Lab Meeting: Mike Rosenblatt
“The biggest breakthroughs are those that wipe away disease.”
At 31 years of age, Dr. Mike Rosenblatt hurried home to tell his wife that they could finally unpack the boxes in their basement. He had a job offer.
The offer was quite something: “when I became the Chief of Endocrinology at MGH, I had just turned 31. It was my dream job,” recounts Rosenblatt, now a senior advisor at Flagship Pioneering, Ascenta Capital and Bain Capital Life Sciences. After all, this was the department that first used parathyroid hormone to treat osteoporosis, developed radioactive iodine to combat hyperthyroidism and conducted early studies pointing to the use of GLP-1 in diabetes. Working with Dr. John T. Potts,Jr., Rosenblatt had already helped uncover the structural basis by which parathyroid hormone (PTH) activated its receptor. The newly minted chief of endocrinology figured that he, his wife and their recently unpacked boxes would never leave Boston or MGH.
But just 3 years later (1984), Rosenblatt found himself leading the colossal Merck, Sharp & Dohme Research Laboratories. The career change was motivated by several factors, including science and clinical impact. Chief amongst them was his own mother’s example: “What enabled me to make that change [to industry] was the model of my mother. When I was eight years old, my father died. My mother took over his business…I saw her learning something new, challenging herself and doing good work.” Because of her influence, Rosenblatt didn’t reflexively see industry as a negative. Rather, he saw the power of industry to help patients by inventing new therapies for unmet medical needs.
It was at Merck that he learned drug invention and development from the likes of Roy Vagelos, and pioneered the clinical development of alendronate (FOSAMAX) for treatment of osteoporosis. Rosenblatt found that impacting drug development entails both external and internal challenges: “we had to convince Merck to take this gamble [to develop FOSAMAX], against great skepticism.” It paid off: the drug became a blockbuster and is still the most widely prescribed drug for osteoporosis. After then going back to academia (to Harvard and then as Dean of Tufts University School of Medicine), Rosenblatt returned for his “second tour of duty” at Merck (2009-2016): “it was a bit different this time, because I was the chief medical officer…my job was to be the voice of the mission. To remind people that even when there are commercial pressures, we're here for patients.” Since 2016, Rosenblatt has been at Flagship Pioneering—first as its CMO and now as senior advisor. In addition to advising many companies in the Flagship ecosystem, he played a pivotal role in helping Moderna navigate clinical development of its mRNA-based vaccine during the COVID-19 pandemic (Q#9).
Harvard medical school graduate, 31-year-old chief at MGH, Professor at Harvard, Dean at Tufts, Chief Medical Officer of Merck and then CMO of Flagship Pioneering. Rosenblatt’s CV reads as if he has waltzed from one success to the next.
The man himself is somewhat more circumspect about his career. The first in his family to go to college, Rosenblatt at one point thought he should resign from his post-doctoral lab position after a series of failed peptide syntheses (Q#3). As a medical intern, when he missed a diagnosis of tetanus, he tendered his resignation to the chief of medicine. Fortunately, in both cases, his mentors encouraged him to keep going.
When asked about his success, Rosenblatt replies: “People were willing to take a gamble on me… I actively sought out mentorship and as a result they felt a sense of ownership.” He gives similar advice to trainees looking to succeed in academia or industry: “surround yourself with people you really admire…and from whom you can learn a great deal.”
Above all else, Rosenblatt suggests that the only part of a career one can truly plan is its guiding force: “careers often encounter a lot of challenges or stresses. I think you need to have a North Star…you need to know what is going to guide you through a crisis.”
Whether re-designing healthcare systems, uncovering the innerworkings of the cell, synthesizing drugs, or designing novel algorithms, following one’s North Star is key: “I believe health can be improved most through new therapeutics…the biggest breakthroughs are discoveries that wipe away disease,” says Rosenblatt. In closing, he poses the question to those just starting out: “What do you believe in? Which principles guide you?”
Below is an interview with Dr. Michael Rosenblatt, from February 2024:
1. What was your first taste of science and medicine? Briefly, what about this initial experience drew you in?
In high school I liked the sciences, but also enjoyed the humanities and literature. I thought I was headed towards chemistry or engineering, but one of my high school teachers said: “if you want to combine the humanistic element with science, you should think about medicine.” Nobody in my family was a physician—actually I was the first person in my family to go to college, let alone medical school.
When I got to Columbia for undergrad, I had a transformative experience in science. I was pre-med, so I was taking organic chemistry. There was a famous chemistry professor at the time named Gilbert Stork. He asked the graduate students who ran the laboratory course to find him one or two students who could work in his lab.
I got nominated, so instead of taking the actual organic chemistry lab course, I worked in the Stork lab.
What was special about this situation was that Professor Stork felt his grad students and postdocs should be independent and figure things out things for themselves. If they needed him, they would call him. But he loved being in the laboratory and working at the bench. So, he used us college students as assistants to help run his own experiments. We would come into the lab and get to work shoulder-to-shoulder with one of the giants of organic chemistry. So I did that for two years, including summers, and I just couldn't get enough. It was just so much fun and so challenging. The only downside perhaps was that he [Stork] was brilliant—at the time, I didn't have the perspective to realize that not everybody was a Gilbert Stork. I honestly felt that compared to him, I could not make it as a chemist. So I decided to pursue medicine instead. But I just loved the whole discovery process of research. I loved the fact that I could do something new in the lab. I loved that there were all these instruments I could use to tell me what was going on with molecules—or eventually with cells, as my research became more translational.
2. What was medical school like for you?
Going into medical school, I thought I would likely wind up being a doctor in Northern New Jersey. While growing up, I loved our family doctor. He was my “model” of a physician. I had no knowledge of a career in academic medicine—I didn’t know such careers existed. When I got to Harvard Medical School, I met physician-scientists for the first time, and a light bulb went off.
I’ve had several mentors who have really helped my career. My advisor in medical school was a man named George Cahill, who was a famous endocrinologist based at the Joslin Clinic. I really like reasoning out signaling pathways, so had an interest in endocrinology. It was also a specialty where I felt there was not as much memorization: you either have too much or too little [hormone], and there are only 10 glands that are truly important. I went to Dr. Cahill and asked to do research in his laboratory. He was not taking students at the time, but recommended working with Dr. John Potts at MGH. Potts was using peptide and protein chemistry—this was long before recombinant DNA technology—to study parathyroid hormone. I was initially reluctant—I didn’t find the medical school lectures on calcium and bone to be that interesting. But after I met with Dr. Potts, I became fascinated with his work. The problem I went on to study during my fourth year of medical school was: how does parathyroid hormone [PTH] bind its receptor? Where does it specifically bind, and how does this lead to receptor activation? Over the next decade, I then went on to design inhibitors of this interaction based on structural characterization of PTH and its receptor. It was painstaking work—we didn’t have the same NMR or crystallography techniques available—but I loved it.
3. What were some of the highpoints and lowpoints during your training as a physician-scientist?
Research entails long stretches of working on a question without any positive feedback. Then one day, you get an answer to the question. This answer either depresses you, or makes you ecstatic. If you are hooked on the process, no matter the answer, you go on to do it again. It’s a manic-depressive exercise! I'll share one high point and one low moment.
One of the “highs” was when I was studying how hormones bind and activate G-protein coupled receptors (GPCRs). This is a general problem of potential clinical significance. I finally figured out and mapped the activation domain of parathyroid hormone after it bound its receptor. I reasoned that if we chopped off the activation domain, the modified PTH could still bind its receptor but block the function of endogenous hormone. In other words, by removing the activation domain we would create a hormone inhibitor. I’ll never forget looking at the data from our scintillation counter—seeing that we could block binding of endogenous PTH with our inhibitor. A related success was that in order to figure out the touch points between the hormone and the receptor, I had inserted photo-activatable moieties in place of certain amino acids. These moieties allowed us to use light to crosslink PTH to its receptor, and then shear the protein to find the actual points of contact between the hormone and the receptor.
A very low point occurred when I was working for John Potts at MGH. He had a team in the lab doing peptide synthesis and sequencing. These key team members were Australian, and decided to go back to Australia for family reasons. The lab was disrupted. Dr. Potts thought that I should travel to Australia and learn the peptide synthesis and sequencing techniques from these two former lab members. It was a great opportunity, and I took it very seriously. I went to Australia for several months to learn how to chemically synthesize PTH analogs—or at least the 34-amino acid long active fragment. I came back to MGH with my “chest all puffed out,” confident in my skills. When I got back into the lab, the first synthesis failed. The second did as well. I was crestfallen, but my mentor told me to try again: “these things happen.” I tried for the third time, and again it was a complete failure: the material was totally dead.
At this point, I felt I had no choice. I thought I better go resign. I went to Dr. Potts and said: “you've invested in the wrong guy, and I can't make this work. I don't know what's going on.” Fortunately, he didn't give up on me. We eventually worked it out and made good products. I had a similar low moment when I was an intern at MGH.
I was medical intern at MGH. In the first two weeks, I saw these cases that I had never learned about in medical school: for instance, I saw someone with leprosy and another with transposition of the great vessels. I also saw a patient with tetanus—actual tetanus—and I missed the diagnosis. I went to the Chief of Medicine and said: “either I have to quit this residency, or I need to come back next year after learning what I somehow missed in medical school.” He paused and then asked me: “what did you do when these cases came in?” I replied that I was unsure, so I called in the specialists from each field. He replied: “Well then I think you're going to be okay Mike.” I learned that it’s good to know what you don’t know and a good consult goes a long way in clinical medicine.
4. You graduated from Harvard medical school in 1973 and eight years later were chief of Endocrinology at MGH. What allowed you to ascend so quickly?
I have always had great enthusiasm for what I am doing. I actively sought out mentorship The connection that you make with a mentor gives him or her a sense of ownership in you. They start supporting you. I really needed this support because I had no knowledge of how careers work in academia. Perhaps this “ownership” is what led Dr. Potts to put his faith in me. Potts was the chief of the endocrine unit, and I was just one member of a very large integrated division. He then became chairman of medicine and had to choose his successor. He chose me—the youngest guy in the whole group. Part of it was a successful research trajectory, but I also helped fix the administration for the endocrinology outpatient clinic, which was a mess. So, he felt that I had administrative talents and the potential for leadership.
But your question points out the ethos of the time. People were willing to take a gamble on young people who had not “completed every step,” or climbed the career ladder in a conventional step-by-step. Higher ups were willing to promote based on the notion of raw talent. MGH was at one time famous for this ethos. The former chief of medicine—a man named Walter Bauer—made an endocrinologist the head of arthritis. The longtime head of cardiology was an immunologist, whereas the head of endocrinology was a nephrologist at the start of his career. These folks were all young and Bauer was just betting on the best athletes. There was a desire to keep really talented folks within the institution.
5. Who were some of your early clinical or scientific mentors?
I mentioned Gilbert Stork and John Potts. Later on in my career, Dan Tosteson became a close mentor. He helped me figure out how to navigate administrative responsibilities vs. research vs. clinical work, and how to innovate in education. Dan was an intellectual giant. He inspired me. I really am grateful to him for doing that. He pushed me when I was mid-career to take on new challenges outside my comfort zone.
6. What led you to transition from academia to industry?
When I got the offer to be the Chief of Endocrinology, I was 31 years old. It was my dream job, and it was arguably one of the historic seats in US or global endocrinology. I remember coming home and telling my wife: “We can unpack all of the boxes in the basement because we won’t ever leave Boston.” But over the next three years, I started to meet the folks at Merck. At that time, they had several drug discovery programs in endocrinology, and I started to consult for them. I would go down to their headquarters three or four times a year to meet with various researchers at the company. For me, a whole bunch of myths got blown away. One myth was that the only smart people were in academia, and the people in industry were intellectually “second class.” When I was talking to the folks at Merck, they were every bit as smart as the people at Harvard and MGH. The second myth was that: “folks in industry are only motivated by money.” Not true—they were motivated to create drugs that made a difference to patients. I started to realize that in all of my grant applications, the “preamble” was always the same: if my research is successful, it will provide insights to pathways that will enable us to make drugs.
I began to feel that the people at Merck were doing what I had been claiming to do in my grant applications: make new medicines. By happenstance, during this time a major position at Merck opened up. They offered me the job because they didn’t have an internal successor. I was tasked with converting a chemistry-oriented organization into one more focused on biology and medicine.
What enabled me to make that change was the model of my mother. When I was eight years old, my father died. My mother had to take over his business with no technical experience. When I was growing up, my mother would discuss business challenges with my younger sister and me. I always thought these challenges were interesting—and I certainly never viewed “business” as evil. My mother was learning something new, challenging herself and doing good work. When I was thinking about going to Merck, I had lots of people tell me that I was “crazy” and that my career would be “over.” Many said I would become “totally forgotten.” I felt that the model of my mother gave me the confidence to make this change. In addition, I had already gotten to the place I dreamed about in academia—chief of endocrinology. At this point I felt open to anything—especially once I saw the exciting science going on at Merck.
7. What were some early lessons about how operating in industry was different from your positions in academia? What series of events led to the development of FOSAMAX?
Joining Merck was a huge learning curve. To be honest that is part of the reason I did it. My prior training did not teach me anything about making a drug: there are whole scientific disciplines inside pharmaceutical companies that aren't represented at all within academia…areas like safety assessment, drug metabolism, formulation. Compare this breadth with my previous work, which was being an expert on parathyroid hormone. At Merck, I was suddenly in charge of an integrated unit that covered areas like cardiology, GI and nephrology. At the time there were no endocrinology programs in the division that I was recruited to lead. uI had to learn about therapeutic areas that were new to me, in addition to learning how to make drugs. In many respects, it was terrifying. However, I had very experienced people helping me. By the end of the first year, I started to feel comfortable. But it was an illusion--by the end of year two, I again realized I knew nothing!
I was lucky that the Head of Research at the time was Roy Vagelos. During my annual reviews, he would always say: “Mike, you're an expert in bone and calcium. There must be opportunities in osteoporosis…why aren't we working on that?” At the time, we didn’t have any clear targets. But by the third year I was at Merck, I felt the science had matured a bit. Around this time, we tried to license the drug that became FOSAMAX. The drug [alendronate] was the chemical discovery of a little Italian company, Gentili—but as Vagelos liked to say: “it was a biological and medical discovery of Merck.”
[On the development of FOSAMAX]
The Italian company that developed the drug was looking at an important medical application: the hypercalcemia of malignancy. Breast and prostate cancer metastasize to bone and cause massive amounts of calcium release. This bisphosphonate compound looked like it would work there. But we understood the biology—that if you blocked osteoclast function and halted osteoclast resorption, you could give bone a chance to recover. Osteoporosis is a disease of too much bone resorption. When we saw the early data for alendronate, we knew it had the potential to be applied in this larger indication. Ultimately it was a roll of the dice that this molecule would work. A small group of us had to convince Merck to take this gamble, against great skepticism—it paid off and the drug became a blockbuster.
8. What advice do you have for physicians and scientists who also want to jump to industry to develop drugs? When is the “right” time do you feel?
In academia, individual contributions are very much the coin of the realm. The roster and order of authors on a publication is very important, as well as where you publish. In industry, it is much more of a team effort. There is an understanding that to take a drug all the way from the laboratory to approval is a campaign, often involving hundreds of people. You need to be a team player.
Another point is that in industry, you always have a boss. I don't care what level you are—you answer to someone in a way that is quite different than the relative independence of academia.
In industry, the company makes strategic decisions to focus on some areas that are hot--the way oncology, rare disease and immunology are now. That means stopping other programs. If you are unwilling to “reboot” and learn new things, then you are going to have a problem in industry.
There are many potential jumping off points from academia to industry and many good reasons to make that transition. However, if you want to enter industry at a level where you immediately help decide the direction of where a company goes, it is better first to remain in academia for long enough to become an expert in a field. It gives you credibility in science and medicine. I tend to advise young people to wait a little bit [before going to industry]. If a student really wants to become an investor or work in biotech immediately, and can’t picture going through additional years of training, the I encourage them to make the switch earlier. But making the MD “real” by finishing residency is valuable in my view. Learning how to write grants and do science well is also a valuable.
9. Leading some of Merck’s clinical development programs you must have gained a broader perspective on drug development and the biotech ecosystem. What were some of these learnings?
After my “first round” at Merck, I went back to academia for nearly two decades. I then returned to Merck for a second “tour of duty.” This time it was a bit different because I was the chief medical officer. I realized that the big pharma companies—Merck, Novartis, J&J, GSK—are mission-driven and have a deep commitment to patients and shareholders alike.
When I came back as CMO, my job was to be the voice of that mission—remind people that even when there are commercial pressures, we exist for patients. We are here to create new medicines. Ironically, I thought being CMO would entail mostly being the person who “blows the whistle” and says that a drug is not safe; to be a voice of extreme caution above all else. It turned out to be quite. Merck [and other large pharma companies] are so conservative that sometimes they lose sight of the reason a drug is being developed. Often I had to remind them that: “diseases also cause problems and adverse effects.” You've got to hold up the adverse events of the untreated disease versus the potential adverse effects of a drug. in a drug trial. I learned that being the voice of patients often entailed pushing the development of certain programs forward when the benfit:risk ratio is appropriate, rather than holding the drug back.
10. What led you to Flagship Pioneering in 2016? What excited you about that move? What excites you about your current work?
After about 10 years working at Merck, I began to feel like I wanted to learn something new. What was attractive about Flagship Pioneering is that they have a distinctive methodology: they're not a traditional venture capital firm. Unlike VC’s, they are an organization that creates new companies: with their own scientists, discoveries, and methodologies in its own labs. They are always pushing the boundary, and on the edge of science. Flagship begins the creation of all their companies with a simple question: “what if?…” The creation of Moderna was based on: “what if?” we could make the body into a molecular factory? What if we could use mRNA to make peptides and proteins that the body could use to fight disease. Coming from big pharma, I was intrigued by that methodology. For me, this involved unlearning some of the “de-risking” strategies I used in the past. If you are at big pharma or even academia, you have to point to existing data, otherwise taking a risk with no preliminary data would lead people woto think you are crazy. At Flagship, you create a supposition and you start the project without data or existining publications, with little justification for taking on risk other than if you guess right, you wil have a breakthrough.
[On Moderna]
In the second week of January 2020, I called the Chief Medical Officer of Moderna—Tal Zaks.
I said: “I am looking at this report from Wuhan, China. There is this virus there. I wonder if our mRNA technology could be applied to making a vaccine.” He replied: “Mike you are about a week late. We've gotten the sequence, and already started.” Tal was a first time CMO and asked me to help him navigate calls from the CDC, FDA and other regulatory issues. Moderna went all in—they put other projects on hold and “bet the farm” on their technology. By the way, mRNA was highly doubted by 90% of those in academia—almost everyone I spoke to in early 2020 said that RNA is too short-lived and inflammatory to be used be useful in humans. Of course, when it worked, they said it was “obvious” from the start! The company took a huge risk, and their leadership is to be commended. It was a intense, once-in-a-lifetime experience for. To me, it really illustrated how exciting platform technologies that can be applied to multiple areas can truly be.
11. Any parting advice for trainees in science or medicine?
A couple parting words of advice. It is important to know who you are, and who you are not. Be honest with yourself about that. What do you really like to do? Second, careers often encounter challenges or stresses. You need to have a North Star: you need to know what is going to guide you through a crisis. My North Star is patient impact, and it has guided me through several career crises. More than that, I believe health can be improved most through research that leads to new inventions, new therapeutics. I think making health systems more efficient is terrific. But the biggest breakthroughs in health come from discoveries that wipe away disease. I'm a great believer in research as the tool to change health. Ask yourself: what do you believe, and which principles guide you?
Another point is that I didn't plan any part of my career. There is just too much that is up to chance, and things aren't going to work out the exact way you want. I advise people early in their careers to just take it one step at a time. A final piece of advice applies to when you are assuming a new role or job. The three things that I looked for always are: one, how can I contribute? Do I feel that I can help with the mission? Second, will I learn new things? Third, what is the quality of the people involved? What is their reputation? Are these people I will enjoy being with? Ask yourself these three questions whenever you are making a career decision.