Lab Meeting: Richard Ransohoff
“Articulate data are often beautiful data.”
Dr. Richard Ransohoff appreciates a good story. His own career makes for one: a literature major in college, short-lived humanities PhD student (a late-‘60s his school closed for the semester due to a late-‘60s riot), night admitting clerk at Lenox Hill Hospital, medical and neurology resident, molecular biology post-doc, renowned physician-scientist at Cleveland Clinic, lab and department head at Biogen and now venture partner at Third Rock. His path has taken some twists and turns: “medicine and science are big houses, and you can do a lot of interesting things in your lifetime.” (Q #7).
After medical school, residency, and just as he was beginning his post-doctoral research at Case Western Reserve University School of Medicine, Ransohoff joined the faculty of the Cleveland Clinic in 1984. Drawn to science for its “beauty and precision,” Ransohoff made a series of discoveries characterizing the immune-inflammatory reaction that underlies the pathogenesis of multiple sclerosis (MS). Over the course of 30 years at “The Clinic,” he showed that chemokines such as CXCL10/IP-10 and CCL2/MCP-1, entice immune cells from brain perivascular spaces into the central nervous system (CNS) parenchyma where they can attack vulnerable tissue components such as myelin. His work on leukocyte trafficking to the CNS, and discovery that interferon signaling regulates such neuro-immune crosstalk, provided a conceptual framework for understanding the efficacy of several MS-treatments. His basic and translational work has resulted in over 450 scientific articles and reviews (h-index 140). In addition to running a lab and directing the Cleveland Clinic’s Neuroinflammation Research Center, Dr. Ransohoff was an attending neurologist for over three decades. He was cited in the “Best Doctors” compendium continuously from 1996-2014 (when he left practice), and his research was recognized by the John Dystel Prize for MS (2012). In 2014, he joined Biogen as Senior Research Fellow and, ultimately, Research/Early Development Unit Head for Neuroimmunology, Pain and Acute Neurology. There he directed work focused on leveraging insights in neuroimmunology to treat neurologic illness. In January 2018, he joined Third Rock Ventures, initially as entrepreneur-in-residence and later as venture partner. He is a co-founder and currently Chief Medical Officer of Abata Therapeutics, which is developing regulatory T-cell therapies for immunologic diseases, including progressive MS.
When speaking about one of his favorite books, George Eliot’s Middlemarch, Ransohoff comments that novelty in medicine can be threatening: “a young doctor [Tertius Lydgate] rides into town and he is bringing a lot of new ideas. The other doctors are very threatened…it shows that threat from new ideas is universal.”
Possessing the ability not only to analyze a text, but also to put it into practice, Ransohoff has made a career embracing new ideas that might help patients —blending emerging concepts from immunology into neurology, striving to make fundamental discoveries and leveraging cutting-edge science to start companies at Third Rock: “there are like 900 things going on [at TRV] that I am learning about for the first time.” Eliot’s Dr. Lydgate, perhaps the first physician-scientist depicted in Western literature, would certainly be proud.
Below is an interview with Richard Ransohoff from August 2022:
What is one book you would recommend reading for a doctor in training? What about an aspiring biotech investor? How have these books influenced the way you think?
I am going to give you a mini bookshelf, because I can’t choose just one book. The first is House of God [by Samuel Shem], because so many medical trainees read it anyway. This book is interesting through several lenses: the first is that it is very important when under the enormous stress of learning to treat patients, to understand how shared perceptions (in his case in the form of crude jokes) can engender teamwork and bonding—it [humor] can really bring people together. It is also important to realize that every episode or incident in the book is biased to make the protagonist appear heroic. There is an enormous neediness in this character to be seen as the smooth, funny, lovable, ‘cool guy.’ It is really important to read this novel, take a step back, and see what a jerk he [the protagonist] can be—he often makes it about himself, much too much. When you are a doctor it ‘ain’t about you.’ You are not sick, that other person is sick. You are not the suffering family member, it is that other person who is the suffering family member. I am not trying to be holier than thou—though I may sound like it. I am trying to say that this is an entertaining book, which has been a seminal ‘welcome to the profession’ for many medical trainees. It is a work of fiction that should not be a guide to life. And it’s important to get perspective on that.
The second book, in case anyone has a taste for the 19th century classics, is Middlemarch [by Mary Anne Evans writing as George Eliot]. It incorporates phenomenally hilarious social satire—and one of the central characters is a physician [Tertius Lydgate]. A lesson I got out of Middlemarch is that the role of the doctor in society and in the patient’s life has relatively little to do with the ability to deliver a scientific, evidence-based cure. This guy [Lydgate] was cutting edge by refusing to ‘bleed’ patients – apologies for the bad pun. Yet, people really wanted to see him when they were sick. People need this figure, a healer, in society and culture—remember [as a doctor in training] to be that person. It is not all about ordering the right tests and prescriptions—you should without question do that, and be as evidence-based as you can—but you also have to be the person who comforts and brings authority.
Another remarkable thing about Middlemarch—doctors then act exactly the same as doctors now in many ways. In the novel, Tertius Lydgate rides into town and brings new ideas that challenge the received knowledge. The other doctors are very threatened by him—and it shows that this threat from new ideas is universal. The other behavior [that is similar today] is frankly the economic competition in medicine—he [Tertius Lydgate] is the bright, shiny new object in town, and the older docs are scared they will lose their patients. We may think that this behavior is based in current medical economics, but it is not. Doctors have been jealous guardians of their practices for a long time.
The third book I want to call out for medical trainees is Witches, Midwives and Nurses by Barbara Ehrenreich. I read this book in the mid 70s when I was starting medical school. It describes in vivid detail how a male patriarchy with nothing to offer in terms of scientific basis of disease, squeezed out, stigmatized and excommunicated the women healers of the time, which included midwives. It is very important to be aware of the social basis of our behaviors in medicine. Some of what we do and say has little relevance to scientific understanding of disease, and is more about social influences.
On how his undergraduate training in literature influenced his career in medicine]:
What literature did for me is give me an appreciation for beauty and precision. When I got into lab and started doing experiments, I felt like there was a relationship between making beautiful data and drawing firm and precise conclusions. I feel that my taste for this process came from seeing beauty and precision in language. This was also the ethos in the lab where I trained—until the results were clear and technically superb, it was not worth investigating further.
You have had a storied career in medicine and translational research. What drew you into medicine initially?
I did grow up in a family that featured a lot of doctors—my dad’s brother was a physician, and my father’s first cousin was a well-known neurosurgeon. Going back three generations there were docs sprinkled through the family. Growing up, I wanted nothing to do with being a doctor. I went into literature and [after college] went to get a humanities PhD at San Francisco State. I happened to register and start there at the same time there was a movement on campus to set up a black studies program. At the time [late ‘60s], this was wildly controversial and the administration said, ‘absolutely not.’ There was a strong student movement in the other direction—picketing and marching every day. The administration fired the university president because he wasn’t ‘tough enough,’ and hired another guy [as president] who called in the police. The police went absolutely out of their minds to crush these student protests—it was a disaster and they ended up closing the school for a semester.
So that was it for San Francisco State. I had nothing to do at that point and I moved back to New York—I had gone to college just outside the city and had friends there. I got a job as a night-time hospital admitting clerk at Lenox Hill, which was a fascinating place. The Park Avenue side of Lenox Hill took care of very wealthy people, and the other side that faced Lex, took care of people of more modest means. As a night-time admitting clerk you got to meet everybody. This was my first real exposure to a very broad spectrum of people—as a clerk you wheel people all over the hospital to their rooms. I met celebrities, athletes, intellectuals, politicians along with plumbers and auto mechanics, working as a Lenox Hill Hospital admitting clerk.
I realized I was a little bit bored just thinking about books and meeting other people who were also only focused on books. This [my experience as a clerk] was immersion in an entire universe of drama and excitement, and you got to see so much of human nature. I decided I really liked the hospital environment and thought ‘let’s just see if I can go to med school.’ I had a night-job, so I began taking my pre-med classes during the day, one at a time.
It took me about 5 years [to get through all the classes]. During this whole time, I got more and more interested in biology, and got more experience being in a hospital. By the time I started med school I was smart enough to know that you should listen to the nurses or you won’t survive.
As I began my medical training [at Case Western] I started to think about an academic career. So, I did 30 months of medical residency training (enough for Board certification in Internal Medicine, and then a 6-month research experience in immunology —where I decided I really liked research. I was glad to have the full medical training before Neurology residency — if I wanted to see patients one day a week, but still be a decent physician, I needed two things. The first is a solid grounding in medical practice—so I could still contribute value, even only being part-time. The second was to really focus my medical practice, not try to be a generalist, but do one thing well. While I was doing my subsequent post-doctoral training in molecular biology, the Cleveland Clinic set up both a specialty multiple sclerosis clinic and a molecular biology department—so it was the perfect home for me. I ended up being one of the first practicing staff physicians with a bench [basic-science] R01 at the Cleveland Clinic.
For how long did you see patients, and what are the most exciting discoveries you made as a clinician-scientist?
I started seeing MS patients right out of residency in 1984, about one day a week. The rest of the time was reserved for my post-doctoral research in Timothy Nilsen’s group. Fortunately for me, this very good scientist [Tim Nilsen] was willing to take me on and train me from scratch. He became the founding editor-in-chief of RNA, the journal, and also founded the Center for RNA Science and Therapeutics at Case Western Reserve University School of Medicine.
[On his most exciting scientific discoveries]:
For this researcher, the best plan was to be lucky. Good fortune isn’t under your control, but you can pay attention and take advantage of unexpected findings. I did my post-doctoral work on the cellular mechanism by which interferon inhibits flu virus replication—in the years before the interferon receptors or JAK/STAT pathways were uncovered. So, it was an early phase of interferon research, and I set up a lab at the Cleveland Clinic to work on the question: what is different between gamma interferon and beta interferon? There was preliminary clinical evidence that beta-interferon was beneficial for MS, but gamma-interferon was clearly deleterious. Several lucky things then happened. One: Cleveland Clinic scientist, Tom Hamilton, was studying a set of brand-new molecules that came to be known as ‘chemokines.’ He showed that they were strongly induced by gamma-interferon in mice. Two: at the time, I was working with a super brilliant post-doc, Marie Tani [a neurologist], who learned in-situ hybridization and brought it back to our lab. She then developed this assay to localize the expression of interferon-gamma-inducible genes that Tom Hamilton was studying in mice with a model of MS called EAE. These genes eventually turned out to be two chemokines, CXCL10 and CCL2. As I recall, she had mislabeled the active sample and the negative control. We looked at the slide labeled ‘active’ first and saw absolutely nothing—so depressing. We then looked at the ‘negative control’ slide and saw this gorgeous, unbelievably specific pattern of expression [of the chemokines] in the reactive astrocytes around the perivascular inflammatory cuffs in the inflamed spinal cord tissue. We very quickly figured out the slides were mislabeled, and the data were replicated many times by our lab and others. But what a moment! To see such an incredibly articulate biology—a clear dialogue between immune cells and brain cells in this model disease process. It just floored me. This moment happened around ’91 or ’92 and influenced the rest of my career—I never stopped researching chemokines and immune-cell trafficking in the brain. Ten years later we did the first experiments studying chemokines in human cerebrospinal fluid and human brain tissue.
When did you first get involved in industry? When did you first get to interact with TRV and what drew you to this firm?
What happened in a broad sense was in 2014 I started looking at jobs outside of Cleveland—the reason was simple: my younger daughter left for college and we had an empty nest. Both daughters went to the East Coast, so I was looking at academic centers there. Biogen heard that I was ‘out and about.’ At that time, Biogen was ambitious to build neuroscience research inside the company and bring new targets to clinical development. Their vision attracted a number of excellent folks in different areas: neurodegeneration, cell death, proteinopathies, and leadership was interested to build out neuroimmunology. Beginning in the early ‘90s I had done consulting work for Biogen in the context of their trial of Avonex [interferon-beta-1a]. I had been consistently impressed with Biogen’s MS clinical development team —Nancy Simonian, Al Sandrock and others -- bright, committed, scholarly neurologists with their hearts in the right place. At the time [in 2014] I didn’t know much about Biogen research, but the people I met there, George Scangos, the CEO, and Spyros Artavanis-Tsakonas, the CSO, presented a galvanizing vision to build and develop neuroscience at Biogen. And, finally, it was my wife who said: ‘you have been doing the same thing for 30 years, why don’t you try something new?’ My thinking wasn’t much deeper than that. I didn’t know much about companies or their research, but I did have a vague sense that there might be more to life than grants and papers. I thought I could be helpful, and really liked working at Biogen—my colleagues in the labs and in other areas of neuroscience, immunology and drug development were incredibly bright and fun to be with. The first year I joined as a senior research fellow and continued my research, and the second year I developed a neuroimmunology department, which was a lot of fun. The third year, I had additional responsibility for some early clinical-development activities. At the end of this third year, I was contacted by Third Rock Ventures (TRV) to consider an opportunity there. I was really impressed by their team.
What motivates you at your current job at TRV? What are your chief responsibilities and what do you find most fulfilling about the work?
At TRV I am primarily responsible for contributing according to my background in science and medicine. In my position as venture partner at TRV, I help conceive, build and launch companies. I am co-founder and interim CMO at Abata Therapeutics, which is very exciting, and I am also in the midst of helping build other potential companies.
Working with people you really like and admire, and have a lot of trust in, is an enormous motivator. In the pandemic, I suffered because of being isolated from the team. The second motivating aspect of my work at Third Rock is just the enormous diversity of activity. For example, Abata is developing regulatory T cell therapies for immunologically mediated disease, including progressive MS. There are like 900 things going on at Abata that I am learning about for the first time, starting with how to manufacture a cell therapy.
Sticking with Abata for a moment—in 2004 when the Tysabri [natalizumab] efficacy data were released, I had an existential crisis. I had been working on relapsing MS and leukocyte trafficking to the nervous system. Here was a drug [Tysabri] that addressed trafficking to the CNS—so my idea was right, and Tysabri virtually abolished the relapsing pathology associated with the disease. After that, I didn’t want to work at the edges trying to make a drug ‘a little better.’ I wanted to do fundamental, basic work and go after unmet medical need. So, I could either try to study progressive MS, or other neurologic diseases that had an inflammatory component but lacked treatment. I decided not to work on progressive MS, because I didn’t have a good idea, based on science, how to conceptualize a treatment for it. So, to find myself 17 years later with this phenomenal team at Abata, to go after progressive MS is unimaginably motivating.
The other stuff I am doing at Third Rock is so different from what we do at Abata—not only the company stage, but also different diseases, different approaches and different foundational science. It is incredibly stimulating. Also interacting with outside experts is like running mini-experiments—you take an idea and go to somebody really smart and experienced and say, ‘what do you think?’ Their response lets you know if you are on to something or should revisit the drawing board. It is a great job if you like learning new things and don’t mind being wrong.
What was hardest about making the transition from academic medicine to working in venture?
Every day, in every way, I am inadequate in some fashion. I don’t know quite enough about this, I should have read that, I wish I knew this other thing. However, taking care of patients for thirty years will humble you. You learn that there are things that you could have known if you read one more article, or simply could never have known because you are a human being at a moment in time, and both science and medicine have limits. It [medicine] is not a job that causes you to be puffed up about yourself, if you have any sanity.
[Despite this learning curve] working at Third Rock is a thoroughly immersive, exciting and gratifying activity. I am deeply grateful to be in this position. You have the real possibility to help patients in the not very distant future—this is a very rare circumstance to be in. I do also feel at Third Rock that they get what I am about—they know what I can do and enable me to feel useful. One obvious feature of pharma and biotech, which is not the case in academia, is teamwork. In biotech you really work together. There is a great deal of mutual support with everyone pulling in the same direction. I miss seeing patients and being a doctor. I also miss writing papers. But I still can’t imagine that things in my former position [as an academic physician] would be more stimulating than what I am doing now.
The advice I would give someone in your position [trainee] is that you can always make a career change and do something different. It can even be a pretty radical change—medicine and science are big houses, and you can do a lot of interesting things in your lifetime. Don’t be afraid to choose a non-obvious direction --- you can make a mid-course correction if needed.
What are some areas of science or medicine that you are most excited about seeing develop in the next 5-10 years? If applicable, which academic labs or companies are the ones to watch?
Mostly drug development is a story of failure. This is especially true in the neuropsychiatric and neurodegenerative diseases. It is my opinion that a good deal of the experimental practice of relying on reductive model systems is largely off-target with respect to disease biology. I think animal models, as one example, can be useful for pharmacology—PK, PD and target engagement. I don’t think they are great for disease biology in the brain. So, what do I like?
I am thrilled about the advent of using human genetics to study disease, and progress in understanding gene regulation: how is the genome interpreted and deployed? How many tricks are there for modulating gene expression? In which cells are those tricks used, and how do you leverage this insight to drive drug development? The existence of resources like the UK biobank, and the types of questions you can ask, such as: ‘what are the genetic variants associated with structural MRI changes?’ is incredibly exciting. The value of places like the Broad Institute is hard to overstate, in terms of contributing to understanding disease.
I also really like being in the era where we can do spatial transcriptomics, now at pretty high resolution, using techniques like expansion microscopy—work from Ed Boyden’s group among others. Such technologies are relatively early in their development, but I think will pay off greatly in the future.
Perhaps on a more granular level, antibody development is still crucial. A good antibody can upend an area of science, and can tell you everything you need to know: ‘Is a protein there? What cell-type is it localized to, and what tissue compartment? How does this localization change during disease?’ The existence of a place like the Institute for Protein Innovation, makes me very excited. It is something I have been dreaming about for a long time.
Lastly the advances in bioinformatics, in handling big data, are just dazzling. I have been around long enough to see data science change beyond my wildest imaginings. Bioinformatics is one such example. It is also exciting to see such tools eventually be democratized and accessible to everyone. Right now, to study a family with a hereditary illness, do whole genome sequencing, and find out which gene is responsible--you need to be a trained scientist with a big team, in a lab at NIH, Rockefeller or similar top institution. But eventually, this type of analysis could perhaps be carried out by a local doctor in a small hospital in Southern Ohio.
