Ignorance

by Firestein, Stuart

  In a variety of tests in which patients were asked to perform some action faster than they preferred, there was no difference in their accuracy than in healthy control subjects. In other words, accuracy was not the problem. Instead, Parkinson’s patients appear to be making a faulty calculation about the cost to make movements of a certain speed, and this miscalculation causes them to move slower. They could go faster; they are simply not motivated to do so. It is this unintuitive insight that may bring together a variety of previously disparate facts, forming an explanation, or at least a model, of how movement control could be unexpectedly related to phenomena like addiction and skill. Stick with me on this; it’s tricky but worth it.

  The pathology of Parkinson’s has been known for some time. A small collection of 25,000 neurons deep in the brain begins to die off, for unknown reasons. This is not many neurons (compared to the more than 80 billion in your brain), and it’s surprising how their loss can cause such devastating and widespread effects. Some time ago it was discovered that these 25,000 neurons make connections widely throughout the brain and that they communicate with other neurons using the chemical dopamine. Dopamine is used by numerous other brain cells besides this group of 25,000 and appears to have a confusing array of effects on the brain—from movement control to addiction to reward circuits in learning, to schizophrenia.

  The effect of dopamine on movement—at least on the slowed movement of Parkinson’s patients—is really a question of reward calculations. Their diminished dopamine levels, caused by the loss of those 25,000 neurons, have compromised the brain’s reward system. They are not motivated (note that the word motivated has the same root as motor) to move faster because for them there is no reward for doing so. The puzzling array of dopamine actions in the brain becomes clearer when you begin to think that behaviors are calculated by the brain to have a value associated with them—thus, movement and reward are not so disconnected as you might have thought by simple introspection. This is surprising, and again unintuitive, because calculating rewards seems to be a very cognitive activity—it involves planning, prediction, learned experience, intuition—“if I do this what are the chances of my being rewarded rather than disappointed or worse.” The hot new “field” of neuroeconomics, which attempts to understand our predilections and aversions toward gambling and risk taking, uses calculations no different from the one the brain evolved to make about the cost-benefit of reaching for a piece of fruit at a particular speed. And thus dopamine is part of the motor system and the reward system at the same time—not by accident but because the motor and reward systems are highly connected in our prehistoric brains. Who would have thought?

  I have outlined two small examples of work going on in neuroscience that are not necessarily about the big questions you might have thought dominated the field: the nature of consciousness, developmental pathologies of the nervous system, learning, and memory. They certainly touch on these issues, but the actual questions being asked are much more detailed. As important, they spring from almost obvious questions—so obvious that they failed to attract much attention for decades. And the result is that a seemingly mature field finds a new direction—searching new dark rooms for black cats that no one is sure are going to be there. Just when it seemed that we neuroscientists were getting to the bottom of sensory systems and some explanations for how the brain works, a whole new area of ignorance opened up before us, with even greater promise. These new questions prove how full the magic well of the brain still is—full of questions still unimagined by the brain under study.

  4. AUTOBIOGRAPHY

  How does someone, a scientist, arrive at the questions that determine the course of the rest of his or her life? What is the personal debate that leads a young scientist to one field or another, to one set of unknowns, to a group of questions around which he or she will build a laboratory, a research group, a career, a life? We have seen that choosing the question is the essential act in science. It may then be surprising that this so often happens in what is described as a flash of insight, an “ah-ha” moment, an epiphany. But like many such experiences, careful reflection shows that there was, in fact, a long, if clandestine, preparation for the moment of recognition. Can we recover that process? Is there value in knowing the history? Can we understand the process better than just chalking it up to a happy accident? In retrospect, it is often possible to see the route that may not have been very apparent during the journey itself, that with perspective something sensible can be extracted from an otherwise haphazard appearing odyssey. There is of course the danger that “in retrospect” we distill what was in fact a chaotic process into a tidy linear narrative, but such is the nature of memory and the desire to have a story.

  Here then I have decided to use my personal story, my own case history. It has some unusual elements in it, but they serve to highlight many of the decisive factors, both intended and serendipitous, common to the creation stories of scientific careers. And there is certainly more than enough ignorance woven through it to provide a lesson or two.

  So here it is: Stuart Firestein, Professor of Neuroscience at the Department of Biological Sciences, Columbia University, New York.

  I came to science late, after a career in, of all things, the theater, where I spent more than 15 years working professionally as a stage manager and director and had the opportunity to run my own repertory company. Although now there are university programs for training in the theater, the traditional path then was to apprentice yourself to professionals and learn by hanging around with accomplished artists. You started as a stage worker, setting up scenery and lighting equipment, attending production planning meetings, working the lights, or moving scenery at performances in the evening. You then graduated, if you desired and were any good, to assistant stage manager, an especially interesting position because you attended all the rehearsals, but the position had no set of assigned responsibilities. You simply did whatever came up, from getting coffee to copying scripts to organizing rehearsal props, to whatever. The nice thing about this position was that you spent a lot of time at the rehearsals, involved in the production but not burdened with responsibilities, and so you had the opportunity to see how things work—and just as important how they don’t work. You could watch actors work out scenes and develop character business while directors tried to find the right staging and develop an ensemble feel. You were part of the production but also had a critical distance that allowed you to learn while doing. It’s a system, I realize, not so different from the way we train graduate students in our laboratories, and it is one that I recommend highly. It is not so easy to create the condition where you can have perspective and involvement simultaneously, where you can be invested but not fully responsible, immersed yet without the pressures of liability. But having such an environment seems fundamental to a mentoring process that allows us to explore questions. This is one lesson from this case history.

  I was pursuing a reasonably successful career as a theatrical director involved in a variety of productions from avant garde experimental works to frankly commercial projects, mainly with repertory companies up and down the Eastern seaboard. I often joked that my hometown in those days was the Amtrak Northeast Corridor. In early 1979 an opportunity came my way, which I took on a lark and probably because I needed the money, to move to San Francisco with a touring production. Somewhat to my surprise I found the active theater scene there attractive, and I decided to stay on and explore it. A few years later I was involved in a successful production with a promised long run, leaving my days relatively free. I had a lifelong interest in animal behavior that I had never really followed beyond popular reading, and this unusual moment of stable employment gave me an opportunity to pursue it more seriously. I decided to take a course at the local college, San Francisco State University, where I found a class in Animal Communication taught by a Professor named Hal Markowitz. I mention his name because it was a very happy accident that I ran into him. He became an important mentor to m
e, and mentors are often a critical part of the story for any scientist. I had never been to college before and here I was a 30-year-old student. I found it remarkable. Someone stands up in front of a group of people and tells you everything he/she knows about something. What a great idea, who thought of this? As it turns out, I think it was Aristotle.

  Hal Markowitz, my latter-day Aristotle, was a generous fellow with his accumulated knowledge but also with his accumulated cynicism. The field of Animal Behavior can attract a lot of people who love animals and have deep relations with pets and other creatures they volunteer to work with. They are often delightful people with very good hearts, but they are rarely scientists. Hal Markowitz would have none of that; animal behavior was as serious a science as physics for Hal, and no less rigorous. I was impressed by this because, frankly, I was one of those folks who were interested in animal behavior because I liked animals. Not that Hal didn’t like animals; he liked them in what I believe is a truer way than most—he liked animals for what they are, not how similar to humans they might be or what use they might be. Hal was not interested in whether animal thinking approached that of humans; he was interested in animal thinking, period. He wanted to know about all sorts of animals and how they behaved because the very variety of biology was for him the source of endless questions. The intensity of Hal’s inquiry into something that had been a kind of hobby for me was something quite new, quite striking. I had not imagined how much there could be to know about animal behavior, how many deep questions there could be, if you just refused to be satisfied with a superficial or cursory exploration. This was an adventure.

  Hal posed questions that were hard. Does a dog urinating on a tree intend to communicate something? Does it appreciate the message that the next dog will sniff? How about the message a deer rubbing on a tree communicates to a predator? What’s different about those? Is it better to study animal behavior in the wild, like Konrad Lorenz and the European school of ethology, or in the laboratory like B.F. Skinner and the American discipline of behaviorism? Philosophically one answers the question in favor of the ethologists, but the overwhelming explanatory power of the behaviorists cannot be dismissed.

  Hal hooked me. I took another course from him and we became friends (still are). He convinced me to take more biology courses and to consider working toward a degree. I was 30 years old, I had been working in the theater since I was 18, had never been to college, and had never thought of earning a degree. Could I really handle serious chemistry and physics and math? Hal assured me so, although I’m not so sure to this day that he was all that convinced himself. I enrolled as a full-time undergraduate student, but I kept up some work in the theater, mostly tech work at night, just in case. Organic Chemistry was a Biology degree requirement, and I realized that would be the great challenge. I would have to defy Orgo, as it is known among students, the great monster that sorts out the real science students from the wannabes. Or so is its reputation. If I couldn’t get through Orgo, then I would know this was simply beyond me. So I took it as soon as I could. To no one’s surprise more than my own, it turned out to be my favorite course and one of my best. At least part of the reason was that organic chemistry requires a lot of memorization, and this is where it gets its fearful reputation as an impossible course. The thing was, memorization was trivial for me. For 15 or so years I had been memorizing scripts for a living. You often don’t know what you bring to the table, and this is the second lesson from this case history.

  Once the memorization was not a factor, the complexity of carbon-based chemistry, one of the most beautiful rule-based systems in the universe, was well … fun. I aced Orgo, and it seemed I was on my way. To where? After 4 years I had a BS in biology. I was proud of the accomplishment, but truth be told, the degree was worthless as far as altering my life. A career in biology would require a higher degree, a PhD earned in graduate school. I applied to a few graduate programs and thought that I would leave it to the admissions committees to decide my fate. If I was accepted into a graduate program, I would give up the theater for good and change my career to science; if not, I would go back to the theater full time, with my BS, my pride, and a curiously interesting background for a theatrical director. Remarkable, in retrospect, that I left such a life-altering decision up to an anonymous admissions committee, but I have since learned that this is often the case. Scientists are a strange lot this way—they seek to control every aspect of an experiment, but life decisions they leave up to committees and review panels with often anonymous memberships.

  As it happens the Neuroscience program at the University of California, Berkeley called to say that they had accepted me into their program. Surely the result of a clerical error, I thought. No matter, I accepted their offer immediately, and at 35 years of age, I quit the theater for good and showed up for graduate school.

  I wish I had a sensible narrative about all this, but as you can see it was largely happenstance—some good luck, an excellent mentor, the right bit of preparation, some more good luck, and perhaps a clerical error. Will Rogers used to say that people don’t so much fall in love as step in it. I think the same may often be said of science. Even those who know from their third birthday that they will be a scientist can’t tell you precisely how they got to be doing exactly what they are doing. They try this or that, run into a professor or a graduate student who takes him or her under their wing and infects them with their mystery, and that’s it.

  Only in retrospect does it seem that the question and you were made for each other. This is the fallacy of design, not much different from the misleading arguments made against evolution with its random mutations and post hoc selection. Once the function of something is known, it always appears to have been designed. This, of course, was Darwin’s great intellectual leap—to see that such utilitarian structures as eyes were not designed for their purpose, but that their purpose selected for them. We often wonder at the miraculous circumstances that bring together two lovers. How in the more than 7 billion people inhabiting the planet did these two people, so ideally suited to each other, find one another? What are the chances? Actually they are probably pretty good, which is why it happens so regularly. For one we are wrong to believe that there is only one other person in the world who is “perfect” for each of us. Probably there are thousands. And then we often start with less than perfect, and each becomes more perfect—or we get divorced. Is this the case with scientific questions? There certainly is no lack of questions, I hope we’ve established that. So you run into them, you can hardly help running into them, and then precipitously one of them sticks, for reasons that may be unfathomable, and in the end may not matter. One of them hooks you because the bait looks especially tasty, or you are especially hungry. And then sometimes it doesn’t last and you get divorced. This is the third, or is it the fourth, lesson from this ever more bizarre case history. There’s a lot to be said for making the most of happy accidents, and relying on happy accidents is no shame. But keep in mind that “Chance favors the prepared mind,” as Louis Pasteur famously noted.

  I am often asked if I miss the theater, by which I guess people mean the excitement, the glamour, the creativity. The short answer is, no. The glamour I don’t know much about; I remember hard work, late nights, exhaustion, fear, arguments, people crying, but only fleeting moments of what might be called glamour. So nothing to miss there. But as for excitement and creativity, I don’t think that science has any less of that than the theater, or any of the arts. I knew actors who showed up on opening night with the same performance they brought to the start of rehearsals 6 weeks earlier—which was often not much different from the role they had been performing in everything else they did. I knew directors who used the same bag of tricks in production after production; in fact, they were often hired by producers for their reliable bag of tricks. This is not what I consider creative. Of course, I know scientists who are the same, whose work is just as pedestrian and derivative and repetitive. But then there are the creative
ones, just like there are creative artists, and they are no less adventurous, no less bold, no less perceptive than the best of artists.

  And the excitement—I am afraid that it is impossible to convey completely the excitement of discovery, of seeing the result of an experiment and knowing that you know something new, something fundamental, and that for this moment at least, only you, in the entire world, knows it. When I was a graduate student, I was working late one night at the lab and I obtained a really unexpected result that answered a long-standing question. It was quite late and there was no one to tell. I remember going home that night and thinking that I should be extra careful in traffic because only I knew this thing and I needed to protect it. There was a kind of thrill in this and the whole world looked different that night.

  The one rational decision I did make was that in graduate school I would work on something more reductionist than behavior. The brain is the source of behavior, so I decided to look at how the brain works. This was perhaps a little naïve, but naiveté can be important at certain times, like at the beginning. As Hal Markowitz used to put it, all behavior is just stretching and squirting—neurons squirt out neurotransmitters that cause muscles to stretch. So I thought, let’s study how neurons squirt neurotransmitters, and this may lead to a deeper, or at least more mechanistic, understanding of behavior. Admittedly this may sound radically reductionist, and I am perhaps overstating it a bit. But there is some middle ground between simply observing animals or humans behave, and trying to figure out what’s going on inside of them that makes them behave that particular way, and I thought, no I knew, that this was the ground for me. I hit upon the olfactory system, the sense of smell, as a possible place where that middle ground may be accessible to study. Smell governs, or at least modulates, a wide range of behaviors in many animals, including those associated with feeding, aggression, sex—pretty much all the things that matter. I thought that perhaps learning about how smell works would eventually lead me back to behavior, that if I became expert in the physiology of smell and odor perception, then I could go back to behavioral studies with a new and deeper appreciation for its underlying causes. About all of this I was almost completely wrong, but about the study of smell being a frontier I was presciently correct. Lesson five (four?), predictions are useless, except for when they are helpful.