Uli Stilz (Postdoc '90-'92), Chemical Biologist and Biotechnologist

As Vice President and Founder of Novo Nordisk's Bio Innovation Hub, Uli Stilz brings together his dual passions of fundamental science and translational research. Located in Cambridge, Massachusetts, Stilz is leading an exciting new era of drug discovery and therapies for a legendary pharmaceutical company that was founded in 1923 with its successful effort to produce and commercialize insulin.

In the discussion below, Stilz reflects on his education in biochemistry at the Max Planck Institute, and his postdoctoral appointment in the lab of Peter Dervan. During his time at Caltech, Stilz witnessed firsthand the ascendancy of Dervan's vision for chemical biology, which had revolutionized the perspectives and capabilities of the chemist's toolkit as applied to biological problems. Stilz focused on triplicating the double helix of a DNA molecule, which proved to be the perfect balance between basic research, and a foundation point for his subsequent career in biotechnology.

Returning to Germany in 1992, Stilz quickly rose through the ranks at Sanofi Pharmaceuticals. He was Director of Medicinal Chemistry before becoming Associate Vice President with specific focus on diabetes therapies. In 2014 Stilz joined Novo Nordisk, which first took him to the company headquarters in Copenhagen, where he developed strategic partnerships across industry, universities, and government entitites. Five years later, Stilz launched the Innovation Hub in Cambridge, and through the Covid years, he has built a diverse and impressive team focused on research and development that is focused on a broad range of cardiometabolic diseases. As Stilz reflects, much of his success can be sourced to his Caltech days, where he saw firsthand that research excellence rests on a foundation of hard work, and pursuing the most impactful questions.

DAVID ZIERLER: This is David Zierler, Director of the Caltech Heritage Project. It's Wednesday, January 17th, 2024. It's my great pleasure to be here with Dr. Uli Stilz. Uli, it's wonderful to be with you. Thank you so much for joining me today.

ULI STILZ: Thank you, David, and it's a real pleasure to meet with you today.

ZIERLER: Oh, wonderful. Thank you, Uli. To start, would you please tell me your title and institutional affiliation?

STILZ: I'm at the moment heading up the Bio Innovation Hub as the Vice President for Novo Nordisk here in Cambridge, Massachusetts. Maybe to give it a little bit of context, we can start with, "What's the Bio Innovation Hub?" It's the unit we created in Cambridge, which is very much focused on developing next-generation therapeutic solutions for people living with obesity, diabetes, and cardiovascular disease, as a primary focus. We do this in a unique way. We have created a cross-functional R&D team of scientists, including physician scientists, disease biologists, and scientists thinking about next-generation modalities. In this way, we bring a cross-functional team with a very deep insight into cardiometabolic diseases into a very vibrant entrepreneurial environment in Cambridge and Boston to work with entrepreneurs, biotechs, venture capital groups but also academic institutions, teaching hospitals to co-create new ideas, discuss how to untangle cardiometabolic disease, and address unmet medical needs, and then develop ideas for therapeutic concepts, which we then start to mature and develop towards clinical testing.

The Boston Biotech Hub

ZIERLER: Uli, you mentioned Bio Innovation as a Hub. I wonder if you could talk more broadly, as you alluded to, how Novo Nordisk fits into all of the exciting things that are happening in biotech in Boston and Cambridge.

STILZ: Of course, Boston is a very vibrant life science ecosystem in many ways. I think it's fair to say Boston and also parts of the West Coast, like San Francisco down to San Diego, are the leading hubs worldwide in terms of life sciences innovation, where many things come together, very strong, basic, fundamental research, translational medicine, and teaching hospitals, but then also an environment of investor, venture capital management teams to build biotech companies and, of course, us along with other pharma companies also being present in this ecosystem where we bring this very deep insight into cardiometabolic disease for people living with diabetes, obesity, and cardiovascular disease. What are unmet medical needs? What do we know about the disease biology? What does it actually then take if we find a new experimental medicine to take it through clinical development?

We bring all those elements and then work with those emerging biotech companies. I think I spoke to this on a few occasions over the last few weeks and months. It's an innovation ecosystem in many ways, with different entities bringing unique capabilities. These biotechnology companies have a unique capability to develop next-generation platform capabilities that can be to uncover new biology, oftentimes now based on single-cell sequencing capabilities and AI and ML capabilities, or it can be to build the next-generation modality where there's a very strong emphasis on RNA therapeutics, gene therapies, cell therapies, and new modalities which will help to unlock new biology which could not be unlocked so far. It is very exciting to see that those companies create the energy to build those platforms at the outset, which are therapy area agnostic. Whereas as a pharma company, we come with a very strong therapy area focus, and we know a lot about the people living with and impacted by certain conditions. We want to understand how we can make their life better. What is the unmet medical need? Then, we deeply integrate it through clinical development to research a therapy area focus and drive projects along the therapy area focus. At the same time, that has, I think, led to this very deep focus on disease biology and projects along the value chain as a main innovation driver, which is very particular to those bioplatform companies. I got so intrigued a few years ago that at this intersection, we can uniquely innovate. There is a new platform, which is, at the outset, created with a big "what if?". What if messenger RNA could become a new therapeutic modality? Yes, that needs to be established and proven. Then the next question, of course, is where could it be applied? We bring the disease area expertise; those bioplatform companies bring a capability that we don't have, which typically a pharma company is not so likely to create because it's a very different innovation model. There is really an organic synergy between those bioplatforms and integrated pharma companies like Novo Nordisk.

At the Interface of Industry and Academia

ZIERLER: Uli, do you have direct interface? Are there partnerships that you pursue with academic laboratories? Are you working with investigators at MIT and Harvard and places like that?

STILZ: Yes, David, we do, and that comes in different flavors. But I'll give you two examples of collaborations that I'm super excited about. We recently signed an agreement with the Broad Institute. The key question we are asking with the Broad is, in many ways, a frontier of understanding biology and at this intersection between biology and data science. We created a strategic partnership with the Broad to dive deeper into disease understanding for diabetes and diabetes subtypes as we understand it today, like what is driving diabetes as a disease, and together with the Broad, aiming to see if we can unlock root causes of disease drivers. This could lead to developing new insights into how we could potentially develop a disease-modifying agent. I think this is important because now it's a little bit over 100 years since the discovery of insulin. We discovered a number of medicines to treat diabetes. At the same time, for the most part, those treatments are symptomatic. They allow us to lower glucose, but they don't allow us to stop the disease progression. People living with diabetes still progress along a disease trajectory. We have not yet found an agent, an intervention that modifies the cause of the disease, which could slow it down, which potentially could stop it or hopefully reverse it or maybe even prevent it. That's, of course, what we want to achieve by more deeply understanding the complexity of this disease process and where to intervene.

That's something we do with the Broad, but it also involves investigators at the Massachusetts General Hospital (MGH). Through this collaboration, we are able to link the clinic and human data, so it's a very human-centric biology approach to understanding diabetes deeply as a disease. We have two different projects in diabetes with them. We also have a project in cardiac fibrosis looking at how we can better understand it and then find intervention points of this fibrotic process in the heart to treat heart disease. That's one example of fundamentally trying to understand the disease process with a very enlightened institution like the Broad and MGH. Then, as a second example in terms of working with academia, we created an accelerator together with Evotec as a partner to help translate academic discoveries that have come to a point where they can potentially start the translation journey. We uniquely created this framework together and have several participating institutions, including Harvard, Yale, Mass General Brigham, and Beth Israel Deaconess Center. The notion here is that academic institutions are very curiosity-driven, with fundamental basic research, and they bring new insights. At some point, they reach an inflection point where this discovery could become a reality and could start a translational journey to develop an experimental medicine to be tested in humans. Oftentimes, those ideas continue to sit in an academic lab, and they don't really start the translation journey because all the tools and capabilities that are required are actually missing in an academic environment. But, at the same time, if it's an earlier idea, there may not always be the possibility to create a start-up company, especially in this chronic disease space where still, up until today, there are not the same level of venture investments that we have seen in over the last 10–15 years in oncology. We felt like we wanted to help this and create a structure where we, as Novo Nordisk, bring deep cardiometabolic disease expertise and clinical development capabilities and then also a commercial ability to bring therapies to people living with those conditions. At the same time, Evotec brings a broad platform of capabilities to both validate targets and then also to find molecules to modulate the targets. Then, the academic institute brings the scientific idea.

Amongst those three parties, we feel we have all the pieces together to actually help those early ideas make it all the way towards an IND and to be evaluated in humans, where they have the potential to impact the lives of people living with obesity, diabetes, and cardiovascular disease. That's a completely different entity than what we do with the Broad. LAB eN² is meant to create a novel, unique partnership model to support a translational journey and make it through what the industry sometimes calls the "Valley of Death." We wanted to create a new, unique vehicle with very high intensity and energy to translate more early ideas in the cardiometabolic field.

ZIERLER: Now, in 2021, was COVID, was the pandemic part of the story for the creation of the Innovation Hub?

STILZ: See, it impacted it, but it was not the trigger. The reason for creating the Bio Innovation Hub was from a deeper reflection of how we want to extend the innovation landscape in Novo Nordisk. By this, I mean that, of course, as an integrated pharmaceutical company, we historically have very strong internal R&D. We ideate projects and drive them all along the value chain and then toward the market, so strong internal research and a strong commitment to internal research. Then, as a second pillar, we have a very capable business development/corporate development team that scans the landscape to see what others have been inventing and what therapeutic solutions they are working on. Are some of them complementary to what we are doing, and do we want to own them? In a way, it's a hedging strategy that we use to bring those assets into Novo Nordisk. Then we thought about what else is needed. That led to '18 and early '19 reflections that we actually want to be also trendsetters. We want to shape the environment. That created this notion that we want to co-create with others. By co-create, I mean if, for instance, a bioplatform brings a unique capability and is most of the time therapy area agnostic, and we bring the deep therapy area insights, at this intersection, we can create new ideas, ideas which otherwise would never happen, and ideas which neither Novo Nordisk could realize, nor this bioplatform company could realize alone, but which we can only do together. In a way, by definition, it drives us in our interest in the space of disruptive innovation by co-creating with others where we have complementary capabilities.

We felt that it was important to drive our own journey to shape the environment and create new ideas from medical intervention and therapeutic options that otherwise would never occur. That was, I would say, to build basically a third pillar, and that's why we created the Bio Innovation Hub. Now, you asked the COVID question. We decided at the end of 2019 to create this unit. Part of it was that we wanted to build a team here in Cambridge, Massachusetts, where we wanted to be deeply connected to the local ecosystem but where we also wanted to be very deeply connected to Novo Nordisk and what Novo Nordisk knows. We, of course, had planned to bring a number of scientists from Copenhagen to Cambridge, which was a bit impacted by COVID because the borders closed. We started to work virtually as a team because we couldn't relocate the scientific talent at the time. We started building and working for a year, basically on Zoom and Teams.

Staying Close to the Science

ZIERLER: Uli, at this stage in your career, do you get to still work as a scientist, or are administrative responsibilities too much of a burden on your schedule?

STILZ: David, that is a good question, and there are a number of answers to it or reflections on it. First of all, I joined the pharmaceutical industry in 1992, when I came from Caltech. I'm now more than 30 years in applied research to find new medicines, and mostly was focused on finding targets and validating targets and what it takes, all the way to phase 2B studies and finding molecules. I was in the lab and supervising lab work until '96. Because I was very successful and had, in four years, nine molecules that made it to the clinic, I was assumed to also be talented in managing people.

STILZ: I started in '96 to become a line manager. From today to tomorrow, I had all of a sudden a group of 60 people to supervise. In many ways, I was the youngest and maybe, for sure, not the most experienced. But I learned on the journey what it actually takes to supervise, and I made all the mistakes you can make in terms of first micromanaging to then understanding over time my role is completely different. It's no longer my role to be the scientist in the lab and primarily create ideas myself. But my main task is to help others to be successful and to create an environment for others to be succeed. As I got into more senior roles over time and worked both in-line functions and franchise-based functions but then also became more and more excited about how to innovate in the innovation ecosystems, I developed a very deep insight in terms of science, and got a good feeling for science, and what can be successful, and what could we stumble over. At the same time, I would say, I have a very good overview and a sense of how to direct science and pick exciting projects. If you would ask me tomorrow, "Go into the lab, and pick up a pipette, and do experiments," I probably would need a few weeks to get used to it again to be in the lab again. But it's different skills, of course, that are developed over time. It's more or less do you to have a good feeling for all the elements that have to come together to set up a potentially productive and successful project, how to drive it, and, now, in my role here, heading up the Bio Innovation Hub, also to deeply understand the intersection between science and business. Everything that we do has a business component because there's another party involved. There's also the system I mentioned about how do we share benefits? How do we structure contracts? How do we structure a framework? How to collaborate? How do we structure the intellectual property framework? How do we finance those projects? All of those questions I'm, of course, thinking about.

ZIERLER: Now, working of course in a business environment, how do you weigh the considerations of partnering with other organizations for the purpose of discovery, for the purpose of human health, while also developing products that are exclusively of business value to Novo Nordisk? How do you balance the sharing of knowledge within the private entity of what's required of running a business?

STILZ: I think, David, I always felt like one doesn't exclude the other because, at the front end, there is the scientific curiosity. There is an inception of an idea, an ideation process. I do think, in particular, academic institutions are very strong in this curiosity-driven research, which is the foundation for everything: what happens in the life science industry, the advancement in basic science, and the insights that come from basic science. At the same time, I appreciate, over a long career now in this industry, how much it takes to then start to translate an early idea into a medicine, which changes the life of people, from developing a molecule to making it really robust, to make it reliable, to be able to produce it, to produce evidence in clinical trials, and then have a consistent manufacturing production quality process that we can, in an ethical and safe way, help people consistently. It takes a private enterprise, resources, and cross-function capabilities to do this. I think that's also important. There is this early phase of ideation and idea generation, and then a deeply concerted collaborative, cross-functional effort in a private enterprise to advance an idea to assess whether it can eventually become a medicine. I think both of those parts are really important that they play together, support each other, and, in the end, that we can have a real impact on human life and well-being.

The Question of Chemical Biology

ZIERLER: Uli, let's now move on to the main research question that I'm focusing on, and that is the history of the field, the development, even the creation of the term "chemical biology." What does that term mean to you, and has it changed in its meaning over the course of your career?

STILZ: I think, David, it, of course, means for me the exploration. It's the interface between chemistry and biology. It, of course, deeply resonated with me as a young scientist, and I'll speak to it in a second about how this came about for me. I started as a high school kid. I was really excited about science. I started in biology with a microscope. I was about 10 years old, I believe. Then, for the microscope, I needed color, so I got more into chemistry. As I got into chemistry, I also got into how to build rockets and all this stuff a teenager loves to do. But then, of course, I became more interested in the foundation of chemistry. How does the world function? How can molecules be made? I got deeply intrigued by chemistry and also physics and how to understand this. I went to ETH and got a master's degree in chemistry. Mostly, I was focused on understanding how to synthesize molecules and how to, on the more fundamental physical level, understand chemical bonds, reactivity, and quantum mechanics. That's how I was educated. Then I felt like at the time—and that is maybe why I bring you through this as a longer story—at the time, ETH chemistry was completely separated from biology. When I finished my master's, I wanted to learn more about biology. I wanted to understand more diseases, and I knew nothing about biology because the disciplines were so separated. Then, I started to think about where to go, and I interviewed with a few faculty members in Zurich. But I was also pointed to a Max Planck Institute in Munich, to an investigator, Dieter Oesterhelt, who invited me for an interview. It was a fascinating interview because it took him about two minutes to find out that I knew absolutely nothing about biology.

ZIERLER: [laugh]

STILZ: I came to him with the question, "Can I join your group for a PhD?"

ZIERLER: What was Dieter's research? What was he known for?

STILZ: Dieter was a student from Feodor Lynen as a Nobel Laureate. As a postdoc, he discovered bacterio-rhodopsin, which is a light-driven membrane pump. He brought it back from his postdoc and started his career, an independent career, based on this discovery and to understand this protein. That later enabled two fields. One field was that Dieter and some of his students, Peter Hegemann, discovered there were more family members of this rhodopsin class proteins. Over long journeys, this developed. Also, Deisseroth at Stanford became part of it. This created the field of optogenetics, which is how to understand brain functions by using those proteins as two molecules. Dieter Oesterhelt was awarded, together with Deisseroth and Peter Hegemann, the Lasker Award in 2021, shortly before he passed away. That was really nice to see, and I'll tell you why, because I felt like Dieter was also a very generous man.

ZIERLER: [laugh]

STILZ: When he had independent group leaders with him, he didn't go on any of their publications because he wanted to foster their careers.

ZIERLER: Wow.

STILZ: That was the generosity in Dieter Oesterhelt, where I felt like, you know, sometimes in German, we use this word, Doktorvater, so your PhD father, your supervisor. I learned many things from him in terms of interdisciplinarity and how these are important in science, where a breakthrough happens, but also his notion of generosity, fostering young people, and developing and supporting their careers. I think he was a real role model. I learned about biology and noticed that this Max Planck Institute was completely separated from chemistry.

ZIERLER: It's a separate problem from the ETH?

STILZ: That was a separate problem. There was an institute sitting a little bit on the outskirts of Munich, doing fundamental biological research but completely disconnected from chemistry. That was fascinating for me to see. Then I went to Caltech, working with Peter Dervan. What occurred to me, what was different, was that Peter Dervan had created a group where biologists and chemists were working hand-in-hand in one research team.

ZIERLER: Now, how did you learn of Peter Dervan? Was it through Dieter?

STILZ: I learned through, you know, with Dieter, I had a dialogue about where to go. I said to him at the time, "I find this interface between chemistry and biology so fascinating." I had a dialogue with Dieter about certain research groups. I also had a dialogue with Dieter Seebach, who was my supervisor at ETH. Dieter Seebach pointed me to Peter Dervan. I wrote him a letter, and he accepted me to join his research group. That's how I came in 1990, leaving the Max Planck Institute and going over to California.

Joining the Dervan Lab

ZIERLER: Uli, what was it like coming to California? Had you ever traveled to the States before?

STILZ: No. It was for me the first time coming to the States. It had an interesting dialogue with Dieter Oesterhelt to say, "I want to go and learn about how science is done in the US." He felt like we also have fantastic places in Europe. But I think he saw a young man who was really passionate about going to the United States. I remember I had an airplane ticket—it was early November—from Frankfurt to Los Angeles. It was freezing cold in Frankfurt, and I had a thick coat. I arrived at the airport, and two postdocs in Peter Dervan's group picked me up at the airport, Erick Carreira and Yitzhak Tor. They looked at me when I came out of this airport with my suitcases and started laughing—

ZIERLER: [laugh]

STILZ: —and said, "OK." Then they said, "You won't need this coat here any longer."

ZIERLER: [laugh]

STILZ: Sure enough, it made it somewhere in the corner of my little apartment in Pasadena. But it certainly was a completely different world: sunshine, dry in winter, 20 degrees Celsius—that was the outside—and this deeply optimistic culture in California. Everything is possible. That became a wonderful time in my life, and it also started to become the time when I got deeply connected with the United States, to the science community, culturally. It was for me, a young man—I was 27—some of my founding years working with Peter Dervan in a very vibrant group of outstanding graduate students but a stellar group of postdocs.

ZIERLER: Uli, what were the big projects in the Dervan Lab at this point, and how did you slot in?

STILZ: Peter was mostly concerned about this big question: could it be possible to, in a selective way, recognize DNA?

ZIERLER: What does that mean, recognize DNA in a selective way?

STILZ: The question Peter Dervan was raising was whether it is possible to design molecules to selectively recognize DNA. Peter Dervan was trained in physical organic chemistry at Yale. Thereafter Peter Dervan pivoted into chemical biology using chemical tools to study biology. But, of course, this physical, organic training he had was still driving him in terms of this chemistry question of molecular recognition. The question he had in mind was, is it possible to develop new tools and molecules that would recognize DNA in a very selective way? Meaning, if you think about it statistically, it's a human genome. If you have 14 base pairs in a row, this sequence occurs only once, so it's unique. If you recognize more than 14 base pairs in a unique way, you can develop a tool that would recognize only one spot in the human genome. Of course, it's easy to see the vision if that can be obtained. You could develop completely different medicines because you could, at a DNA level, interfere with certain disease processes. That, I think, was the mission he set out to do. Could this be done at this intersection between biological sciences and chemistry?

I think that was his contribution to chemical biology—now we come back to this term—working at this intersection between biology, understanding biological questions, and then developing tools to study biology. The type of tools he wanted to develop was tools to select and recognize DNA. Most of the group sits in different shapes and forms, making tool molecules and studying biology around those tool molecules. Now, fast-forward, it's fascinating to see, David, what Peter had as a vision 30 years ago has now become a reality with CRISPR-Cas9, a bacterial system that was discovered, and now, of course, also driving the first medicines, the first approvals. But CRISPR-Cas9 solves in a different way what Peter was looking for 30 years ago and created the ability to very selectively recognize pieces of DNA, and then intervene and find intervention points. In a way, it's now a 30-year journey, with Peter at the outset having a big vision and then many others contributing over the course of time. But now, it brings us to a place where we can find new ways to intervene with diseases. We barely had any tools before. But Peter clearly was at the outset of this development, so he became one of the founders of this field of chemical biology, making chemical tools to understand biology. I think the United States was leading this because I believe there was an earlier movement to break down barriers between disciplines. What we have seen in Europe, when I left Europe in 1987, it was still very segmented, like I described it. It was either chemistry or biology, but there was not the collaboration established. Peter started this at Caltech, Stuart Schreiber at Harvard, and certainly Pete Schultz, one of Peter's graduate students who then worked on antibodies and transition states. Maybe these are the three key names, I would say, who were the founding fathers of the field of chemical biology.

ZIERLER: Now, was the term "chemical biology" in use during your postdoc? Would people talk about doing chemical biology, or that comes later?

STILZ: David, that is a really good question, and I'm actually not sure ever—I'm not sure to what extent we talked about chemical biology at the time as a term because now, 30 years have passed, and I have talked so many times about chemical biology. But when did we first talk about it? I would think we already talked about chemical biology at the time, but that would be really important to double-click on.

ZIERLER: Certainly, bioorganic chemistry.

STILZ: Bioorganic chemistry was a strong wording, and that changed. That changed into the notion of chemical biology. I think bioorganic chemistry was more, OK, yes, it's still chemistry. But chemical biology, I believe, had much more of an inclination to understand biology, so it was pushing much more into biology using chemical tools as a means to understand biology. I think there was a gradual shift over time, moving away from chemistry as a core discipline into really, really trying and creating a group of scientists who could deeply interdisciplinary way, think about biology and the intersection between biology and chemistry.

ZIERLER: Uli, what about the distinctions during your time at the Dervan lab between the emphasis on fundamental research and translation? Were people in the Dervan lab thinking ultimately about these applications in biotechnology, or was that still too early on?

STILZ: I think that was still early on. At the same time, Peter was an entrepreneur and a founder. He was one of the founders of Gilead, and Gilead was founded on this notion of antisense. Could you block some of those processes, such as these antisense molecules? I remember a dialogue with Peter, where I was smiling, in a way, in a conversation many years later. When I was visiting, I was already in the industry for 5 or 10 years.

But Gilead, of course, had a unique insight. It's what John Martin and Norbert Bischofberger said they realized that this is a longer haul. Then, I believe they also had a reflection. "What do we know really well?" They concluded, "We know nucleoside chemistry really very well." That brought them into antivirals, which oftentimes many of those molecules were nucleoside-based. They used their strengths in understanding nucleotide chemistry and pivoting from antisense molecules, which was a long haul, into something that could become a shorter-term win. That made Gilead into a very successful company. I believe that a part of it is that they found a molecule at the universities and licensed it. But it was an insightful company at a given time point. That's, I think, what Peter meant, "What we originally wanted it to be successful of that we didn't realize," because, of course, biotech has a certain time, but they successfully pivoted into something that became extremely fruitful.

ZIERLER: What was Peter's style like as a mentor? Did you get to interact with him? Did you get to learn about his interests, what he was trying to accomplish?

STILZ: I think, yes, of course, I had close contact, and I still have close contact with him. I think Peter is a very visionary person. He was working from a big vision, what he wanted to achieve, and then how to get there in a stepwise manner. I think that was one of his passions, what energized him, and how I perceived him at the time. At the same time, I also saw him as a mentor and a scientist who got deeply energized by developing talent, nurturing students, creating a field, of course, interdisciplinary training, how to train people in the rigor of science, and creating a school of talent. Many of his students attended either academic institutions or had successful industrial careers.

ZIERLER: Uli, between your experience at the Max Planck, and then coming to Caltech, and then thinking, you know, to your undergraduate education where you had no biology experience, by the time you had completed your postdoc, did you feel comfortable enough in biology that the distinctions between chemistry and biology were no longer very important to you?

STILZ: Yes, I felt biliteral or bilingual after these 10 years of training, where I first started very deeply in chemistry, and then, beginning in '87 to '92, being deeply embedded in biology. It was fascinating. When I started at the Max Planck Institute, I was in the lab, and at night, I was reading up on molecular biology and cell biology and everything I didn't know. It was a pretty intense time. But I felt comfortable in both fields and the crossover between the two. Actually, I deeply felt like those two disciplines had very different core anticipations, so biology is coming from a functional understanding; why is something working in this way? The deep question is about function. In chemistry, the deep question is about structure and how does structure code properties? Then, of course, if you think about it in life science and developing new therapeutic solutions, it's all about this connection between a molecule, how the properties of the molecule drive properties, and the interaction with the biological system to impact function, or in a way to disturb a biological system to bring it back from a more diseased stage to a more healthy state. In many ways, today, I talked about my unit here and how I designed the unit here was deeply motivated by my scientific career.

Everything is in this triad between a physician and understanding human disease and the unmet need to deeply understand disease biology and, at the same time, deeply understand how then to perturb a disease system with a molecular intervention. In this triad, I feel like all the innovations actually happen in the life science industry. Yes, I felt bilingual at the time, and I learned a few more languages over time. I learned the intersection between science and business. I also, of course, learned what it takes to lead people and bring teams together, both on one floor but also how to build teams across different cultures and continents. I worked in quite a few different cultures: the French culture, German culture, Danish culture, and the American culture. What does it take to bring diverse people together to be jointly creative, add to each other in a unique way, and create a vibrant and creative environment?

Tripling the DNA Helix

ZIERLER: Uli, what was your main research at the Dervan lab? What did you focus on?

STILZ: I worked on the triple helix. DNA is a double helix. Can you wrap around a third strand of DNA, can you get a molecule recognition in a triple helix, and can this be expanded to all four base pairs? It was known that it was possible for two base pair combinations, but could it be expanded to all four? In this way, can a general language we developed create a triple helix as a general mechanism to recognize DNA in selective ways? That's what I focused on. It was a mix of synthesis, experimental studies, and working with biological systems and tools.

ZIERLER: Uli, you mentioned developing such a close affinity with scientific culture in the United States. When your postdoc was wrapping up, were you determined to stay in the United States? Is this where you wanted to build a life and a career?

STILZ: David, that was, for me, an open question at the time. Of course, I had European roots, family in Europe, and also a life partner whom I had met. Actually, we started our joint journey together in North America. But she had gone back to Munich as an assistant professor. There were a number of reasons why, in the end, I decided to go back to Europe at the time. However, I always kept closely connected to the US life science community and traveled many times back and forth per year. Then I felt five years ago that it was so appealing to go back to the United States and build a unit here in Boston, which is such an energizing, entrepreneurial, creative, and forward-looking environment. In many ways, now I feel like a global citizen. But, in many ways, I feel like Boston is now my new home.

ZIERLER: Uli, did you think about faculty positions and biotechnology in tandem? Were both available to you? Did you have options in that regard?

STILZ: I was thinking about this, yes, and David, part of when I went to the US; I always wanted to broaden my experience in the academic environment because originally, I was thinking more about an academic career. Then, there were life events in my own family, where I saw what it can mean if health is impacted. I felt like during this period in Peter's lab that I actually wanted to make a contribution to applied research, that I wanted to be on the side to develop new medicines, and that I had the instinct at the time that required me to be in a private enterprise to really learn how to develop a drug. I was super fortunate in my first year in Höchst in Frankfurt that I had a number of molecules, which made it towards clinical testing. I learned the ins and outs; what does it actually take? You almost would say it sounds like a trivial problem, but it wasn't a trivial problem, a question like in a molecule, would it crystallize or be polymorphic or not crystallize?

Some experienced colleagues told me, "That's a really important question," and I wondered why. I later got to it that said, when you cannot crystallize, you cannot secure a 100% purity, and your shelf-life stability is much lower, so really very practical, technical questions besides thinking about the biology and what is the disease you want to treat. What does it all take? What does it take to upscale to make a ton of material, to think about the complexity of the chemistry, and to think about how to design the clinical study? All sorts of questions about the pharmacology. I learned so many things in the first four or five years. I believe that for young scientists, it's good to be in a larger organization to learn all the ins and outs and what it takes. Sometimes, also thinking about a biotech company, it's good to start in a way where you really learn also multifaceted, interdisciplinary components and then bring this expertise into a smaller start-up company. That's maybe what I would give as advice to young scientists today. But I think, David, I often thought about it now I'm associated with Frankfurt University as an adjunct professor, and I do teachings there, and that's wonderful. At the same time, I think my heart was in finding new medicines.

ZIERLER: Tell me about Sanofi. What kind of organization is it? What is its mission?

STILZ: Sanofi I left 10 years ago.

ZIERLER: But I mean at the beginning of your career, when you started.

STILZ: At the beginning of my career, it actually wasn't Sanofi; it was a German company called Hoechst AG, which then later merged into or became, over a number of merchant acquisitions, became Sanofi. At the time, it was a large chemical pharmaceutical company with different divisions. There was a pharma division. I started my career in the pharma division because that's what I wanted to do. But there were also agrichemical polymers and a strong focus, I think, on cardiovascular medicine. Diabetes was a strong focus. We also had autoimmune diseases, rheumatoid arthritis, asthma, and there were projects in oncology. That's what I got exposed to. In the beginning, I was mostly working on cardiovascular and diabetes projects.

Then, over time, people also had autoimmune diseases. Then, it went through a transformation from a conglomerate to a pharma company. This journey started in '96 and culminated in 2000 with the formation of Aventis, which was a merger between Rhône-Poulenc and Hoechst. Then I got exposure to, you know, what it actually takes, large-scale M&A through very large companies merging. What does it take to build a new culture in an organization and to seek an agreement and build an agreement? What is the strategy in an organization? Then it became Sanofi-Aventis in 2004 or '05. Aventis was bought by Sanofi, so another large M&A. At this time, it became a pure pharmaceutical play. All the other divisions were spun off. Aventis still had an agrichemical business. All the chemical business was spun off already. It was more Novartis-focused, so early Novartis focused on life science, pharmaceuticals, and agricultural products. Then, over a few years, it became a pure pharmaceutical company.

ZIERLER: What were the human health ailments that you were focused on at this point in your career?

STILZ: In 2000, I was leading a large team of medical chemists and computational chemists, working with different modalities on small molecules, peptides, antibody-drug conjugates, carbohydrate-based medicines, Lovenox, it's a family of heparin products, and RNA therapeutics. I had a group of scientists working on RNA therapeutics, you know, antisense. We worked towards finding antisense molecules. We have early days. In 2000, it was very early days. That was my focus, and I worked across therapy areas. I was sitting on the Sanofi discovery leadership team, so I had an overview of all the research projects in Sanofi.

ZIERLER: Uli, tell me about your affiliation with the Goethe University in Frankfurt.

STILZ: With Goethe University, I'm basically a faculty member. I'm an adjunct professor teaching either chemistry or pharmacy students, mostly on drug discovery—What is applied research? How do we invent a medicine? What does it take?—to give some real-life insight from, in a way, a practitioner and an applied researcher.

ZIERLER: I'm thinking about the term "chemical biology." I want to know about your time as leader, president of the European Federation of Medicinal Chemistry. Is medicinal chemistry more or less synonymous with what we now think of as chemical biology?

STILZ: That is a really good question. I was proposing this or promoting this thinking when I was president of the European Federation of Medicinal Chemistry. I believe I also gave at the time an interview which, for me, was always important to have them know that medicinal chemistry is not only about making small molecules, but I think in a broader sense it should be chemical biology, and chemists in a very broad and deep sense understanding how to perturb a biological system. I always felt like in chemistry communities; they should also be in this question about nucleotide chemistry, next-generation platforms, antibodies, and antibody-drug conjugates. It's all molecules. They may be synthesized by different processes; some are by purely synthetics, some by biological fermentation processes, but, in the end, it's all molecules, that are made with the notion to perturb and understand the function of a biological system. I was very much in favor of amending the name towards medicine chemistry, to broaden it into chemical biology as a broader context, and to be real scientific drivers so as not to be too narrow in a way around small molecules and the art of designing small molecules, but take a much broader, holistic perspective of molecular scientists who want to understand biology.

An Exciting Opportunity at Novo Nordisk

ZIERLER: Uli, tell me about your decision in 2014 to change your career, and join Novo Nordisk. What was compelling about that for you?

STILZ: I think, David, of course, at the starting point, up until 2010, I was mostly on the molecular side, leading large line functions of mostly chemists, thinking about different types of modalities. That was my focus. Then in 2010, after Chris Viehbacher became CEO, there was a search for key talent, and I was identified as one of them. In this process, I was asked to take on a completely different role, to lead and build an innovation unit for diabetes. All of a sudden, I became responsible for a team of biologists and systems biologists to think about diabetes as a disease, and how we can find new targets and intervention points.

ZIERLER: How long back does Novo Nordisk go in diabetes research?

STILZ: Novo, I think, was founded in 1923. We recently celebrated 100 years. It's all based on insulin discovery. But to your question, just to complete the circle, Sanofi all of a sudden focused on diabetes. For my upbringing, I studied in Switzerland, and lived in the US. I was so deeply connected to the Swiss pharma industry. It's the US pharma industry. The only company I never had any contact with was Novo Nordisk. In a way, you would say it was very unlikely that I would ever end up in Novo Nordisk, would I not have completely changed a little bit my scope of work in 2010, and Sanofi to become focused on diabetes. Then, of course, I started going to diabetes meetings because I was now more on the diabetes franchise role. I went to American diabetes meetings and European diabetes meetings. I also became focused on how not only to innovate in Sanofi but also how to build partnerships with biotech and academia.

That brought me in contact with Novo Nordisk colleagues and leaders. I got inspired by a culture of a deeply ethical business and a strong commitment to patients, but also a focus on making a real impact in this very large group of patients living with diabetes and also obesity and cardiovascular disease. Through this contact, these meetings, and getting to know senior leaders in Novo, I got offered the opportunity to join them in 2014 and to help actually Novo Nordisk, which, at the time, was very much focused on internal research, to help them to open the door to the outside world. My interest was in changing that thinking to the view that integrating ourselves into innovation ecosystems gives us so many more additional insights and opportunities to innovate in different ways, so to also drive a change journey now over 10 years in Novo Nordisk, how we think about innovating not only in the corporate world but innovating in innovation ecosystems.

ZIERLER: Culturally, what was it like moving to Copenhagen for you?

STILZ: I moved with the family, or part of the family, with my spouse and my son. My daughter had already left for college, so she didn't move with us. That was one feeling that our family got a little bit disrupted. Then, of course, it's a different country, even though in Europe, in the European Union, but a country with a different language, a different culture, living abroad with the family, which was a wonderful experience, but then also discovering a different organization, and how a different organization had thought about things differently than my previous company Sanofi, with a very different culture. What was noticeable is Sanofi occurred through a series of three or four large M&As. Because of this, different pockets of Sanofi felt very different. Novo Nordisk felt much more homogeneous, an organically grown organization over a very long period of time. Many things that I was very impressed with had been carefully thought through and articulated, such as how to do certain things in a very systematic manner, so it was a very thoughtful, organically grown organization; it was quite a different culture. I think it's a unique learning opportunity to work in more than one organization and then reflect on unique strengths and capabilities in different organizations and actually how to combine the best elements I've seen in my life.

ZIERLER: What was the frontier of knowledge in diabetes research by the time you joined Novo Nordisk? What were the big questions to be solved?

STILZ: I think at the time, there was still a strong foundation in insulin chemistry and biology, pharmacology, and how to make the best insulins to treat people living with both type 1 and type 2 diabetes. There was an emerging new class of—now, of course, it's a well-established GLP-1. But in 2014, 10 years ago, it was an emerging drug class that started in diabetes and the first molecules, approved for diabetes, which I think I probably, like most people, would not have fully seen in 2014 how important GLP-1 would become as a drug class, both in diabetes and obesity.

ZIERLER: What were the discussions that led to the Bio Innovation Hub and, ultimately, why was Cambridge chosen as the site for this?

STILZ: As I described at the beginning of our conversation today, the discussion was that we felt like, I think, also to see it a bit in the context that the insulin market was disrupted around 2015–2016, mainly because basal insulin became generic. We started to reflect more on how we can up the game in terms of innovation. How can we find more disruptive medicines? We started this dialogue in 2016, '17, '18.

Then increasingly, in 2018, Marcus Schindler joined our R&ED organization from outside, from AstraZeneca. He became my manager, and we had an intense dialogue about highly disruptive innovation and how to bring in and work with the outside world. That led us to this idea of co-creation and working with others at the unique intersection of complementary skills. This could be a very fruitful journey to get to completely new ideas, which otherwise wouldn't occur. How can we push a boundary of innovation into wide spaces and develop completely new ideas? That was at the outset of 2018, and then, at some point, led to the question of where would we place a unit like this? Over a few weeks and a few months, the idea crystallized more and more to actually create a small group in Boston, mainly because we felt like this was a very vibrant and entrepreneurial ecosystem with a lot of start-up companies moving. It was an interesting discussion in Novo Nordisk at the time because there was a feeling that we joined too late. Everybody had already moved to Boston. We had a panel discussion in Boston with a few biotech CEOs and academic investigators like Bob Langer. At the time, we then started to reframe it. No, it's never too late because science always progresses, and the scientific train actually starts to accelerate. At some point, we just have to jump on the train and then become part of it. We decided to create a small group as a starting point in late 2019. But before that, I went there as a pioneer. I went there in early 2019 with, like I said, my spouse and four suitcases to figure out a little bit of what we wanted to do. That led, at the end of 2019, to a proposal to create a small team, which later became the Bio Innovation Hub.

Innovation Means Transformation

ZIERLER: Now, thinking about transformational research, doing all of this innovation, it sounds like there were some rules that needed to be broken, culturally, in biotechnology. What was not working, or where was the opportunity in creating this new division, to create new rules, to push these discoveries forward?

STILZ: New rules are an interesting question. I would say, how do we ideate at the front end? How do we ideate between entities? How do we create a structured process for ideating with other entities, which was not existing? I couldn't go out and say, "Here's a database, and company A has asset A or B." But we needed to meet and see if there was something that we could jointly do? How can we create a very collaborative and inviting culture that is also very open to new ideas that were untested in the beginning? How can we ring-fence this a little bit to create a safe space for ideating concepts? That was a question. Then how can we create enough intensity and energy? From this perspective, we created this Bio Innovation Hub as a biotech-like structure so that it operates similarly, you know, to the biotechs here, the environment, rather than like a corporation with a lot of processes. We created a biotech-like environment, with a team of a certain size and deep interdisciplinary insight, but also with mechanisms like a ring-fenced budget and a certain level of autonomy. At the same time, my unit is guided by a board. Marcus, Novo's CSO, is chairing the board to give the unit strategic guidance. We also thought about structurally how to embed a unit like this in Novo Nordisk so that we can drive more disruptive innovation in an organization that historically has felt more comfortable with making improvements.

ZIERLER: Now, we talked about COVID not being a direct trigger for the creation of the Hub. Did it slow things down or did it change course of what the Hub was designed to accomplish?

STILZ: I think it just made building the team a bit more challenging in the beginning. At the same time—and that's really interesting, David, your question—it made us from the outset inventive, because the question was now we cannot meet in person, how can we develop a new style of working and be creative? We started to work with new IT tools that we could have flip charts online to brainstorm in a virtual room. From the very outset, we became inventive in terms of working differently because we were forced to work differently. In some way, it propelled a culture of working differently. As much as it was disruptive to bring people together, it fostered creative thinking, how to work differently, and how to ideate differently. We created this way to work in the team virtually, but then, of course, it also enabled us to bring others from outside into this virtual discussion space. Actually, in some way, COVID triggered or was a creative impulse.

ZIERLER: Uli, we'll bring the story right up to the present. What are you currently focused on? What's most important to you and to the Hub?

STILZ: Most importantly, we have now created quite a few frameworks with Flagship, the Broad, Evotec, and some leading institutions. Now, a key focus is for me and my team, with so much breadth of science and concrete ideas, to really drive and execute on exciting ideas as a key focus for the unit. At the end, we want to generate an impact on Novo Nordisk's pipeline and have an impact on people living with obesity, diabetes, and cardiovascular disease. We want to bring it to people living with these conditions, so we have a strong focus on it. At the same time, I always want to be creative and find new things at the front end, so it's important to balance executing exciting ideas and then keep ideating and finding new ideas, and finding the right balance between the two.

ZIERLER: Uli, I don't know if when you started, you thought about a one-year plan, a three-year plan. As we're now five years out, how close are you, if you articulated what that plan is, and what are some new and surprising directions that the Hub has taken that you couldn't have foreseen at the time?

STILZ: David, that's always fascinating. Of course, I had an idea where I wanted the ship to sail, and that's also very important for a leader to have a vision for the future and mobilize your team behind it. At the same time, I'm also a deeply curious person, and I'm probably most excited about things I don't know yet. There were many things along the journey I didn't foresee. We created a unique partnership with Flagship, a trendsetting agreement between a venture firm and 40 to 50 platform companies at the moment, having a portfolio and Novo Nordisk as an integrated pharma company. It was anything other than trivial to create this framework because many things had to fall into place, both on the science side, how we ideate together, and the business structure. But now we have it in place. We just announced the first two programs with Cellarity and Omega on January 4th, and there's so much energy now. But when we created the framework, I didn't know those would be the first two programs. But those are super, super exciting science that could lead to an impact in MASH and a completely different approach to obesity treatment. That's what I'm most excited about, new things that I would not have seen. But the bigger picture, what I wanted to do, was clearly in my mind. There's this notion of co-creation. That has not left me. That's maybe the North Star for the unit in terms of how to think about innovation in a different way.

The Depth of Caltech Interdisciplinarity

ZIERLER: Uli, now that we've worked right up to the present, if I may, for the last part of our talk, a few retrospective questions, and then we'll end looking to the future. Very briefly, of course, what brings us together is Caltech. What has stayed with you from your time at the Dervan lab? How has it influenced the kind of scientist you became?

STILZ: What stayed with me was this deep interdisciplinary thinking in Peter's group. I was at the Beckman Institute, and next door was Leroy Hood at his office. Lee also had a huge group, pushing some boundaries in a different way than Peter. But oftentimes, I bumped into Lee at midnight, one in the morning, and we had fantastic discussions. There were inspiring scientific leaders at Caltech, which shaped me to think about science. It takes a vision—where do you want to go?—and then experimentation, this notion of experimentation, and a deep curiosity at the interface between disciplines. I think that it has lasted from my time in Caltech, and of course, also many wonderful people, both supervisor and senior faculty members at the time, as well as graduate students and postdocs at the time, who became close friends. Now we have, of course, this generation of more senior people 30 years later. But it also created this deep and emotional connection to the United States, which brought me back here.

ZIERLER: Uli, the road not traveled, your initial interest in joining an academic organization, a faculty position. All of the impact and discovery that you've been a part of in your career, have you ever wondered what that would have looked like had you become Professor Stilz?

STILZ: It's a good question, and it's always this question: going back, would my life have been completely different? I don't wonder about this so much, but I would say, sitting here in Boston, there's an environment where academic investigators can be entrepreneurs, become founders of biotechs, and make a lasting impact. An academic career also allows this to be part of it and insert your curiosity into this life science ecosystem. But, of course, I cannot tell you how my career would have been if I had become a Professor Stilz. But I feel energized and grateful for what I can do, so I'm very content with my life journey, the many wonderful people I have met, and the opportunities to mentor younger colleagues, for which I'm grateful.

ZIERLER: Finally, Uli, looking to the future, for however long you want to remain active, what is most important for you and your team to accomplish?

STILZ: The most important thing is to develop experimental medicines, and then help them to start a journey towards clinical development. The end goal is to make a contribution to human health. Along the way, I also have this passion to help develop young talent and help them on their career journey.

ZIERLER: Which really is not so different than what professors do, working in a translational space, mentorship and discovery, not too different.

STILZ: No. It's wonderful, a unit like this, which is also a talent hub for Novo Nordisk, I'm surrounded by many wonderful young colleagues, and that keeps me young too.

ZIERLER: [laugh] I love it.

STILZ: [laugh] That's actually wonderful.

ZIERLER: Uli, this has been a terrific conversation. I'm so grateful for our time together. Thank you so much.

STILZ: Thank you so much, David.

[END]