as founding CEO, what culture are you building at Empress, and how is it helping you achieve all these goals you just explained to me?

Jason Park: That's a great question. So our mission, we should start there, our mission is to make good medicines fast. And why do we say that? The words good and fast have particular meaning. And so we're talking about small molecule medicines, and it still remains true that they're the longest used, most versatile tool that we have in our therapeutic armamentarium. And so if you think, when most patients think of when you tell them, hey, here's a good medicine, the first thing they think of, obviously, is, does it work? And is it safe? But they also think about things like, is this something I can take at home? Is this something I can just take as a pill? If I start to have a reaction, can I stop taking it? If the doctor tells me to lower the dose, can I break the pill in half? And that is true with small molecule drugs, which are chemical drugs, which can often be administered in oral pills. And that's one of the things that we focus on. But the other part is you got to get that to the patients fast. And I personally, like many other people listening to this podcast, and certainly people at Empress, have patients or friends, loved ones who are waiting for medicines, who have serious diseases or chronic illnesses. And speed matters, when you're looking out there at options and realize that there aren't medicines on the near-term horizon, that's something that we think we can change, again, because we can make these things, these drug candidates so quickly. So back to your question about culture. It starts with the patient, it starts about thinking about that mission of making these great, versatile medicines much more quickly than we've ever been able to do before, which invokes a spirit of urgency, it invokes a spirit of rigor, making sure that we focus on the medicines with the most possible impact. And it invokes a spirit of creativity and entrepreneurship, because we're doing things that people have never done before. We have to even build some technologies that didn't exist. And so we've got to figure out different ways of approaching this problem.

Liz Pavone: So a good medicine that is made fast is one that's efficacious and also, you're saying, have a good patient experience.

Jason Park: We think about the word validation and qualification, those words a lot in drug discovery. And it's become this, like, technical term, where we often think about, well, is that a validated mechanism or a validated drug target? But at the end of the day, what we're trying to validate or qualify is a drug product. And to answer your question, when we think about that, people often think about safety and efficacy because that's how clinical trials are set up. But there's so much more to making a product that can help a lot of people. You got to be able to manufacture it, you got to be able to distribute it, it's got to be easy for people to take. And those are considerations that small molecules often have a really great advantage in.

Liz Pavone: You've been with flagship for about eight years. What have you learned about company creation in that time? And how have you applied those learnings to Empress?

Jason Park: So I came to flagship because when I met Noubar and Doug, and I'd never heard of anything like this. And one of the things that really appealed to me, and one of the things I've learned through practice over the last eight years is that big ideas often take the same amount of effort and have—we talk about risk and uncertainty—they can have the same risk and uncertainty as a small idea or an adjacent idea. And it's not to say that there's a right or wrong here. It's just that one of the things I've learned is you should aim for the biggest possible version of what you think the science could unlock. Even if you fall short of it, or you hit to the left or to the right, or you end up doing something slightly different, at least you've thought about the biggest possible impact, and that gives you the greatest potential for having a transformative impact. And then the second thing I've probably learned is related to this is it's all about the people. It's about, can you find the right people, build the right culture, and set the right goals?

Liz Pavone: When you're not launching companies, what keeps you occupied outside of work?

Jason Park: Empress is obviously a 24/7 job, thinking about it constantly. But in the free time that we have, my wife and I are foster parents in the state of Massachusetts. And over the last three, four years, we've taken in three kids ranging in age from six months to three and a half years. And as you can imagine, that's a pretty significant time and mental commitment. the other thing is, unfortunately, my wife has developed some pretty severe long COVID after getting COVID for the first time last year. And so I spend quite a lot of time trying to talk to folks, and this is a call to anyone out there who's working on this, but I'm, looking for folks and ideas as to how to tackle what looks to be a very large problem.

Liz Pavone: Thank you for joining us, Jason. For more on Empress and other Flagship-founded companies, visit flagshippioneering.com.