Dr. Thomas Sudhof - Nobel Prize Winner in Medicine

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.

  1. SÜDHOF: My background is a little unusual in many ways. It is unusual because I come from a different country and a different system, but it’s even unusual for a German audience because I grew up in a movement that’s a little bit outside of the regular stream of people. We were a very traditional anthroposophical family, with roots way back to the originator. My grandparents were closely associated with Rudolph Steiner himself.

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.

  1. SÜDHOF: As a result I grew up in that sphere. I left that sphere very early on because of my personal views, and my independence, but the rest of my German family was still deeply into it. I have talked a lot about this in the public and particularly in Germany, as people in Germany have an interest in the subject. My view is generally positive, but critical. I think that the intentions are wonderful, and some of the practices are really good. I also think that it is not for everyone, and I cannot accept the philosophical underpinnings because I think they are not compelling. And I felt that way already when I was a young teenager, and that hasn’t changed.

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.

  1. SÜDHOF: The Waldorf education was certainly very beneficial for me personally, and I think it’s a great approach. I think that there are many aspects of it that I strongly endorse. I spent my entire school education in the Waldorf system. When I emerged from it, I’m sure I wasn’t as well trained in many of the STEM systems. But I don’t think that matters. In particular, I feel that today’s education, at every level — certainly in school, but even in college — is way too much focused on the so called “STEM subjects”: science, technology, engineering and math. The fear that we may become illiterate in those subjects, is probably well founded, but you can’t just cram it into people. It’s not productive, and certainly not in young children. So I think that fostering creative thinking and individual initiative early on is tremendously positive.

    The conversation then moved to the premise for the interview – the relationship between musical training and science.
  3. SÜDHOF: First, I was exposed to playing music in school, the recorder. Then I began the violin. I wasn’t very good at it. I didn’t like the teacher. Perhaps it was the age, possibly the instrument. So I stopped playing the violin on my own initiative. But after a while, I decided I needed to do some music. So I picked the bassoon. I have no idea why. It may have been after all the subtle hints of some of my teachers. I doubt it was my parents. It may have been that I liked those sonorous deep sounds.

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?

  1. SÜDHOF: So where is the creativity in figuring out what is true? A good question. There is a lot of creativity because the nature of truth from a human perspective – the only one we know — is that you formulate it — you describe it. As a scientist, or a human, you cannot simply discover truth that’s there, because you actually have to describe it. In describing truth you are creating an understanding of an aspect of the world. This process of description, this understanding, in some ways, you could call creating truth. Although you are not actually creating something — in the sense that it could go in multiple ways. It has to be only one way — though to put it together in that way is actually a very creative process. I don’t think that ‘creating truth’ is the right description. But that the process of discovering connections, and how something works, involves putting it into words or into a model – into a way you can actually envision — into some representation. It is usually verbal, but not always, and that represents the creative process.

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.

  1. SÜDHOF: First, let’s remember there is a lot of science that is not creative. That has to be non-creative and is still good science, basically the part of science that collects data — from clinical trials to the study of genome sequences. Once you have a blueprint, the data, you can look it over, think about it, and possibly make something out of it. That is an important aspect of science and is valuable, but that is not where the creativity comes in. The first creative issue comes about in how you actually are going to approach the question? Yes, you are selecting what you are going to look at. But the biggest element of creativity is how not to be bound by those selections.

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.

  1. SÜDHOF: I wasn’t one of those people who were destined to be a scientist as a teenager. Though I had always been interested in solving puzzles, I had no intention of becoming a scientist growing up. First, I studied medicine. Then I got into science because it intrigued me that there were so many things nobody knew anything about, including, in particular, medicine. There were so many diseases which were totally enigmatic. Moreover, I was intrigued by the fact that there were medical doctors then, maybe even more so now that had no interest whatsoever in why people are sick. They just basically accepted sickness as a fate. They would try to do something about it, but they had no interest in what actually happened. Whereas, I felt strongly that we needed to get at the root of things.

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.

  1. SÜDHOF: Obviously consciousness is a big question, and I’m not sure that biological interpretation of consciousness is going to be possible. I have my doubts. But I am definitely fascinated by the fact that it’s the brain that makes us human, and that allows us basically to think, speak, and so on.

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.

  1. SÜDHOF: All these technological developments are great! We have learned a lot. However, I would posit that there are principles that precede the need for modern instrumentation, and are a result of logical thinking. For example, evolution has nothing to do with religion. That’s just Darwin and the ability to observe and apply clear logical thought.

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?

  1. SÜDHOF: Human experience, as such, is consciousness. And there is a tendency for famous scientists (and sometimes not so famous scientists) to start working on that when they get older. But I don’t see at this point any fundamental paradigm shift. It’s not as though we have reached a significant amount of progress in understanding the brain. We can see where we need to go for a better understanding, but we don’t actually know yet what’s there. There’s a lot of often acrimonious discussion about what is actually worthwhile studying, and what are the best approaches.

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?

  1. SÜDHOF: Chinese medicine is quite good, and a lot of it works. I think that some of the reasons it works, however, has to do with the nature of medicine. Medicine is not only a science, it is an art and there are many issues in medicine that are difficult to control for in clinical trials. The biggest, most difficult issue, obviously is the placebo effect, which seems to grow with time. The placebo effect now is having much more importance than it did 20 or 30 years ago — which is an amazing observation on its own.

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.

  1. SÜDHOF: Time is important on many levels. Most neurobiologists, when they study the brain, only study one time dimension, which is the time dimension of very rapid reactions – the timings found in synopsis and synaptic transmission. But as important for the individual, and also for understanding diseases, are different time frames that utilize additional systems besides synopsis and synaptic transmission.

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?

  1. SÜDHOF: Does relativity come into play? Obviously not in the Einsteinian sense, but of course, it is a valid question. One of the things that I’m interested in is this discrepancy. When we think about the brain normally — as scientists, but also as laypersons — we think of the brain usually in two ways. One is in terms of fast and quick abilities, what’s often referred to as intelligence. How quickly we can calculate, how quickly we can respond, or in sports for example, reaction times, and so on. Or we think of it in terms of emotional states, moods and well-being. But the brain has many different layers in between. And these are almost two separate systems — but they are not really separate, in that they are not only connected by being in the brain, but actually they are connected at multiple levels that work at completely different time frames. And while these time levels are not a continuum, we postulate it as levels — how they interact is quite an interesting question.

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.

  1. SÜDHOF: Very philosophical question. And I would personally think that one cannot formulate healing in the sense of absence of disease, because disease itself is a somewhat difficult concept. So I would think that healing should be defined, or formulated, or thought of as alleviation of suffering or other physical burdens. We may or may not actually reverse or end a disease process, as it is defined, but we may be able to suspend the negative effects of the disease process upon the individual. I think that it’s most likely that many diseases in the future will never be fully eradicated, but people will be able to cope with them for the normal lifespan of an individual.

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.