Lab Meeting: Phil Sharp
“I grew up on a farm. I know what hard work is.”
In high school, math and science came easy. What worried a 15-year-old Phillip Sharp, was making the basketball team: “I played basketball for my high school in a small town in Kentucky…the game was considered a big event Friday or Saturday night. I intensely wanted to be on the varsity team” (Q#1).
He made the team—his self-described “enthusiastic” style often leading to more fouls than points (Q#1). Nonetheless a valuable lesson was learned: “[basketball] taught me if you really want something, you work hard, and understand how other people need you…well you can succeed.”
Just 15 years later (in 1974), the Kentucky boy who grew up on a farm and was the “muscle” for his basketball team, was recruited to MIT by Salvador Luria—to start his own lab next to the likes of David Baltimore and Bob Weinberg. Three years later (1977) his small research group published work describing the “split-gene,” and coined the term “RNA-splicing.” Within a month, he was famous: “It was totally intimidating,” reflects Sharp, now an Institute Professor at MIT. “The world exploded. You talk about viral ‘tweets’—back then it took longer than a day. But within a month, everyone knew this story” (Q#6). In 1993, he was awarded the Nobel Prize in Physiology or Medicine for his efforts.
The rest is history—one enshrined in our molecular biology textbooks. Sharp went on to develop systems to study RNA splicing in vitro, leading to the biochemical discovery of the lariat and spliceosome. His subsequent work on transcription factors, miRNAs and RNAi have yielded countless insights into gene expression, viral pathogenesis, the molecular hallmarks of disease, and development of novel therapeutics: “If you can work at the core of the problem, you will eventually have a bigger impact. The implications of what you find…will ultimately change everything” (Q#6).
A pragmatist (Q#8), Sharp knew that translating this work into therapies for patients would require efforts outside of academia. As co-founder of Biogen (1978) and Alnylam (2002), he is undoubtedly a founding father of modern-biotech—an exemplar of how rigorous basic science can translate to lifesaving treatments (not to mention profits for investors). Now an Institute Professor and Professor of Biology at MIT, Sharp maintains a lab in the Koch Institute: “Even now [at 78], I spend my days teaching, working with students and doing science” (Q#8).
As I sit across from Phil Sharp in his office to record this interview, I’m struck by how empty the rest of the building is. It’s a typical winter afternoon in Boston: bitterly cold, snowy, and already pitch-black outside. The lights are off in the other offices on the floor—many have opted to work from home or leave early to beat rush hour traffic made worse by the slush.
In his well-lit office, Sharp has printed out the interview questions ahead of time and laid them on the small circular table between us. With his characteristic enthusiasm, Sharp begins—he launches into his early concerns about coming from small town Kentucky, and wondering if the world of science would “accept” him. He discusses “taking risks,” and his decision to switch fields and move from Illinois to Caltech to Cold Spring Harbor. We touch on “disruptive science,” ranging from black holes and nuclear fusion to condensate biology and cellular “non-equilibrium” states. In recounting his personal history, Sharp is quick to pass the ball to others when assigning credit—praising Norm Davidson, Ron Davis, Joe Sambrook, Magda Konarska, Jerry Vinograd, David Baltimore, Wally Gilbert and many others.
MIT Institute Professor, Nobel laureate, biotech legend, scientific thought leader—the 15-year-old boy in Kentucky with hopes of making the varsity squad, may not recognize his future self. Yet I’d like to think that a teenage Phil Sharp would find one trait immediately familiar. Even at 78, Sharp is the consummate teammate –always prepared, willing to learn, placing others above himself (Q#6), honest about his stengths and weaknesses (Q#3). Most importantly, on those cold, dark winter days—even after winning every accolade—he still shows up, turns on the lights and puts in the work.
Below is an interview with Dr. Phillip Allen Sharp from January 2023:
1. I’ve heard that you are a basketball fan—do you still shoot around, and who are you rooting for these days?
I played basketball for my high school in a small town in Kentucky—so the game was considered a big event Friday or Saturday night. I intensely wanted to be on the varsity team, so I worked very hard. I'm not very talented at basketball, but I was enthusiastic. I think I still hold the record for number of fouls per minute at that high school. My senior year on the varsity team, we were 25-4 and we had a blast. I made great friends who I still have contact with. It taught me if you really want something, you work hard, and understand how other people need you, well you can succeed. In my frame of reference at the time, it was a significant growing experience.
I was always very strong in math and science, at this little rural school—that came easy. So, basketball was another component that was linked to my social life. I played intramural basketball in college and played up till I was 35 or 40 in Newton with friends. But once you get in that 45 to older range, I found you are just asking for an injury—particularly when you play with a young person. But I still played a bit, and I enjoy watching the Celtics.
My favorite Celtic is a fellow named Grant Williams. Grant came out of Tennessee, he's an engineer and is very accomplished at the collegiate level as an engineer. He was recruited to Princeton, but turned them down to play SEC basketball. He’s 6’ 5’’ and can’t jump—unlike a young Charles Barkley. To see [Williams] take his remarkable talents, and knowledge of the game, and turn himself into a player that gets on the order of 15 to 20 minutes a game on this great team is incredible. Last game, he scored 25 points [01/21/23 Celtics v. Toronto]. He plays such a clever game, and I've enjoyed watching him adapt himself to a pro game that is played above him in most cases. I also like Jaylen Brown, Jason Tatum and all the others. But Grant is the one I most enjoy watching.
2. In your interview with Sid Mukherjee (CUNY 2022) you said that coming from a small, rural town in Kentucky: “I didn’t know what the world was like, or how it would accept me.” Is there a short piece of advice you would offer to those in a similar position, as they pursue science?
The specific situation was that I grew up in a rural community on a farm without people around me who were college educated or held professional positions. The professions I knew [about] were limited to the doctor and the dentist, but none amongst the cadre of my family's social friends.
Coming from that community, I saw education as a way of expanding and opening up a world of possibilities. I wanted to go to a college where people [professors and students] would know me, and where I would be supported on a day-to-day basis with friendship.
Also, I wanted to find a place where there would be the expectation that people would encourage me. I went to a very small school called Union College in the mountains of Kentucky. The experience was very supportive, and taught me a lot. I was a very good student there. But in thinking of moving to the next level [grad school], there was a professor named Dan Foote [1935-2021] who had just come out of his educational training [chemistry PhD at Illinois]. He taught me and I worked with him as a teaching assistant for a few semesters; eventually he encouraged me to go to graduate school—he was the first one who said: “you can do it.”
[Would you have gone to grad school without Foote’s encouragement?]
I hope I would have. But I don't know for sure. It was very good and reassuring for somebody who was from a similar background and knew me [to help and encourage me]. So I applied to a number of schools but went to University of Illinois, where Dan Foote also trained. It was a very big state school, with an excellent chemistry department. I went there, and I failed three of the four entrance exams in chemistry. And they did exactly what they should have done—they told me to take three undergraduate [senior] classes. So I took all three senior classes, and did well. Then I got a PhD three years later.
For someone coming from a similar background—one that doesn’t have the scientist path in their social environment—I would say that you have to work really hard to discover these [professional] paths. At the same time, you're setting your expectations and your hopes for what you can achieve in your career—this is harder than for someone from a background where they are exposed to these careers in their social scene.
You have to build this “social scene” for yourself as you move through life, and in that way figure out if you want a life of reflection and being an academic, if you want a life of action, or whatever it is. Sometimes figuring all of this out requires taking risks.
3. What do you consider to be your first taste of running an experiment?
I grew up on a family farm. So, from the time I was six or seven, I was involved in chores. And by the time I was 9 or 10, I was involved almost daily in the summertime, and then before school and after school, I helped take care of animals. When you are farming, working with your hands and doing that sort of thing, every day is an experiment. Often, something doesn't work. You have to figure out why it doesn't work, and then how to take what's around you and make it work to get that job done. So it wasn't that I went out and bought a chemistry set—that wasn’t in the cards for me. But solving problems and experimentation was something that I did every day.
[Did you have an immediate aptitude then for experimental science in grad school?]
I did experiments in the laboratory in grad school, but most of my grad school work, and all of my publications were in theory. I would say that I'm too impatient to be a good experimentalist. Each superb experimentalist I've ever worked with has patience: Ron Davis, who is a Professor at Stanford, was unbelievably good. Joe Sambrook, who was a Professor many places and died and in Australia, ran beautiful experiments—he’d lay out a chart and it gave us all the controls, controls of the controls, and everything would be documented. Magda Konarska who is now in Poland and before was a Professor at Rockefeller—just a beautiful experimentalist. I'm not an orderly man. I'm not a great experimentalist so I design my experiments to be as conceptual as possible, using as direct a protocol as I can…and I was successful doing it, and getting others to work with me.
4. In graduate school you studied polymer chemistry, at what point did you become more interested in molecular biology?
As I was getting my PhD at the University of Illinois I came to the conclusion that I did not want to continue in biophysics. I wanted to move my own research into molecular biology. I had skills and knowledge of what polymers were like that most people did not, and I was fascinated by DNA. I understood a bit about DNA, Watson and Crick, the source of the information, how could you study it, manipulate it, and that genes were expressed from it. So, I really thought that was the most interesting area of science that fit my interests. I wanted to go and make the transition to molecular biology and find the environment to do that, because no one else around me was really studying this [in the Illinois Chemistry Department]. This realization led me to applying to Norman Davidson’s lab at Caltech. If I had not gone to his group, things would certainly have been different for me. But I did get an acceptance from Norman, and then I moved to an environment where my background and my interests were totally supported by people around me. There were great physical chemists like Norman, embedded in an environment of molecular biology par excellence at Caltech. In many places, as I look back throughout my career, there were specific events—if these hadn't happened, I would not be sitting in this position.
I think that's something you have to have faith, in or at least some expectations, if you're going to be successful. You have to say: “okay, this is so important to me that I'm willing to take risks. I may not succeed, and I can deal with that. But I need to take that step.” Illinois was a great environment where there were lots of very excellent people. I knew I had gained a respect by the time I got my PhD degree there. So, I was in a different position than when I first came to Illinois. But then there was this next step across the country, in a new area, with a totally new environment of people—so yeah it felt like a major step.
[What do you think made Norman Davidson accept you into his lab?]
I'm pretty sure he took me because my mentor at Illinois [Victor A Bloomfield] spoke to him, and said: “Phil's been in my lab three years. I've taught him everything I can teach. He’s the best student I’ve had.” I didn't know this at the time [but was told later this conversation took place].
I selected my mentor at Illinois [Bloomfied] to be someone I could talk to, and communicate with. I thought I'd get a lot of his attention, and I did, for which I'm very thankful. But it was a major transition [to Caltech]. At the end of my two-year post-doc with Norm Davidson [1971], the job market was just pathetic. I was making a move from one field to another, right? And it wasn't clear what I would do [for a next step]. I went on the interview tour: the places that I was excited about didn't make any offers, and places that I wasn't excited about made only some offers. I knew that I needed to “step up” my work—from studying bacterial systems into mammalian cells.
I wanted to study genes in eukaryotic cells and figure out how they were expressed. Pretty simple objective. But the only way you could do that at the time, was to do it was with DNA tumor viruses. A Caltech colleague of Norman Davison, adjacent to his lab, was Jerry Vinograd. He worked on SV40, and I became a friend of Jerry’s, attended his lab meetings, and we even published a paper on SV40 heterogeneity. So, I knew that I wanted to work on DNA tumor viruses. Luckily, Watson was starting a new lab at Cold Spring Harbor. He called, I applied to him, and he made an offer. The reason he made me the offer was Norman Davidson’s recommendation, I'm sure.
[What led you in first place to switch fields and use DNA tumor viruses to study mammalian gene regulation?]
In eukaryotes, I knew that at the level of defining a gene there was a big unknown. Yes, we knew what was going on in bacteria by and large—we had various genetic maps and were beginning to develop methods to map out some of the physical activity. This was all pre-restriction enzymes and recombinant DNA. But we knew what DNA tumor viruses were like, though we didn't know what how many genes they had. I knew that you could do electron microscopy and answer many of those questions. There was an opportunity to find some big questions that could be answered. I thought my particular set of expertise and interests were the strongest to find answer, so I went that way.
5. You worked with Norm Davidson (Caltech), James Watson (CSHL) and were recruited to MIT by Salvador Luria in 1974. What was it like being in such vibrant research environments?
My immediate neighbor, and I came to MIT in large part to be his neighbor, was David Baltimore. Bob Weinberg was also just recruited as a young assistant professor—same age as I was, in terms of academics. David's research program was viruses, early on mostly RNA viruses, and then with the discovery of reverse transcriptase, DNA viruses. He got the Nobel Prize a year after I came to MIT, so he was already famous at that point.
But I had my own independent interests in DNA viruses and their cell biology, not anything related to his [Baltimore’s] work. But we have enough overlapping interest in cell biology, biology, molecular biology that our two groups talked a lot. I found it easy to recruit postdocs, and graduate students in that environment with a common interest in molecular biology.
Using these viruses, what can we learn about how viruses cause tumors, and use them to study gene expression in viral systems? That was an extraordinarily exciting time [mid 1970s MIT]. There was no question that it was one of those vibrant environments in which people just came in and contributed to the ecosystem and made it a little more exciting, and a little more fun.
[Is there a parallel area today, where you have a tractable experimental system yielding lots of great science?]
Well, it's clearly CRISPR. If you take a broad view of CRISPR it is really: how to engineer proteins to interrogate systems. As you know, RNAi came along and was used to interrogate system, and now CRISPR is much more convenient to use because it is more black and white in terms of inactivating genes. This has given us a very powerful, high throughput way of doing science. There will be other systems [to interrogate biology] in time. RNA biology has proven to be a 50-year adventure. I still think there are exciting developments in that area to be made. I'm involved in work now that I think will lead to us rewriting textbooks—work regarding condensate biology and liquid-liquid phase transitions.
It's totally a fascinating new field. When viewed from the perspective of a physical property, it opens up a whole set of possibilities that we just hadn't considered before. And I often lie away at nights saying: “Oh, that could be true! Maybe I should talk to someone about it.” So I have been collaborating and discussing with Rick Young's postdocs and others in my lab. This work has really opened new and broad venues: as you said, all the way from neuroscience and synapse formation, to creating biological systems with memory. [Condensate biology] is just a fascinating conceptual advance.
6. Your discovery of the split gene in 1977 resulted in a new field, with many coming to unpick implications and mechanisms of RNA splicing—what was it like to be a young, relatively unknown scientist at the center of this frenzy?
Totally intimidating. It took us about a year to get to the point where we were confident enough to really publish the paper and talk about it. When we visualized those loops in that structure of a messenger RNA hybridized with the adenovirus (DNA) genome, I just knew it explained the observations of “heterogeneous nuclear RNA.”
You're too young, you've never read a paper with “heterogeneous nuclear RNA” in the title. When I was your age, there was a subset of the field—Jim Darnell and Bob Perry were major players in it—that described this very long nuclear RNA that contained sequences, as far as you can tell with the experimental tools you had of the mature message. But it was long, and it was capped on one end and polyadenylated on the other. As people showed when you looked in the cytoplasm, there was a cap and poly-A tail on the smaller cytoplasmic mRNA—but the difference between these (nuclear/cytoplasmic) RNAs were five to ten-fold.
We saw the splicing out of the intervening segments, and I was like: “Oh my god!” I knew that was the explanation, and I coined the term “RNA splicing.” In the Spring of ‘77, we started talking about it, especially at the Cold Spring Harbor gene expression symposium. We were major speakers there, and everyone in science seemed to be there: from Pierre Chambon to Richard Flavell. They all opened their notebooks at that meeting and also said: “Oh, my God.” They went back and the field just exploded that year: you will see ovalbumin from Chambon, globin from Leder, immunoglobulin genes from Tonegawa. The world exploded. You talk about viral tweets on Twitter--yes, back then it longer than a day. But within that month, everyone knew this story.
This discovery just went beyond the capacity of my lab at the time, which had five to six people. But they were all doing something for their PhD thesis, and I wasn't going to pull them off. My students were more important to me than pursuing all of these other avenues. But then looking at that whole spectrum [of remaining questions] I asked: “what is the most likely area where I can contribute? And that turned me to biochemistry.”
We then developing the system to do splicing in vitro. We finally did get such a system, which allowed us to see the lariat and the spliceosome—and that is where I spent the next 10 years, on that mechanistic work. I later added to that [the study of] transcription, and DNA binding factors and various things. So, I was working on transcription and the splicing process, by molecularly relating it to cell biology and oncogenes.
[All of us who are in science dream of making a fundamental discovery that pushes science beyond what any individual lab can achieve. In hearing you talk about your work now—gene expression, splicing, transcription factors, RNAi—it essentially comprises entire chapters or our molecular biology textbooks, and has led to countless other breakthroughs.]
You said something very important, and I put significant weight on it. When you are making decisions about what to investigate, try to study the “centrality of the system.” It may take you longer to understand, and may not be as instantly meaningful to people. But in the long term, it changes the world. There is a movement towards studying things that are more practical and have societal impact. This is very important, but I can tell you, if you can work at the core of the problem you will eventually have a bigger impact. The implications of what you find, and what other people learn from it, will ultimately change everything.
7. There was a paper published in Nature suggesting the “disruptiveness of science has decreased over time. The methodology and conclusions can be debated, but what are the “disruptive” and important problems you see being worked on today?
I’ve read the paper, and yes the methods can certainly be discussed.
In any case, I would say the following. Science has become such an important part of our day-to-day lives: our immediate health, the food we eat, the cars we drive, the way we communicate. If you take a portion the tools we use in our day-to-day lives and trace them all back: it's new technology, maybe not over 30 years old. It is very empowering. Life and progress are better than ever before.
What that tells you is we're continuing to make very important scientific advances. But the application of those advances to us in our daily lives is now more immediate, more generalizable, and impacts a much larger fraction of the whole scientific and tech community. You live in Boston, and we are in Cambridge: a significant fraction of people here work on the implications or translation of science. That’s also true in telecom. It's true in electric cars. It's true in almost everything we do, including food production. So yes, there are a lot more people today using science to make immediate impacts on society.
That said, the core [basic] discovery process is still very vibrant, and we have to keep it vibrant. But how are we keeping it vibrant? Are we really seeing new things?
You look at superconducting—we are now understanding ways of making superconductors out of new, more malleable materials. This is advancing theory but also moving towards having less expensive more energy efficient superconductors. Why is that important? Well, it's the secret to fusion. I can guarantee you fusion is the most important thing being studied, right now. Understanding this process will allow us to get adequate energy to continue this lifestyle. The whole physics community has been struggling between the gravitational and physical interpretation of black holes. We don't know what the outcome will be. We don't even know if we will ever be able to do it. But it will certainly require a re-drawing and new visualization of the nature of forces in the universe. So these are all big and “disruptive” questions that are exciting to watch
During this interview, we are batting things back and forth in our minds. We have no idea how humans are able to do this—thought, memory the nature of consciousness. And yet it's all chemistry, biology and synapses, and should [in theory] be knowable. We are currently bringing our technology to understand how individual synapses are reinforced through activity, and modulated by suppressor and activator circuits. This is a big important problem, with lots of disruptive science being done.
On a more fundamental level, we can't even describe the non-equilibrium state of a cell. I mean have you ever seen a textbook chapter on “non-equilibrium?” How [energetically] does the cell manage to carry out all of these orderly reactions? Synthesis, regulation, signaling, replication, duplication, and maintain itself as this non-chaotic, we think, set of processes away from equilibrium. Classically, we describe the cell in a state of equilibrium biochemistry, but it’s not.
This is a bigger problem than we have admitted. We want to understand aging, and we want to understand chronic diseases related to aging. These are fascinating core problems that we have not been able to solve in a satisfactory way, in part because we don’t understand the non-equilibrium state of the cell.
I have a good friend and collaborator Arup Chakraborty, who is a chemical engineer, physicist and chemist. He's working with condensates now, but we have a paper describing how transcriptional system can be viewed as a non-equilibrium system. For example, you form a transcriptional condensate paired with a promoter, and a burst of transcription feeds back to dissociate the condensate. We know the transcription “bursts” and the condensate “blips.” This is a very interesting finding, but it’s a microcosm of a bigger process.
8. You co-founded Biogen and Alnylam, two pillars in pharma/biotech. Initially what motivated you as a founder—when starting Biogen with Wally Gilbert in ‘78?
In the spring of 1977, I got a call from a venture capitalist who invested in nickel and metals, but trained at MIT as an undergrad. He wanted to find someone from MIT who was relatively young and in this new field of molecular cell biology. So, he called me and I went to California to help him look at a company, called Genentech. I didn't understand what was going on when he initially reached out. But soon I knew he was for real and a serious guy because I checked him out with another professor here at MIT. So, I thought it was worth a ticket to California.
And so we met people who were the founders of Genentech, Swanson, Boyer, Riggs, Itakura. They laid out the synthetic chemistry of making insulin and growth hormone, and how they were going to do it, deals with people to fund this research and produce synthetic insulin. I told Schaffer [VC], I I didn't know if they can make a buck but they were certainly going to do this science. Schaefer did make a sizable, but not large investment, and got a big part of the company actually.
And back in Boston I started talking with Wally [Gilbert] and some European colleagues. We had this amazing new science that turned into the technology of sequencing DNA, synthesizing DNA, recombining DNA—we were doing synthetic biology. We'd never been able to do synthetic biology. We had previously always took what nature had given us. I came out of Illinois in chemistry—three out of every four grad students was going into industry.
Taking this [synthetic biology] technology, it felt we were sitting at the origins of synthetic organic chemistry. I just felt like: “we know how to do this!” I was much more interested in seeing the process of synthetic biology become a professionally practiced technology that could really benefit people—in medicine and energy and materials. So that was happened in 1978, and Biogen was going to do it all. Well, that didn't turn out quite that way. But they became a very important pharmaceutical company, and I'm totally proud. We had to hire everyone initially, all out of academia. There was no one in Pharma at the time who really knew this technology. They said: “you’ll never be able to make it work.” Originally, we made a big bet on making recombinant interferon. In the mid to late 80s that led to an interest in multiple sclerosis with interferon-beta…and in development of other products. I was on the board for 28 years or something like that, and chair of the SAB for most of that period.
[How has the relationship between academia and industry changed?]
No one comes into MIT or Harvard now that has not been in the in the immediate environment of a faculty member who is deeply involved in either starting a company, being a member of a Scientific Advisory Board, or consulting in biotech. So it's a very different world than in the 1980s. When I got involved in Biogen, I went to the head of the department and asked: “who around here is involved in consulting with pharmaceutical companies?” There was only one person that was visible, Irv London an MD, PhD working with J&J.
[What do you think of this trend?]
I'm a practical guy. I grew up on a farm. I worked with my hands. I know what hard work is. So these types of collaboration are necessary to be able to make people's lives better, treat disease, provide food and other ways of enhancing our lives. These advances will hopefully allow us to be more human and more interactive and supportive. That’s something I find very valuable, and I’m very pleased that I've been able to help. It's made my life much more full. But even now, I spend my days teaching, working with students and doing science.
9. Any books that you are reading in your spare time, outside of the lab?
I just finished reading Song of the Cell by Sid Mukherjee, and greatly enjoyed it. New science, history of discoveries, patient stories and his own experiences are mixed in a lively engaging text. I have read all three of Sid’s books with pleasure. In my opinion, the Song of the Cell is his best writing. Hoping he will write more books. I also just read another book about the pandemic and the first lung transplant to save COVID patients by Ankit Bharat: Innovation Amid Despair. Ankit is a lung surgeon in Chicago and tells striking stories of the struggle to save the lives of severely infected patients. It is about passion, commitment, and innovation.