Lab Meeting: Mark Fishman
“You have to open up a new field. The way to do that often lies at interdisciplinary boundaries.”
Mark Fishman’s career in medicine and science began with the African lungfish.
As an adaptation to periods of drought, the lungfish can breathe through its mouth using its lungs alone, which expand upon inhalation. As a high school student in his father’s laboratory, Fishman made an Archimedean contraption to measure the lungfish’s tidal volume (Q#5). His device placed the body of the animal in a shallow pool of water, leaving the head in a separate spirometry chamber with a higher water level—thus changes in the expanding lung volume were not transmitted to the spirometry system.
The air removed from the spirometer as the fish breathed could be accurately measured, and a paper was published: “it was hardly breathtaking [no pun intended], but it was interesting,” recounts Fishman. And yet, Mark C. Fishman was notably absent from the paper’s author list: “The lab wrote up a paper and my name wasn't on it. That's okay, even though it was my idea. But what did hurt is that when they thanked me in the acknowledgements, in my father's own paper, he misspelled my name.”
Undeterred by authorship issues inherent to academia, Fishman forged ahead to have what can only be described as an astounding career. After undergrad at Yale College and medical school at Harvard, he trained in internal medicine (chief resident) and cardiology at the MGH. He then completed a post-doc at the NIH with Marshall Nirenberg (Q #6). Fishman was among the first to realize that genetic screens in zebrafish could be leveraged to study organ structure and function during late development. In the 1990s, in collaboration with Wolfgang Driever and contemporaneously with Janni Nuesslein-Volhard, Fishman helped establish the zebrafish as a linchpin of developmental biology. Using elegant genetic screens, followed by rigorous phenotyping and cloning, his lab characterized several pathways that dictate proper organogenesis—particularly of the heart and vessels (Q #7). From 2002-2016 Fishman was the founding President of the Novartis Institutes for BioMedical Research (NIBR). His approach to early drug development was based on what he knew—genetics, developmental biology and medicine—rather than unwieldy market size and profit estimates: “We emphasized a focus on unmet need, but where you could have a scientifically tractable approach” (Q #7). His methods yielded stunning results: during his tenure, NIBR discovered and brought through successful clinical trials of 90 new medicines, in more than 120 indications.
Currently, Fishman is a Professor in the Harvard Department of Stem Cell and Regenerative Biology and is Chief of the Pathways Clinical Service at the MGH. Ongoing research in the Fishman lab focuses on how the autonomic nervous system connects the brain and body (particularly the cardiovascular system). In effect, “What does the brain tell the heart, and what does the heart tell the brain?” (Q #8). Previously, Fishman was the Founding Director of the Cardiovascular Research Center and Chief of Cardiology at the Massachusetts General Hospital. He has served on the Executive Committee and Council of the National Academy of Medicine, and is a Fellow of the American Academy of Arts and Sciences. Fishman is also the author of the textbook, Medicine, and of the book Lab: Building a Home for Scientists, which details the history and architectural design of lab buildings.
Fifty-five years after Mark Fishman the high school student measured the tidal volume of the African lungfish, Mark Fishman the Professor continues to use freshwater vertebrates to probe physiology. He is among the select few to have both impacted the way basic science is practiced—using genetic screens to study vertebrate late organ formation—and influenced how biotech and pharma fundamentally approach drug development.
Below is an interview with Dr. Mark C. Fishman from August 2022:
1. What does a day in the life look like for you now? How do you spend most of your time?
My base is my office and lab in the Stem Cell and Regenerative Biology Department at Harvard College. I wander in and out of my lab, which is now focused on mapping the heart-brain connection in zebrafish. During most of the year I am involved in teaching courses for undergraduates and graduate students. I also help to direct and teach in a Masters in Biotechnology Program, which I started with Doug Melton and Amitabh Chandra, and which some HBS students take concurrently with their MBA. I spend some time at the MGH where I see patients with medical residents as part of their Pathways, elective, where we focus on patients whose problems are refractory and which speak to some fundamental pathophysiological issue. I am on a couple of biotech boards, and I started an investment company with Joe Jimenez, the former Novartis CEO, where we in-license drug candidates at the translational medicine phase, especially for patients with unmet medical needs.
[On the Pathways program at MGH]:
In Pathways we focus on patients who seem not to fit into ‘neat’ medical categories and who have disorders that speak to fundamental pathophysiological problems. So, we can approach these medical issues scientifically, and, in doing so, help the patient. The Chief Resident chooses a patient who seems to illustrate a fundamental principle that is not well understood.
For example, a patient might suffer from inexplicable swings in body temperature. The residents work with the team, consultants, and scientific experts from around the country to formulate the issues and potential approaches and present to the entire House Staff and several staff physicians. The program has been quite popular and offered me personally a way to stay in touch with medical trainees, advances in medicine, and with patient care.
For the physician-scientist this exposure provides a time to reflect on their opportunity to find new areas to work, ones based on their medical background. For example, one such direction is integrative biology— how the brain and many organs function together to maintain homeostasis. This was in its heyday in the middle of the last century. Now we have many more tools to understand, for example, enteroception, the autonomic nervous system, and what goes awry in poorly understood disorders like long COVID that lack good therapies.
2. In 2017 you published Lab Building: A Home for Scientists. What was the motivation for writing this book?
I have always enjoyed design. While at Novartis, I had the opportunity to work with fantastic architects to help design 9 lab buildings. Daniel Vasella, then the CEO and Chairman of the Board, had a commitment to design beautiful campuses for the staff, and knew of my interest in architecture. Dan had overseen the new Basel campus, and the new lab buildings in Cambridge and Shanghai were just getting started. When he retired, he asked me if I would take those over.
I realized that most architects had little understanding of how scientists worked, where they came from emotionally or practically. Some believed chaotic building styles would foster great science, without any conception of how scientists like to get work done. Others invoked standard organic chemistry labs of the 1800’s, with fixed benches and closed offices.
I realized that after trying to explain the history and trajectory of modern science and of pharmaceutical discovery to these wonderful artists and architects, that I might as well write it down. Some recurrent themes included flexibility of infrastructure for restructuring programs as needed, enhancing communication by well-placed open spaces, stairwells between floors, ready coffee access sites, and opportunities to reflect in outside gardens.
3. Name an overlooked scientist, whom you feel strongly that every grad student or med student should know and be able to describe their major findings?
The most famous overlooked scientist is Gregor Mendel whom no one recognized in his lifetime. In fact, they burned all his papers when he died, because they thought there was nothing important that he had done.
Mendel understood, without knowing anything about cell biology or the mechanisms of chromosomes, that inheritance is about information flow. This approach underlies, for example, subsequent genetic screens, as well as leading to an understanding of chromosomal biology and DNA. This notion of genetics as a system of quantitative information flow was unanticipated.
4. What are you reading in your free time?
Right now? I've been reading the Irish novelist, Colm Toibin who wrote The Magician about Thomas Mann. It's an amazing book. I also loved Brooklyn and Nora Webster. I also like mystery stories, especially with a flawed protagonist. I recently read John Banville’s Snow. He used to write novels under a pen name, Benjamin Black, a mystery series centered on a Dublin pathologist. His characters are very imperfect people. They're not the characters of an Agatha Christie. You could imagine them as either criminal or the investigator. These books are gritty and realistic, and also provide a sense of uplift along with the powerful humor of survival. In the face of tragedy, the characters can figure out how to laugh. So, I think [these books] are good models, in many ways, for how to live.
5. What drew you into medicine and science initially?
It was actually in high school, because my father had a lab. He was a pulmonologist, and he and my mother went to Europe for the summer. He got me a job as a technician in his lab, which obviously, he paid for, personally, because I wasn’t trained to do anything. And there were very few folks around generally. One problem that lab had not solved, and seemed to be an impediment, was an inability to measure the normal tidal volume of the lung fish (i.e, how much air it breathes in and out) without sticking a tube down into the lung, for which you’d need to anesthetize the fish. If the fish is simply in a closed chamber, when it fills its lungs the overall volume in the chamber doesn’t change. In any case, I figured out a way to get around that dilemma by putting the body of the fish in a giant pool of water [see image below] with the head effectively in a separate chamber. This was hardly a groundbreaking discovery, but it was totally on my own.
When the lab wrote up a paper I was not included as an author—I suspect the post-doc took all the credit. I thought nothing of it at the time. What did hurt a bit is that in the acknowledgements, where they did thank me, they misspelled my name. So, it was my first taste of academic authorship issues. But I had a wonderful time because I discovered something. It was hardly breathtaking, but it was interesting.
6. Who was your first great scientific mentor?
That would be my postdoc mentor, Marshall Nirenberg. Marshall had elucidated the genetic code, for which he received the Nobel Prize for [in 1968]. I joined his lab as he was beginning to explore the genetics of synapse formation. Marshall taught me that you need to address an important question.
7. What has been your scientific high point? — What do you consider to be the most exhilarating discovery or set of discoveries you have been involved in throughout your career?
[Scientifically] the discoveries from our zebrafish genetic screen, a screen done with Wolfgang Driever and contemporaneously with Janni Nüsslein-Volhard. At the time, although Drosophila and C. elegans genetics had led to an understanding of early patterning of the embryo, little was known about fashioning of vertebrate organs. We used the approaches taken in the two invertebrate species especially, in my lab, with an eye to understanding organogenesis. Are there genes that dictate particular facets of organ size, pattern, and function? When we proposed this approach, most folks said it was not sensible. Because genes are often used multiple times during development, and organs form relatively late, they predicted we would find only mutations that affect earlier processes or would grossly derail development. Fortunately, we did find informative mutations, ones that would generate, for example, a heart without valves, or with a chamber missing or too large or too small, or manifesting fate changes amongst the vessels. We also contributed to laying the genomic infrastructure, so the whole community could clone these mutations, which then became entrance points to novel and fascinating pathways that dictate organ form and function. We were lucky in our focus upon organogenesis, and the heart in particular, because it turns out (which we didn't know at the start) that even lacking a heartbeat, fish can live for days by diffusion of oxygen from the water. We never would have found these mutations in a mouse, where the embryos would have died.
When I got to Novartis, to start the Novartis Institutes for BioMedical Research, I was completely naïve about drug discovery. What I brought was an understanding of fundamental science, especially developmental biology, and medicine. So we emphasized focusing on unmet medical needs, with targets that appeared scientifically tractable. This [approach] brought you quickly to rare diseases and diseases that were reasonably homogeneous in their presentation. We did not consider financial attributes, such as market size. This worked quite well in terms of discovery of new drugs, and was a second exhilarating scientific high point.
8. What set of research questions or projects has you most excited about coming into lab today?
What I'm most excited about now is the brain-body connection. What does the brain tell the heart, and what does the heart tell the brain? What are the signals from inside the body and how are they registered? How do they influence brain function? When are we aware of them? And then how does the brain guide the organs?
We are doing this in the zebrafish because its transparency permits visualization of the neurons all along the chain from heart to ganglia to the brain. Which [neurons] are active, and when? This has been a terrific collaboration with Florian Engert , in Molecular and Cell Biology.
9. Which areas of translational science, outside of your direct field, are you most excited about seeing develop in the next 5-10 years? Which areas are ripe for translation to patients?
I would mention two that may be on the cusp of being ready. One is autoimmunity, particularly the understanding of specific tolerance. Can we find the antigens responsible for autoimmune diseases and drugs that would specifically tolerize to those [antigens]. The second is psychiatric illness. We're getting some sense of the genes and circuits that are associated with particular disorders, and we have seen recent successes, such as ketamine, but these types of drugs are still a very big mallet .
10. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?
Try to avoid the current fad. It’s hard, but if you want to open a new field, you may need to lay the groundwork first. Often such approaches land you at interdisciplinary boundaries. So find a scientific partner. Two scientists with different backgrounds, reflecting upon the same question, and bouncing ideas back and forth, is a wonderful way to energize discovery.