Naji Gehchan: Welcome to SpreadLove in Organizations, the healthcare leadership podcast where we explore leadership with purpose.
I’m Naji, your host, and I’m delighted to be joined today by Richard Ransohoff, a renowned neurologist, scientist, and biotech innovator who has spent more than four decades advancing our understanding and treatment of neuroinflammatory disease.
Richard spent 30 years at Cleveland Clinic, where he founded and directed the Neuroinflammation Research Center and cared for patients with multiple sclerosis before moving into industry leadership at Biogen, where he led neuroimmunology and ALS research and early development.
Today, Richard is a venture partner at Third Rock Ventures, where he focuses on building companies around major unmet needs in neurology, immunology, and neuropsychiatry.
He is also a scientific co-founder and clinical advisor to Abata Therapeutics and helped launch Trace Neuroscience.
With more than 460 scientific publications and over 125,000 citations, Richard has made an extraordinary impact on the field. But perhaps even more importantly, he has trained generations of scientists and physicians and helped translate scientific discoveries into new possibilities for patients.
Richard, welcome to Spread Love in Organizations. It’s a real pleasure to have you with us today.
Richard Ransohoff: Thank you, Naji. I’m delighted to be here.
Naji Gehchan: Before we talk about science, companies, and the really inspiring and incredible career you’ve built, I’d love to start with your personal story.
What brought you to medicine, ultimately neuroscience, and now the biotech industry?
Richard Ransohoff: First of all, thank you for the kind introduction. I’m blushing. Nobody can see it, but it’s true.
I’m tempted to start my personal story by saying, “How long do you have?” It was a long and winding road. A great Beatles song, and not such a bad experience for me either.
I began my life in academia as a literature major at Bard College in the 1960s. Bard College at the time, before the years when it emerged as a leading liberal arts college, was a small, sleepy liberal arts college, but it had a terrific literature program.
I was fascinated by books and reading, and I joined the literature department at Bard College. I had a wonderful education there and made some lifelong friends. Even though that wasn’t where I ended up, I was grateful for the experience.
Subsequently, after a couple of years of wandering around, I moved to New York, where most of my friends were living, and got involved in what was essentially a nonprofit job as a poetry editor for a small periodical.
I still needed to put food on the table, so I got a job at Lenox Hill Hospital as a nighttime admitting clerk.
This meant that I brought patients into the hospital, registered them, and then brought them to their rooms. In doing so, I got to learn about all kinds of relatively critical events that were going on in people’s lives. I also got to meet people who worked all over the hospital.
Lenox Hill was a place that, particularly back then, had an extremely mixed clientele. Part of the clientele came from Park Avenue and were extremely well-to-do, while part came from Second Avenue and First Avenue and had more modest means. They all came to Lenox Hill in these critical circumstances when they were being admitted to the hospital.
What turned out to be the case was that I found the hospital environment galvanizing.
This was during the evening hours, from 5 p.m. until midnight. It was really an exciting place to be, and it drew me away from a world that was only books to start thinking about a world that was more real life.
In a moment of borderline insanity, I decided that I wanted to be a physician.
I had zero background in science. As you know, to apply to medical school in the U.S., you need to meet certain essential criteria before you can even take the exam.
So I began taking courses during the daytime while I continued to work nights at Lenox Hill, and then subsequently at Beth Israel and Bellevue Hospital.
I sort of ascended the nighttime administrator ladder while taking my science courses at Hunter College during the day.
Strangely enough, this turned out to be a very happy time in my life. I finally had a focused direction, and the science courses, even without any background, turned out to be manageable.
I started, as you’re supposed to do when you’re starting a new medication, low and slow. I took one course at a time so that I’d have plenty of time to focus on my studies while working nights.
After five years, I had accumulated all the credits I needed, taken the MCATs, done reasonably well, and could apply to medical school.
I went to Case Western Reserve in Cleveland, which had a history of accepting people with unusual backgrounds.
In addition to having the biochemistry and biology majors who make up most of a medical school class, Case Western had a specific mission to bring people with unusual backgrounds into medicine and mix them in with the class to add a little bit of flavor.
So you could think of me as oregano in that sense, in the mix of the medical school class at Case Western.
It was also a place with a mission to remake medical education. It pioneered the organ-system approach to medical education, as well as the problem-based approach, both of which became standard throughout the U.S.
I got to experience medical education in a place where it was taken very seriously and where the students were a considerable focus of attention.
I had a wide-ranging experience through medical education and got to see every aspect of what a professional career could look like.
Much to my surprise, I ended up determining that I wanted to be a physician-scientist.
I had taken the straight MD route. I hadn’t gone the MSTP route because I didn’t even know anything about it when I applied to medical school.
But as I began my postgraduate training, I set aside a decent amount of time to begin working in the lab.
The first takeaway message from my experience is that even if you don’t decide when you’re 10 years old what you’re going to be and start preparing for it, you can still have a successful career.
If you’re going to be an Olympic figure skater, probably 10 years old is a good place to start. If you’re going to be a professional tennis player, the same thing.
But at least for the kind of work I’ve done during my career, it turned out that I could make decisions later than most people and still have a decent career.
I firmly belong in the “better late than never” camp.
I believe you should never give up on your dreams, even if your dreams come to you a little bit late while you’re still waking up from your deep sleep.
During my postgraduate medical training, which included a full internal medicine residency and then a neurology residency, I trained in hospitals in Cleveland. My internal medicine training was at Mount Sinai, a Case Western affiliate, and my neurology training was at Cleveland Clinic.
I began doing apprentice work in various research labs and learned what to do after picking up a pipette to conduct an experiment: how to design an experiment, how to begin interpreting data, and what questions are interesting to ask.
When I finished my neurology residency, I determined that my core interest was multiple sclerosis, in 1984.
This was well before there were any treatments for multiple sclerosis and somewhat before the idea had become solidified that MS was, in fact, an autoimmune disease.
You could make an argument in favor of many other hypotheses, including a chronic viral infection or a neurodegeneration of myelin for which the inflammation was reactive, and so forth.
This was also well before the genetic architecture of MS had been understood. And without any treatments, you couldn’t make hypotheses about what would work.
At the time, what seemed to be the right path for me was to obtain basic research experience because I didn’t have a strong hypothesis about the biology of MS to pursue.
So I stayed in Cleveland. There was a tremendous new investigator at Case Western Reserve, the late Tim Nilsen, who was a molecular biologist.
This was the early era of molecular biology entering biomedical research, and Tim had both a compelling project for me and the opportunity to work in a lab that was just getting started, so I could be exposed to everything.
Tim became an extremely prominent RNA biologist, founded the RNA Center at Case Western Reserve, and directed it for many years. Sadly, he passed away a couple of years ago.
I stayed in Tim’s lab for nearly five years, getting a ground-up exposure to molecular biology research.
By pure coincidence, the project Tim had for me involved the mechanism by which type I interferon treatment inhibits influenza virus replication.
That was an unanswered question at the time. This was even before the discovery of a protein called MX, which specifically inhibits flu virus replication and is induced by interferon.
It was a sort of white space in which to work.
It gave me exposure to interferon biology, which turned out to be an important topic in the pathogenesis of MS, again, just by pure dumb serendipity.
Because this was the era of molecular biology research, before there were a lot of kits and off-the-shelf reagents, I got very hands-on exposure to molecular biology research. That turned out to be extremely helpful when I set up my own lab.
I stayed with Tim, as I said, for nearly five years. During that time, I was able to attract funding from the MS Society for a junior faculty award called the Harry Weaver Award, and also a physician-scientist award from the NIH called a K08.
At the end of that time, I returned to Cleveland Clinic, again by pure dumb luck of timing.
Cleveland Clinic had just attracted a large private gift to set up an MS clinic. I had the advantage of being able to focus my clinical practice entirely on multiple sclerosis and learn from the disease full-time.
That was my clinical practice.
Naji Gehchan: That’s amazing.
And Richard, why MS specifically as you moved from poetry? I love that every time we meet, I learn something new about you.
It’s still brain and intellect, but was there something intriguing about MS specifically that drew you to this disease and to spending so many years researching it?
Richard Ransohoff: Yes, and it wasn’t the type of decision that I wish I had the capacity to make.
When I was a teenager, the James Bond books by Ian Fleming came out. Each book had a supervillain, somebody of great talent who unfortunately turned their powers to evil.
Ian Fleming would always tell a story in which the supervillain surveyed the world and saw something just over the horizon. They would understand that if they cornered the world market in lithium, for example, they would have power over every country and every person.
Something like that.
That was never me. I was always impressed that these supervillains could see exactly how to gain great power.
My interest in MS came because there was a particular neuroscience professor at Case Western Reserve when I was a medical student. His name was Ted Venida, and he made neuroscience galvanizing.
That put neuroscience in play, and there were several professors of immunology who interested the hell out of me.
When I put the two together, MS emerged from that intersection.
It wasn’t that I saw it as something that was going to rule the world. It just happened that the people who interested me were the neuroscience people and the immunology people.
MS was the most important intersection in terms of the number of patients, unmet medical need, and mystery. It was intriguing to work in a field where the disease wasn’t understood and there was no treatment.
That really drew me in.
Naji Gehchan: Yeah. And the field has been lucky to have you in it since you started. No, seriously, all the research you’ve done.
It’s interesting, and I want to explore how you built your lab and how you’ve mentored, helped, and taught so many physicians and scientists.
It’s really interesting that it started for you with other mentors and teachers, and you basically took it forward and did it for tens and tens of other scientists and physicians.
Tell me about the phase when you went to Cleveland Clinic and built your own lab. There’s some poetry in all those publications and citations, too. Tell me more about that phase.
Richard Ransohoff: I will say that the connection between poetry and science, somewhere in my imagination, is very direct.
Poetry is all about precision and concision. It’s the right word in the right place, always. A poem is a piece of writing for which, if you move a single word, it’s not the same anymore.
One of the great advantages of training with Tim Nilsen was that he was fanatical about precision and brevity in scientific communication.
He took the business of writing up research very seriously. He took the business of presenting research very seriously.
There was almost a seamless connection, at least in my mind, between thinking about what it takes to make a poem and what it takes to make a scientific story.
I appreciated that greatly.
Again, I can’t overstate the importance of luck, of being in the right place at the right time.
The MS Center was founded right when I finished my clinical training. It needed an ideal venue for me to practice, and I joined the MS Center right when it started up.
I was fortunate that it attracted the leadership and staff needed to grow beyond our wildest imaginings into one of the foremost centers in the world.
At the same time, when I finished my research training and needed a home at Cleveland Clinic in which to work, Cleveland Clinic started a molecular biology department and attracted a fantastic array of faculty.
It was led by Omi O’Banerjee, a virologist, who also brought in Ganesh Sen from Sloan Kettering, an interferon biologist.
Ganesh became my mentor in how to think about interferon more broadly than I had before. Additionally, he gave me a great deal of direction about how to start up and run a lab.
These figures and others were essential to my ability to start with a relatively thin background. Remember, I hadn’t done a PhD or a postdoc. Despite that relatively thin background, I was able not only to survive but also to get some decent work done in my lab over the years.
I started working essentially on interferon and multiple sclerosis in 1989, right before some of the pivotal trials of interferon as the first real treatment for MS.
The first treatment that could change the natural history of multiple sclerosis was regular injections of type I interferon.
Because MS was still a relatively mysterious disease and interferon is a complex cytokine, it became important to understand how interferon modifies the course of MS.
This was also the time when MRI was becoming an important tool for understanding MS. The biological effects of interferon injections on the MRI-level evolution of the disease became an extremely important research topic.
Around that time, Cleveland Clinic attracted George Stark to direct the Research Institute. He became its chair.
For those who don’t know, George is one of three people who discovered the JAK-STAT pathway.
Very quickly, because George was there and could attract other interferon researchers, Cleveland Clinic became the interferon capital of the world for a while. It was the ideal place to begin developing my research program.
Richard Rudick, a visionary leader, came to run the MS center, called the Mellen Center.
Side by side, the interferon group and the MS group flourished, giving me an absolutely ideal place to develop a line of research around interferon and multiple sclerosis.
Very quickly after I began working on interferon and MS, it became clear that one of the activities of interferons in the whole organism, meaning in an intact animal, was related to chemokines.
We were working with the canonical animal model of MS, experimental autoimmune encephalomyelitis, or EAE.
It turned out that interferons induce chemokines. Chemokines were relatively new at the time; the name hadn’t even been assigned yet. They were initially called chemotactic cytokines.
The expression of these chemokines by brain cells in the context of neuroinflammation fired my imagination and the imaginations of the people working with me in the lab.
We began a parallel process of studying interferons on the one hand and chemokines on the other.
In the 15 years after I set up my lab, interferons established themselves as a foundational treatment for multiple sclerosis.
Subsequently, it turned out that blocking leukocyte trafficking, initially with an antibody to alpha-4 integrin called natalizumab, or Tysabri, was an unbelievably potent way to treat the inflammatory aspect of MS.
All the things I had been working on, again, I would argue pretty serendipitously, became areas of research for which you could attract funding, attract smart and capable people to work with you, and attract journals and conferences that wanted to hear what you were doing.
The MS research program in my lab benefited from that setting, the terrific interferon research, the guidance on how to run a lab, and the fact that successful MS treatments began to bring benefits to patients, thank heavens, while also providing lessons for research.
You begin to understand a disease when you see what treatments work and what treatments don’t work.
I happened to be in the ideal setting to capitalize on all these advances.
I also want to make a little digression to share a couple of points from my experience doing MS research.
One of the best things that can happen to a physician-scientist is to experience the transformation of their particular disease of interest.
I’ve had a wonderful marriage, wonderful kids, and maybe even better grandkids. I’ve had a lot of good luck and happiness in my life.
But I would argue that being part of the transformation of a disease, and MS is a very tough disease for many people, is one of the best things that can ever happen to you.
In addition, it gives you a hands-on experience of what transformation really looks like.
For people like you and me, and anybody listening who works in a small biotech or pharmaceutical company, I think it’s important to realize that transforming a disease doesn’t happen overnight.
It’s a slow, stepwise process. But over time, it develops its own momentum. It becomes, in a way, irresistible.
Each treatment takes a long time to emerge, prove itself, and ultimately show the investigator community, the practicing community, and the patient community where it fits.
Even though that takes a long time, it’s very important to realize that the potency, the effect size, of transforming a disease just can’t be overstated.
To go from having nothing but symptomatic treatment and moral support for patients, to being able to say, “I don’t have anything, but I’ll hang in there with you and try to help you with your symptoms,” and then to being able to say, “You know what? It’s unfortunate that you have MS. That’s a sad thing, but I can really help you.”
That’s a really important journey to be able to take.
I wish that experience for everybody who’s hearing this.
Naji Gehchan: Yeah, it’s so true, Richard.
You’ve said several times that it was serendipity and luck. You’re very humble, I know that. But there’s more than that, too.
You’ve encountered new scientific ideas throughout your career. Fast-forward, and you moved into pharma and then to Third Rock.
What makes you believe an idea has the potential to transform patients’ lives at some point, and how do you make those bets?
Richard Ransohoff: One lesson I learned during my academic career, through my time at Biogen, and now at Third Rock, is the following.
The ability to perceive what a transformative therapy is capable of is very limited.
When I began my academic career, MS was untreatable. I had a track record that made pharma people want to talk to me, so I did lots of consulting with pharmaceutical companies about MS.
What I heard was, “Listen, we benchmarked the commercial opportunity here. We figure it’s around $300 million. That’s well below our threshold. It’s nice to hear your ideas, but we’re not interested.”
Today, MS is a $25 billion market, and it may continue to expand. New treatments are coming in, and unmet medical need remains, as you’re aware, as well as I am.
My point isn’t that the people who were talking to me weren’t thinking clearly or had bad intentions. Nothing like that.
We just don’t understand or envision the possibilities when there is a transformative therapy.
It’s important to keep that in mind.
It’s also important to keep in mind the timeline. Transforming a disease isn’t the result of the early work that you and I do.
The early work that you and I do is to provide proof of principle that there is some benefit for patients in what we do, and to get others involved: people with resources on a different scale from what we bring to bear, who can develop, commercialize, and implement the discoveries and early clinical work that, for the most part, happen in small biotech companies.
That’s where we fit into the ecosystem, in my view.
The lessons I learned in academia about how to treat people, motivate people, get people to work as a team, see each person’s strengths, weaknesses, and limitations, and play to their strengths became invaluable as I transitioned into a different setting.
I think your core question is: What makes a discovery translatable?
Of course, that’s essentially what we do at Third Rock for a living.
We are early investors in company creation. Very often, I would say the great majority of the time, we get involved when there is a discovery and a concept of what translation might look like.
We may work with the discovering scientists, who become founders, to sharpen that vision and begin to define things with great specificity.
Who is this for? How would you select the patients? What would the early clinical trial look like? What are the outcome measures?
Is this an area in which the FDA has articulated criteria for approval? Is there a path to approval? Is there compelling early chemical matter?
These are all things we take into account as we look at where we might make an investment.
The checklist for a discovery that is going to become a company in which we get involved, or a project that later becomes a company, is relatively long.
These days, it’s relatively specific. Ultimately, it comes back to this: Where can Third Rock and Third Rock companies make a difference in the world?
We have substantial resources, lots of brilliant experience, and remarkable people. But we can only do what we do.
To do it well, we have to be disciplined about where we put our efforts.
Naji Gehchan: This is great.
As you advise and build these biotech companies, there’s a rigorous scientific approach tied to a forward-looking view of unmet medical need and commercial opportunity.
What do you look for in the people you want around the table once you say, “Okay, we’re going to build a company”?
Richard Ransohoff: That is very much what we like to call a group genius question, and it couldn’t possibly be a more important question.
Third Rock was founded in 2007 and has now been in business for nearly 20 years. It has created more than 70 companies.
The result of all that work is that we have a good-sized network, and we’ve also learned some lessons.
One lesson we’ve learned is that the leadership team for a new company is arguably as important as anything else in the recipe for making a new company.
Obviously, you need great science. It needs to be rigorous and novel. It needs to point toward a treatment for a genuinely unmet medical need, and one for which there is a way forward on multiple levels.
But if you don’t put the right people in place to execute, the promise will not be realized.
These things don’t happen by themselves. They happen by bringing together great people.
In addition to intrinsic quality and greatness, most of which, by the way, is defined by track record, we also look for complementarity.
A CEO needs a certain track record, as do a CSO, a CTO, a chief medical officer, a chief commercial officer, and so forth.
If there is extraordinary experience on one side of the aisle, we may go with somebody who is a little newer on the other side.
But in all circumstances, we tend to put teams together with people with whom we’ve worked successfully before, or people we know very well who have worked together successfully.
Naji Gehchan: I’m going to give you a word now, Richard, and I’d love to hear the first thing that comes to your mind.
Richard Ransohoff: Okay. Rorschach. Okay.
Naji Gehchan: The first one is leadership.
Richard Ransohoff: Empathy.
Naji Gehchan: I think it’s self-explanatory. It explains how you think about leadership.
The second one is legacy.
Richard Ransohoff: Make a difference for patients.
Naji Gehchan: What about the brain?
Richard Ransohoff: Part of the body.
Naji Gehchan: Oh, I was expecting something more! You’ve been fascinated by this organ.
Richard Ransohoff: That’s certainly true.
What I’ve experienced during my career is that people who work on the rest of the body very often regard the brain as unknown territory. “Don’t go there.”
The same is often true of brain scientists: they may think less about the housing, the support system, than they ought to.
I favor integrating the body and the brain in one’s thinking about brain disease.
Naji Gehchan: And the last phrase is Spread Love in Organizations.
Richard Ransohoff: Authenticity. Be yourself.
Be professional and have a persona that is not just you in the rawest, unfiltered sense.
But at the same time, try to understand who you are, what you bring, and go with that.
Naji Gehchan: I love that.
Any final word of wisdom, Richard, for leaders?
Richard Ransohoff: Resilience. Try to hang in there.
My life is a “better late than never” type of life, and I feel that perspective has served me well.
It’s all too easy at times to dwell on the darkness because it’s there. But it’s not the only thing there.
There’s a horizon. There may be a light just beyond the horizon.
Day does follow night. All the things that poets have said over the years, they say repeatedly because they’re true.
Naji Gehchan: Wow. What an incredible and inspiring way to finish our conversation.
Thanks so much, Richard, again, for joining me.
Richard Ransohoff: Thank you, Naji. This has really been a pleasure for me, and I hope it’s of some interest to you and your listeners. Thank you so much.
Naji Gehchan: It certainly is. Thank you so much.
Naji Gehchan: Thanks for listening to the show! For more episodes, make sure to subscribe to Spreadloveio.com or wherever you listen to your podcasts. Let’s inspire change together and make a positive impact in healthcare, one story at a time.
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