Lab Meeting: Gary Nabel
“How do you take that big picture approach? How do you marry science and the markets?”
Blessed are the virologists for “they shall inherit the earth.”
It was a statement made by Nobel prize winner David Baltimore to his post-doc Gary Nabel, as they sat in an MIT cafeteria in 1986. Baltimore had just been appointed to the first national committee tasked with studying HIV and was recounting the group’s latest findings.
In Baltimore’s lab, Gary Nabel would go on to discover that a human (host) transcription factor (NF-kappa B) was required to drive expression of the HIV genome and promote viral replication. Through the years, Baltimore’s prescient statement about virology stayed with him: “This prediction became true on so many levels during my lifetime,” recounts Nabel, now CEO of ModeX Therapeutics.
Driven by a desire to help others, Gary Nabel first enrolled as an MD-PhD student at Harvard Medical School in 1976. He was drawn to the then “primitive” field of immunology—choosing Harvey Cantor and Edward Boyse as his PhD advisors: “We knew that there were T cells and B cells, but that was about it.” Nabel and his advisors helped bring clarity to the field—defining cell surface markers that identified lymphocyte subsets using antibodies, cloning and characterizing their function. After completing his internal medicine residency at Brigham and Women’s Hospital (1985), Nabel went to David Baltimore’s lab for the science, but gained much more: “Going to work for David Baltimore provided the most meaningful and deep scientific relationship… He taught me so much about science and about life: people, patience and persistence.”
With these life lessons in hand, Nabel accepted a faculty position at the University of Michigan in 1987. There he leveraged his expertise in immunology to study infectious disease and cancer. He even collaborated with his wife, renowned cardiologist Elizabeth Nabel: “We published a paper with Betsy where we showed that we could deliver recombinant genes using viral vectors through catheters into blood vessels feeding the heart. We could get site-specific expression in arteries…that was pretty exciting.”
In 1999, Nabel was tapped by Anthony Fauci, Harold Varmus, and Rick Klausner to lead the NIH Vaccine Research Center (VRC), and says “the time I spent at the NIH running the Vaccine Research Center was one of the most fun and gratifying experiences in my life.” With generous support from the NIH, Nabel turned the VRC into a scientific juggernaut—recruiting premier structural biologists, immunologists, physicians and virologists to pursue basic and translational work, culminating in over 100 clinical trials: “The publication records, the clinical trials and vaccine candidates were outstanding, and eventually culminated in the prototypes for the COVID and more recently, the RSV vaccine,” reflects Nabel.
Though content at the VRC, Nabel eventually realized that he wanted a new experience: “I could have spent another 10 years at the VRC, and I would have loved it. But I felt driven to bring new medicines to patients—ones that could impact millions of lives.” Wanting to learn scalable drug development he joined Sanofi in 2012, as chief scientific officer and head of the “Breakthrough Lab.”
At Sanofi, Nabel helped shepherd drugs like Dupixent through pivotal trials, and developed the first trispecific antibodies for HIV and cancer: “Companies like Sanofi know how to make medicines in a scalable way. How do you take that big picture approach? How can physician-scientists merge the rigors of science with the discipline of the markets?” (Q#6).
Yet after learning to wed medicines and markets, Nabel started to yearn for faster innovation cycles: “Pharma thrives on scale and manufacturability but it is not well-suited for transformative innovation,” he says. In 2020, Nabel left Sanofi to co-found ModeX therapeutics (with close friend and colleague, Elias Zerhouni) to develop multi-specific antibodies and vaccines for oncology and infectious disease. After meeting legendary biotech entrepreneur Phil Frost in Florida, Nabel and Zerhouni joined Frost by merging with his company OPKO in May 2022 (ModeX continues to operate as a wholly-owned subsidiary).
One of ModeX/OPKO’s most advanced programs is an EBV vaccine; in March 2023 they partnered with Merck, with an upfront payment of $50M and up to $872.5M in biobucks: “Merck is the company that developed the HPV vaccine. We have an EBV vaccine candidate that is really in the sweet spot for what they do…if we want to have global reach, having a partner with deep experience is crucial,” he tells Biomarker.
Armed with decades of experience in virology, drug development and biotech, Nabel and ModeX/OPKO are poised to change how we treat infectious disease and cancer. It is as David Baltimore predicted nearly 40 years ago: “the virologists shall inherit the earth.”
1. What was your first taste of science and medicine? Briefly, what about this initial experience drew you in?
I had very little interest in science until I was in high school. Even then I didn't have a lot of interest and was a bit of a jock.
I did however attend a NSF program in biochemistry designed to introduce young students to scientific research. It was a really interesting experience because there was so much happening in research, and biochemistry in particular. We were thrown into an exciting mix of mentors—we had a college professor [as a supervisor], college students who were “group leaders” and then there were other high school students [like me].
We didn’t know what we were doing, but we were just excited by being in the lab. This program was really the beginning. Over time, I kept the appreciation of how fun and interesting research is…so I just kept doing it. In addition to being fun, research also had the potential to help people—which is what I cared about most…and still do.
[On his interest in medicine]
We didn’t have many doctors in the family. I was just driven by this desire to help people. My parents are both Holocaust survivors. If you look at the children of Holocaust survivors, there is a sense that: “we're lucky to be on this planet.” I can't speak for everybody, but at least for me there is a desire to do good for others and to give back.
I was an undergraduate at Harvard, and carried this sense of service. I went to Harvard thinking I was going to become a government major—even though I really liked biochem [during the NSF program]. When I was deciding on my major, I interviewed with the respective head tutors of the biochemistry and gov departments.
I met with the biochem tutor who at that point, believe it or not, was a newly minted junior faculty member, Steve Harrison. Steve was a young pup, and I was even younger. Even after that delightful meeting, I thought I might still choose government. But when I sat down with the gov tutor, he listened to me and said: “I think you should major in biochem.” He told me that one can always get involved in government coming from a biochemistry background, but never the other way around. So, I chose biochemistry.
But I’ve always been interested in getting involved in issues at both the micro [meaning science] and at the macro scale, including government policy.
2. During graduate school and post-doc, what were some lessons you learned from the likes of Harvey Cantor and David Baltimore? How did you apply these learnings to your own work and career?
What drew me to Harvey's lab at the time [1970s] was our evolving understanding of the immune system. Our perspective was incredibly primitive, and we knew that there were T cells and B cells, but that was about it.
But there were pivotal findings in the mid 70s, by Harvey Cantor and Edward Boyse—Ted was at Memorial Sloan Kettering and Harvey was an assistant professor at Harvard Medical School.
They found for the first time that you could define T cell subsets using antibodies to mark the different cells—in the mouse literature these are the Ly-1,2,3 antibodies (in humans, they are CD4 and CD8). This was such a revelation. Even the idea of using antibody markers to delineate subsets was really cutting edge. So, I asked both Harvey and Ted to be my co-mentors. I was a student at Harvard, but I would go down in New York to visit Ted on occasion—he was a brilliant, old school British scientist and I loved talking to him. Harvey was a young, razor-sharp junior faculty member and a brilliant experimentalist. I really enjoyed the environments in both labs.
Going to work for David Baltimore was the most meaningful and deep scientific relationship. I've known David since I joined his lab as a post-doc in 1985. We have stayed in very close touch on so many things since.
When I was in David’s lab, he was running the Whitehead and was on the first national committee to study HIV and figure out what it was. We realized it was an opportunity for scientists to shape the response to an emerging public health crisis and save lives. David was also a great mentor and friend to me. I am obviously not the only one, he did this for many who have gone on to do phenomenal things. I'm not sure anybody will ever equal David’s training record—which includes your current Dean [of HMS], George Daley, whom I shared a bench with when he was a grad student. Later, when I was at the NIH, I asked him to become the chair of our external advisory committee at the Vaccine Research Center (VRC), where he served selflessly for decades.
3. What have been some scientific high points? — What do you consider to be the most exhilarating set of discoveries you have been involved in throughout your career in academia?
I can pick a few high points that stand out: one of my first papers as a graduate student in Harvey’s lab where we were basically the first to clone T cells and show that they were committed to different lineages—within the common differentiation pathway of T cells. We could then study these clones, characterize their function and examine their secreted gene products. From this work, came several seminal studies where some cytokines were first cloned.
I would say that the next high point would be the work with David, where we described the role of NF-kappa beta in activation of HIV in Nature. At the time, NF-kappa B had just been described for its role in regulating a light chain expression and B cells. The HIV genome had just been sequenced, and when we looked in the promoter, we saw these two kappa B sites. What were these two human transcription factor binding sites doing at this viral promoter? We went on to show that the activation of the virus was dependent on the host cell [NF-kB] transcription factor. This discovery really opened up a lot of insights into the question of how HIV latency is regulated.
Later on, the work we did at Michigan in gene therapy was exciting. We published a paper with Betsy [Nabel]where we showed that we can deliver viral vectors through catheters into the heart. We could actually get site specific expression through this combination of molecular engineering and device delivery. Those studies broke new ground related to the understanding and treatment of cardiovascular diseases.
There were several discoveries made at the Vaccine Research Center [VRC] that were remarkable. For example, the finding that there were broadly neutralizing antibodies to HIV that we never thought existed before. We were then able to isolate these antibodies using very sophisticated techniques. Another [high point] was our work in creating multispecific antibodies—we started with HIV first, and we're now going after other targets. Another finding that made a lot of headlines was our development of the first Ebola vaccine that protected monkeys against disease. While it’s nice to see people appreciating your work in the media, I have always appreciated the science for its own sake—solid, compelling science, even when it doesn’t make headlines. I am just as proud of papers that didn't get the broad recognition, where that my postdocs worked hard and got to the root of the problem.
4. What was a difficult moment during your academic career? What are some of the challenges with the physician-scientist path?
I always loved what I was doing 1,000% while I was doing it, whether it be clinical training or bench science. Yet medicine and science are two very different activities, and trying to switch back and forth between them is difficult. In those early years especially, you often feel very torn. I think that most people continue to feel torn until they can commit to a particular pathway and find the blend of things that makes them happy. I think that's just part of the process when you're an MD-PhD—it does take a while to figure out where you can make the best use of your talent. For me, at the end of the day, what I realized was that there were a lot of people who are much better than me at the basic science alone. There were also a lot of people better than me in the clinic. Where I could really contribute was in bridging between science and medicine—I knew enough about science to know what I could trust, and I knew enough about clinical medicine to identify opportunities and unmet need.
5. What was the move to lead vaccine development at the NIH like? How did this role differ from your previous work in academia? What were some of the biggest lessons learned in over a decade at NIH, supervising work that led to > 100 clinical trials?
The time I spent at the NIH running the Vaccine Research Center was one of the most fun and gratifying experiences in my life. I was surrounded by great mentors—the people who brought me there included David Baltimore, Tony Fauci, Harold Varmus, and Rick Klausner. They not only had my back, but they also gave me a lot of very wise advice.
I also had the resources and commitment from the NIH to really put together a program at the VRC that could be synergistic—so we could do things together that none of us could do alone. The trick was in finding the right people. The folks that we recruited and the team that grew together at the VRC was amazing. When we recruited people, we basically said: there's a couple things we want from everybody. Our scientists were both productive and fun to work with all of them,and they have become good friends, including John Mascola, the late Norm Letvin, Rick Koup, Peter Kwong, Barney Graham, Bob Seder, Nancy Sullivan, Julie Ledgerwood, Danny Douek, Mario Roederer and others, not to mention the engagement and support of Tony Fauci who provided inspired vision and encouragement from day 1.
Our criteria in selecting our faculty was to make sure that everyone was scientifically excellent and the best in their field of expertise. In some cases, it was structural biology, and other cases human trials or mouse immunology. We didn't want everybody doing the same thing, and we spread them across the disciplines. A second thing we insisted was that these scientists be collaborative. It ended up a privilege for me, because I got to see over time how the group worked together and collaborated in a synergistic way. Everyone became a better scientist for it. The publication records, the clinical trials and vaccine candidates were outstanding and eventually culminated in what really were the prototypes for the COVID vaccine [under John Mascola’s leadership].
6. When you got recruited to Sanofi in 2012, what was this transition like? How did leadership in “big pharma” differ from your positions in academia and at NIH?
It was a learning experience. There were a lot of great things that we were able to do at Sanofi—a big reason I went was because of [the vision of] Elias Zerhouni, who had been the NIH director and is now a close friend. Elias’ vision of what you could do with the power of a company, building on the science and manufacturing side of things, really gave us [at Sanofi] incredible opportunities.
At the time, I felt that I could have spent another 10 years at the VRC, and I would have loved it. But I really felt driven to be an important part of efforts that bring new medicines to patients—ones that could impact millions of lives. You can't do that in an academic environment, even at a place like the VRC. You really have to learn that, and do that in the setting of pharma. Companies like Sanofi know how to make medicines in a scalable way.
How do you take that big picture approach? How do you marry science and the markets? People often asked me: “what is the biggest difference between being at Sanofi and in academia at Harvard, Michigan or NIH?”
As a scientist, the North Star is the scientific method. Hypothesis-driven research is sacrosanct. That's what we do, and we get pretty good at writing grants to justify it. But when you get to the real world, there's this other equally compelling component, which are market forces. Markets are incredibly powerful, and they tell you so much about whether you are addressing needs on the ground. This was part of what I enjoyed in the pharma space: having really solid science wasn't enough, we had to also understand the markets. The science and the markets together orient our priorities and tell us where we can best spend our time and effort.
7. In your 8 years at Sanofi what were some of the biggest projects you worked on?
Dupixent is probably the most compelling, and it’s a drug that I feel great about: I wasn't the only person involved but was helping on a leadership level. Dupixent really took advantage of fundamental B cell biology—people like Bill Paul had mapped the IL-4 and IL-13 pathways, and it was the Regeneron team that found the antibody that could affect both pathways [binding to IL-4Ra]. But we [Sanofi] undertook the whole process of bringing the drug forward into trials for multiple indications. Now, the impact of this drug is huge and its one of the most widely used medicines out there. It was so great to be part of that.
8. In 2020 you made the move to biotech. What excited you most about this transition to a smaller company? What is the founding story and vision of ModeX?
Pharma thrives on scale and manufacturability but does not do well with innovation. Big companies are under a lot of pressure to generate revenue and stay profitable. They have to come up with blockbusters every so often or else they will go out of business. If you are interested in transformative innovation, it is not often well supported in big pharma.
We developed several products at Sanofi that I thought conceptually, scientifically, and medically had tremendous opportunities to do good. If they stayed within Sanofi, they would have died. If viewed only from a short term commercial perspective, I might have been compelled to deprioritize them myself because of the business pressures.
What excites us about multispecific antibodies [at Modex] is that you have the opportunity to do something by purposeful design that doesn't happen in nature and really open up the opportunities for the basic antibody structure. In nature, when there is an antibody with two arms, they are both directed against the same target. When you have the capacity to target different sites with one antibody, you suddenly can bring many new combinations of things together. This got us thinking about the many applications for a single molecule that could act as multiple therapeutics at once. In chemistry we call the act of bringing things together “catalysis.” When you have a catalyst, you can make things that might take 100 years happen in a few seconds. The applications are substantial. Elias [Zerhouni] left Sanofi about a year or two before I did, but we stayed in touch. As we realized that these products needed more care and feeding than they would get in the pharma environment, we started to strategize on ways that we could create a company to focus on transformative innovation.
9. ModeX has pioneered development of multi-specific antibodies and vaccines in oncology and infectious disease. What scientific breakthroughs enabled the founding of the company?
The first breakthrough was published in a 2017 Science paper. What we realized is that by using our knowledge of antibody structure, we could redesign the molecule in such a way that we could get three arms to bind a different target. Typically, when you make the old versions of bispecific antibodies you often will get steric hindrance of the proximal site by the distal site. And what we realized is that structurally you could put “kinks” in the molecule that would allow the arms to now engage independently. We used HIV as the proving ground for [multispecifics]. We then began to apply these agents to cancer [Nature Cancer 2020], where we developed a molecule for multiple myeloma: we could direct one arm to the myeloma cell, another arm to the T cell and a third arm aimed at keeping that T cell alive. That is really when we began to see that our knowledge of the biology could allow us to do a lot of innovative things.
10. In March OPKO/ModeX entered into a deal with Merck to develop an EBV vaccine candidate.
We are working to advance the EBV vaccine candidate into clinical trials. We're collaborating very closely with Merck, and it's been a very positive experience for us.
In terms of OPKO: Elias and I had the choice going it alone at ModeX or partnering. We ran into Phil Frost in Florida—he has built several successful biotech companies and had been a chairman of Teva Pharmaceuticals. When he heard about our work, he asked us if we would join him at his company OPKO. He bought into the vision and excitement around the technology. We eventually realized that it would just be a lot easier for us to work collaboratively with him take advantage of the infrastructure he had created. It has been a great relationship. Phil has also taught us a lot: he's experienced in the industry, founded multiple biotechs and been a chair of multiple boards. He understands the business, the medicine, and science, which is one of the things I most enjoy about working with him. I will get emails from Phil citing papers, and he stays very grounded in the basics.
With respect to the Merck collaboration, we had several projects where we thought we might work together. But as our discussions progressed, we realized: “Merck is the company that developed the HPV vaccine.” We have an EBV vaccine candidate that is in the sweet spot for what they do and where we want to go—it is potentially a vaccine that can prevent many cancers. If we want to have global reach with the EBV program, having a partner with deep experience in the area is crucial.
11. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries? Any advice specific to physician-scientists?
A lot of young trainees look at established scientists, and often think: “how will I ever get to that level. Look at all the stuff that these people are doing.” But it is important to be patient and realize that nothing happens overnight. The bottom line is that you need to crawl before you can walk and walk before you can run. If you build a solid foundation, you're going to be able to keep expanding your horizons.
When I talk to students, they often ask: “what can I do to be successful in biotech?” I suggest that they master the fundamentals first: learn how to do experiments properly, write a good paper, learn how to give a good presentation, learn how to prepare a grant. Those are skills that are transferable to anything you do, and you can build on them over time. If you don't do those well, you'll have no record to show for it and your options will be limited. I also like is a quote from Teddy Roosevelt inscribed on a monument in the National Park in DC. It says: “keep your feet on the ground while you look to the stars.” I really encourage people to look to the stars, to look for things that really make a difference and are impactful. But make sure that you are grounded in your training and your mastery of science and the things that you take on. When you're a combined MD PhD student, focus on what you're doing while you're doing it. When you're in the clinic, be the best clinician you can be. When you're in the lab, be the best scientist you can be. Don't be the best scientist while you're on the wards, you'll pay a price for that as a trainee.