A Conversation with Dr. Thomas Südhof
by Stuart Diamond, Editor-in-Chief, Empowered Doctor
Dr. Thomas Südhof was awarded the 2013 Noble Prize in Physiology or Medicine. In the spate of interviews that followed, he often acknowledged that the most important teacher in his life was Herbert Tauscher, his bassoon teacher. The implication being that what he learned as a child from a musician became the foundation that led him to winning the most prestigious award in science. An intriguing premise – and one in which I took personal interest, as I too am a former bassoonist, who as a youngster struggled with an ungainly set of wooden pipes, learning how to assemble, dissemble and somehow in between actually learned to play.
So my intention in requesting an interview was not to reiterate another scholarly article about his science. There are numerous webpages online that explain in detail his scientific accomplishments, including his own laboratory website and the Nobel Prize website. Rather, my intent would be to explore matters both musical and medical, as I have always been interested in the creative aspect of scientific research — impressed by the imagination that underlies not only the insight, but the implementation that allows insight to flow into research and ultimately to clinical application.
Just for the record: The Nobel Prize in Physiology or Medicine 2013 was awarded jointly to James E. Rothman, Randy W. Schekman and Thomas C. Südhof “for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells”. Dr. Südhof’s contribution was further described as follows: “The cells inside our bodies produce a host of different molecules that are sent to specific sites. During transport, many of these molecules are grouped together in tiny sac-like structures called vesicles. These vesicles help transport substances to different places inside the cell and send molecules from the cell’s surface as signals to other cells in the body. By studying brain cells from mice, in the 1990s Thomas Südhof demonstrated how vesicles are held in place, ready to release signal-bearing molecules at the right moment.”
A more accessible explanation can be found on Südhof’s laboratory website: “For a person to think, act, or feel, the neurons in their brain must communicate continuously, rapidly, and repeatedly. This communication occurs at synapses, specialized junctions that allow neurons to exchange information on a millisecond timescale and that organize neurons in vast overlapping circuits. When stimulated, a presynaptic neuron releases a chemical neurotransmitter signal that diffuses across the synaptic cleft to react with postsynaptic receptor neurons or muscle cells. Thomas Südhof’s laboratory studies how synapses form in the brain, how their properties are specified, and how they accomplish the rapid and precise signaling that forms the basis for all information processing by the brain.”
Lest we think such basic science is merely abstract, his work has very real world implications – deeper understanding of how cells in the brain communicate may help a range of researchers in both academia and private industry find answers in solving some of our most intransient health problems, such as dementia, Alzheimer’s, ALS, and autism.
As we sit across from each other in his small and tidy office at Stanford University, bantering back and forth, developing some initial rapport, I decide that Tom Südhof has the quintessential personality typically associated with bassoonists – laid-back and affable – someone who had learned how to play with others – sometimes in harmony, sometimes in counterpoint, and occasionally as a soloist.
Eventually we begin the interview in earnest. I ask Dr. Südhof to tell his story – from the beginning in Germany where he was born, as he would like it told.
Rudolph Steiner (1861-1925) was an influential Austrian mystic, philosopher, educator, artist, and architect. A complex and controversial renaissance thinker, he founded in the early 20th Century, an esoteric spiritual movement, anthroposophy, with roots in German idealist philosophy and theosophy. It would not do justice to even begin to discuss such a diverse and complex story in the context of this article. However, it should be noted that Steiner sought a synthesis of science and spirituality, that a disciplined clarity of rational thought is an enlightened path to the perception of true ideas.
There are philosophical and religious underpinnings that require what I feel is a leap of faith. These underpinnings postulate a hierarchy of divine beings, culminating in the Trinity — of course it’s all Christian — very much influenced and inspired by elements of Theosophy that goes back to India and Russia philosophically. So they are kind of interesting plays of the mind -” Gedanken spielen”. Interesting ideas, but in terms of accepting the truth, I had a difficult time and still do. I just don’t think there’s any reason to believe that any of that is actually true.
As I listen to Dr. Südhof speak, I appreciate the ease he possesses for metaphysical and philosophical concepts, how fluid he is with words and the play of ideas, how very skillful he is at the art of “Gedanken spielen”. Even though he may have rejected the core precepts of the anthroposophist philosophy, I can imagine that growing up with such a background has imbued him with a unique set of linguistic and cognitive skills, skills he not only enjoys, but that help him articulate ideas and play with them to powerful effect. During my research on Dr. Südhof, I discovered that he attended Waldorf Schools throughout his elementary and high school education. The Waldorf Schools are an international network of private schools founded on educational principles laid out by Steiner. I ask him about that.
In my own experience playing bassoon puts you in immediate demand. You are courted by any number of ensembles, whether or not you could actually play adequately. But that was not the case with the young Thomas. When he first started to play where he grew up in Germany, there was no youth-training orchestra. So he simply took lessons and played on his own. As he grew older he became more accomplished and played in the State Youth Orchestra and traveled with the group throughout Europe. He considered the possibility of pursuing a career as a professional musician. Though acknowledging how satisfying a career as professional musician could be, he was also well aware of the hard realities of life as an artist. I then asked him exactly what he meant when he said his bassoon teacher was his most important teacher. Did he really mean that?
SÜDHOF: Yes I do. I think, that in general, teaching is extremely dependent on personal relationships. It is important that one has teachers, who you can personally respect – a whole persona you can see. It is true in science as well in music, as well as other aspects of life. My bassoon teacher was the typical German musician that went through the system, learned how to be a bassoonist, and became an orchestra bassoonist in Hanover. He taught me from day one. I only had one teacher ever. He wasn’t set though on turning me into a professional musician. But he was set on having a certain degree of quality instilled in me. What I mean, when I say he was my most important teacher is that I see playing music very much akin to many of the other things I do. In that playing music requires above all a lot of practice and hard work. Creativity is not just imagining stuff. You can’t be creative if you have no mastery of the medium. Some people master the medium, but are never creative. So it’s not like you master the medium and you are automatically creative. But if you don’t master the medium you will never be creative. You will never be good. That relates to what I do as a scientist. It also relates to what doctors do, in that you can’t be good at it, unless you are really technically outstanding. And to become outstanding takes just a lot of hard unimaginative, non-creative, repetitive work. That is most of what we do. And that is the absolute prerequisite. In that sense it is the same as in music.
The conversation shifts as Dr. Südhof transitions back to a philosophical perspective, conjecturing not only on creativity but epistemology – understanding the nature of knowledge itself. The answers to these questions are important, as they can impact how one conducts and thinks about one’s work. So I next ask questions about creativity in science, questions that have been asked in many forms throughout the history of both science and philosophy: Are you discovering truth or creating knowledge? Is it a discovery or is there a creativity in the knowledge drawn from one’s work?
Next, I try to refine the question: How much of the creative process is drawing the box around what you are studying? In a research project you must create boundaries, to limit the variables. Creating the framework of what you are going to study and how you are going to examine it.
Let’s say you were going to try to understand a big question, memory. How could you potentially understand memory? As a scientist, creativity first comes through hard work – the hard work of figuring out what people actually think and how they do it. Then the next step is to analyze and consider all the data, the information collected. And then come up with an idea that is not the same that other people are considering. Because most scientists will just do what everyone else is doing – they will try to do it better, they will try to do it faster, they will try to give it something a little different. But let’s imagine what a creative scientist might do. For example, let’s say he was someone studying the human memory process using a functional MRI, studying memory in mice – looking at their genes, and thinking of a way of connecting those genes with human memory. Coming up with ideas that go beyond what everyone else is doing.
I have observed that this is not only in science. People tend to always do the same stuff. And the attention is always on the same. What’s published and so on, is always the same. Those people, who are doing other things, are usually not noticed, and often neglected. But what they do usually comes up later.
As we begin to explore what it is to be an outlier, especially in medicine, what challenges these researchers face before their work is accepted in the mainstream, Dr. Südhof becomes more reflective about his own path.
I’ve always felt that the most interesting part of doing science is to think about new ways of interpreting data or questions. When I started working on what garnered me the Nobel Prize, initially I was intrigued by the fact that there was a huge problem of fundamental importance of understanding the brain, and other forms of cellular communication in the body — but that there was no molecular information available whatsoever. So I took the then relatively new approach of molecular dissection, to an old problem that had been studied for a long time. And that’s how this whole thing started. And once I had data, I was able to use it, as a way of moving further.
A pattern is emerging. Here is a man, who grew up in a philosophical environment, a community with deep interests in the exploration and evolution of spirit and consciousness. And though he has rejected the orthodoxy in to which he was born, he seems still fascinated and motivated by some of these fundamental questions: The mind-body duality — the difference between consciousness/experience and the body — and how that happens biologically.
I then asked whether breakthroughs in science are dependent on advances in the tools of perception. As better devices to perceive are developed, entire new worlds open for us to explore – telescopes open the heavens, microscopes the world of microorganisms, X-rays take us inside the body and everything else, radio telescopes open dimensions never before imagined. Dr. Südhof’s response though is insightful and again surprising.
I think that what you said about science is partly true, but I think that even more important, possibly, is the liberation of the mind from ideological or religious constraints. Yes, it’s important to make fundamental observations with new instruments. However, what’s more important, before the modern time of instrumentation, was the willingness to judge reality based on sensory information that the individual has, and then draw conclusions based on reasoning — as opposed to abstract postulates that were guided by some kind of fate. That is an important issue, because I feel strongly that we are living in a time where that advance in our thinking as mankind is being challenged, not only by extremist religious movements, but even political factions in our own country — where certain rational perceptions, such as climate change, are simply denied.
So if better scientific tools of perception are only part of the answer to a better understanding of reality, is there a limitation in how we think? Are there cultural limitations in science that have to be broken through, limitations to our cognitive tool set?
It’s very different from physics in the 19th century, which is basically what Einstein emerged from. In which, after the discoveries of people like Maxwell and Helmholtz, the general outline was there, and there wasn’t really that much conceptual novelty in classical approaches. In neuroscience, at least, the classical approaches have not gotten even close to what is a reasonable understanding.
The challenge is the complexity of the brain. The brain is so complex that most neuroscientists feel that it is too complex to understand in molecular terms, and they conclude because it’s too complex, that it is pointless to try. And we can’t understand the brain without understanding its intricate molecular complexity. That’s what most modern neuroscience is based on. Which I find foolish, because it’s like wishful thinking. If you can’t climb a mountain, you pretend it’s not there.
We pursue the issue of complexity in science and in real life medicine. I ask about traditional medicines, such as Chinese herbal remedies, and if they can be adequately studied scientifically. Herbal remedies are usually a concoction of multiple ingredients, representing teeming interactions of hundreds of different molecular formulas. If you include the varying biogenetic response across a spectrum of patients, and add to the mix the influence of individual practioners, you have a medical paradigm of staggering complexity. Is this where science and the art of medicine travel on different paths?
My problems with all of this is that lot of people are working on the systems of complex science and so on. But even if you have the data, if you don’t have new concepts, I don’t think that will get you anywhere. Collecting data is important, but complexity will not be solved by just throwing more computers at it. I think any complexity is often a reflection of a lack of understanding.
As we return to his work on neural transmission, we begin to discuss other issues of complexity, including the concept of time in how the brain functions — the order, the speed, the management of timings in biological and chemical reactions that seem almost instantaneous.
For example, there are hormones. Hormone is a very difficult term, so I like to use the word hormone only in the context of blood transported signals. And there are many different types of signals, and they are similar if you want, to how I’ve defined hormones by carrying information that is more diffusely distributed. But they are not in the circulation, and they can be very local or very broad. There’s neuropeptides, there’s all kinds of lipophilic mediators, there’s all kinds of things happening.
In the brain, electricity is also a way of transferring information, transporting a signal. It happens almost only with so called action potentials, and they travel down axons and dendrites in various fashions, which is like a propagating wave. Very different than electricity in a wire, which is similar to an energy “package.” This is not an energy package, it is a local polarization of the membrane potential. In addition to that, there are other ion fluxes that are more local. Everything in biology always involves transmembrane gradients, that’s why we have membranes, so they can be gradients. Otherwise you don’t need the membranes. And transmembrane gradients invariably create electrochemical potential.
Dr. Sudhof’s discussion about the time makes me wonder about multiple mental processes operating simultaneously, yet in different time frames. How do our various brain and neural activities function, including our experience and consciousness, when they are dependent on biological mechanisms happening at different and relative time frames?
We edge toward an entire new realm of conversational pathways – metaphysical as well as scientific, but we both agree that such a conversation should wait for another day. However, there is additional question I need to ask. The question I have asked of so many physicians and scientists: What is healing? How does the body heal itself? Since Dr. Südhof is both a medical doctor, as well as PhD, his answer is revealing.
Finally, our fascinating conversation comes to an end. Yet, there is still one more question to be answered — the question that was one of the original premises of the interview. “And how good were you at making bassoon reeds?”
Suddenly this brilliant man, a man of so many carefully constructed ideas, thoughts and words was left for a moment speechless. He leaned back and sighed. No, he never really mastered the art of making a good reed. And then he smiled, in seeming appreciation of the daunting range of skills and disciplines it takes to become a professional musician – – and yet deeply respectful of the abilities it did provide him that led him to become a physician, scientist and Nobel Laureate.