The Nobel Prize in Chemistry 2008
Osamu Shimomura, Martin Chalfie, Roger Y. Tsien
I was born on January 15, 1947 in Chicago, Illinois, the oldest of three sons of Vivian and Eli Chalfie (Figure 1). In trying to reconstruct the events that led me to this opportunity to write an autobiographical essay, I realize how much chance, luck, the influence of others, and, in some cases, my own pigheadedness influenced my life. I have tried to show how unexpected this journey has been and, where possible, to find links to Chemistry (one of the ironies of this Prize).
Three of my grandparents were immigrants. My father's parents had immigrated to the United States from the town of Brest-Litovsk on the Russian-Polish border and settled in Cincinnati. My paternal grandmother, Esther, died before I was born and all that I know of her is that she was the cook in the Manischewitz Company executive dinner room in Cincinnati and that my father was devoted to her. I have a picture of him standing proudly beside her, but I do not have any of her recipes. I have only a faint memory of my paternal grandfather, Benjamin, who died when I was five. I remember going for a rowboat ride with him and his giving me the paper ring from the cigar he was smoking. He came to the United States to avoid being recalled for duty by the Russian Army during the Russo-Japanese war. He had trained to be a cabinet maker (I have a few of his tools), but in Cincinnati he worked as a tailor.
|Figure 1. My parents flanking my maternal grandmother.|
My father was born in 1910, a year or so after my grandparents settled in Cincinnati. I do not know much about my father's early life except that he clearly had an aptitude for music, teaching himself how to play mandolin and then banjo and guitar when he was quite young. He went to a two-year trade school instead of high school, but I always thought of him as very worldly-wise and intelligent. He wrote wonderfully crafted and humorous letters and had a handwriting that I still wish I could imitate. He was nineteen when the Great Depression began and already a professional musician. In fact his income as a musician supported his family and allowed his younger brother, Sam, to stay in school and eventually go to law school. He became the staff guitarist at one of the country's largest radio stations, WLW in Cincinnati, and later the guitarist with the Russ Morgan Orchestra. Throughout his life he had a great intuitive feel and love for music. While at WLW he invented a radio quiz program called Tunecode, which he patented. As he envisioned the program, contestants would be asked to name a series of popular songs after hearing short excerpts from them. They then needed to take the first initials of all the songs and rearrange them into the name of a famous person. As far as I can tell, my father was one of the few people in the world who could actually do this. I do not think that the show was ever produced.
My mother and her mother, Madeline Friedlen (Figure 1), were born and raised in Chicago, Illinois. My maternal grandfather, Meyer Friedlen, was born in Moscow, but his parents emigrated when he was a month old. I know little about him because he died well before I was born. My mother adored and revered her mother. Both women were brilliant, hard-working, and very independent. During the Depression Madeline started her own business, a dress-manufacturing company named Mountain Home Smart Apparel (the name allowed her to use up a set of labels left over from a failed sweater-making venture of my grandfather's). I remember her as someone who was always loving and always interesting, whether she was telling me about how much she admired Eleanor Roosevelt, trying to get me interested in studying metallurgy (which she thought would be the science of the future), or giving me a copy of Herman Hesse's Siddhartha. I also remember coming out of Temple during the High Holy Days and hearing her say that the entire story about Abraham's willingness to sacrifice Isaac was ridiculous. She thought that any person that would give up their child for any reason was just nuts. This was my first introduction to questioning religious belief, and it stuck with me.
My mother was born in 1913, and I think she had probably been an excellent student, although she never told me. She was very proud of having graduated from Senn High School in Chicago. She enrolled in the University of Chicago, which she attended for a year and a half. At the start of the second semester of her sophomore year, however, her parents told her that they could no longer afford the $100 tuition. Without hesitation or complaint, she put away her books and joined her parents that day at work. My mother and grandmother worked together until my grandmother became ill in the 1960s. For most of the time that I was growing up my mother was the head of the business. She was one of the most organized people I have ever known, and I regret that I did not inherit this ability. I do, however, have her love of learning and her independence.
It was my father's chronically bad teeth that led to my parents' meeting. My father had enlisted in the Navy during World War II, where he was a musician second class; some mischief he was involved in or insubordination that he never explained to me lost him his first class ranking. He would play his guitar and banjo at officers' club and a few times march in the Navy band (I think he had to carry a drum), but ended up on a battleship in the Pacific. For a while he was stationed at the Great Lakes Naval Station near Chicago. Problems with his teeth caused him to go to a dentist in Chicago, who invited him to a USO breakfast for Jewish service men and women in Chicago called the Lox and Bagel Club. At the breakfast the dentist introduced him to my mother and grandmother who were USO volunteers. My father shipped out soon after this on the USS Missouri, witnessed the signing of the Japanese surrender, and returned to marry my mother. He did not know what he wanted to do at the time, only that he no longer wanted to travel with the orchestra. After a few years he joined Mountain Home and helped run the factory and sold the line on the road.
I would often go with my parents to the office, make fabric swatch cards, and print out the tickets that would accompany the dresses as they were being made. I really got a chance to see my parents' style of business, however, in 1970, when my father had surgery for colon cancer and I, having finished college, took the line on the road for him. My parents believed in building up long term relationships with the shops they sold, so all I had to do was walk in with the samples, show the latest dresses, and fill out the order form. The buyers already knew what to expect and what they liked. I was grateful that I did not have to do any selling (I would not have been able to in any event). More importantly, I got a chance to see the trust and respect all the buyers had for my parents.
My upbringing and that of my brothers Ed and Alan was comfortable, ordinary, and from the age of eight, when my parents moved from Chicago to Skokie, Illinois, suburban. My parents had moved to the suburbs to find better schools for their children. My brothers and I rode our bikes all over the place, played baseball (poorly), and swam at the local swimming pool. We also mowed and edged the lawn in the summer, raked the leaves in the fall, and shoveled snow in the winter. I now live in an apartment to avoid these chores. In general, life was enjoyable and uneventful.
And we were loved and always had our parents' support. My brother Ed has reminded me that my mother predicted, when we were very young, that I would go to Harvard and that he would go to MIT, which we did. This attitude was not one of pushiness on my mother's part, but an extreme pride in her children. Although out of chronological order, a good example of my parents' different styles of affection is seen in an event that occurred when I was in graduate school. During a visit home for the Thanksgiving holiday, my mother asked me if I wanted a tennis racket. The racket was part of a promotion recently started by their bank. I told her that I wasn't interested in learning tennis, I didn't want a racket, I had much too much lab work to do, and I didn't really need to learn how to play tennis to get a girl friend (the real reason for her offer). I thought that the issue was closed, but soon after I returned to the lab I received a package with the tennis racket, t-shirts, shorts, and socks. The package also contained a note that I regret I no longer have. On the note my mother had written: "Marty, we really loved your visit and hope that you love your new tennis racket. We love you, love you, love you, love you, love you [or something like that]. Love, Mom." Under this my father had written: "Get your own balls. Dad."
When I was growing up I became proficient at two activities that have given me much enjoyment throughout my life, as well as a feeling of uniqueness. The first was swimming. I had learned to swim at day camp and turned out to be good at it (I was fairly hopeless at other sports). I remember being eager to go to high school because the school had a swimming team, and I could finally participate in a sport that I could do well in. I also remember thinking after a particularly long practice of unbroken swimming in the high school's bromine-containing pool that Hell had to be a place where you swam laps forever. Nonetheless, I swam (usually butterfly) throughout high school and college. I have swum off-and-on ever since.
My second activity was playing classical guitar. When I was twelve, my father gave me a Gibson C1 Classical Guitar, and taught me how to play for about a year (Figure 2). He was an amazingly good teacher, who never got impatient with my ineptitude. I wish I had his teaching skills. Although I went on to take more formal lessons (with Richard Pick, a well-known teacher at the time), I cherish the fact that my father was my first teacher and all the hours we spent playing duets together. I still play and get immense enjoyment from the guitar, though I do not have his skills. And I wish I had talked with him more about playing. My father suffered from dementia in the last years of his life, but continued to play guitar. On a visit home I gave him some guitar versions of the Bach cello suites, which he would play for hours a day. On a return visit, he told me that he thought this guy Bach was terrific. I realized that with his memory going, he was rediscovering Bach every day, which was the one consoling consequence of such a horrible condition.
|Figure 2. Me and my first guitar.|
I was interested in science or at least nature from an early age, learning the names of planets, cutting cartoons with facts about animals out of the newspaper and gluing them into a scrapbook, and, with a friend when I was five or six, trying to design a submarine. I know I had a child's microscope and a chemistry set. When I was a postdoc, however, I finally realized how deficient my early experiences had been. I, alone of my colleagues (or so it seemed), could not boast of that ultimate young scientific achievement of almost blowing up my home trying to make fulminate of mercury or gunpowder. I do remember, however, sneaking into the chemistry supply area in high school to get ammonium dichromate to make flaming "volcanoes," so maybe I do qualify.
What I did do a lot as a child was read, and I particularly remember reading all the "Hardy Boys" books, a set of history books call the "Landmark Books," and a series of science books called the "All About Books." My mother saved many of these books, which I now have: All About the Planets, All About Insects, All About Rocks, and All About Dinosaurs, among others. The last must have made the biggest impression on me because it was the only book whose author (Roy Chapman Andrews) I remember. Unfortunately, I no longer have a copy of the volume entitled All About The Changing World of Chemistry that I praised in a book report I wrote in fifth grade. Either my spelling was quite horrible at this time or I thought the subject strange and deadly because I referred to Chemistry as "Chemistery" and "Chemitery" in the report.
None of the standard high school science courses made much of an impression on me, but I did enjoy the Advanced Placement Chemistry course I took in my senior year. This course had only eleven students and was taught by a rarity for our school, an exchange teacher from England, Mr. Leslie Sturges. Mr. Sturges taught a very relaxed but rigorous course and gave us a lot of freedom. I remember we would take a break in the middle of our two-period long exams where the eleven of us would attempt to sing Tchaikovsky's 1812 Overture (cannons included) and our own version of a song from the movie Mary Poppins, which had been released that year: "Just a Spoonful of C12H22O11 Helps the Medicine Go Down." We were nerds before it was fashionable. Recently, a member of that class sent me a picture from our senior yearbook showing that I was a member of a student club called the Chemistry Advisory Board (Figure 3). When I first looked at the picture, I had no idea I had been in any club like that. Then I realized that all the people in the picture had been members of the AP Chemistry class, and I remembered that one of my classmates had complained to the yearbook editor that he was not in enough pictures. He found that a club was considered official, and hence eligible for a picture in the yearbook, if it had met for at least one hour during the school year. We probably sat around for an hour, sang our chemistry-related songs, told jokes, and then had the picture taken to be published with an impressive caption for posterity.
|Figure 3. The "Chemistry Advisory Board." I am in the middle in the back row.|
I entered Harvard in 1965 not really knowing what I wanted to do. This confusion seems to have lost me a fellowship. G. D. Searle and Company, the pharmaceutical firm, had their home office in Skokie, and they gave a fellowship each year to a graduate from my high school that was going to major in science in college. My brother Ed reminded me that I was interviewed for this fellowship, but felt compelled to say that I was not sure what my major would be and could not even guarantee that I would major in a science. I was disqualified. Apparently, when I got back from the interview and told my mother what I had said, she remarked that total honesty might not be the best policy.
In any case, when I started at Harvard, I took second and third year calculus in my first year, mainly because I was very impressed by a wonderful professor (Jerry Kazdan). I flirted with the idea of majoring in Math, but soon discovered that I did not have the intuitive grasp of the material that I thought I needed. I then decided to become a Biochemistry major because the subject matter felt more exciting than a Biology major and because it required a broad range of courses, and I could satisfy some of the requirements with the math courses I had already taken.
I realized that if I was going to major in Biochemistry, I needed to have some laboratory experience. My first research experience was in the lab of Dr. Paul Kohn in the Biochemistry Department at the University of Illinois at Chicago during the summer between my sophomore and junior years. He was interested in synthesizing furanosyl nucleosides (purines and pyrimidines linked to six carbon sugars with five member rings) as potential antitumor drugs. I do not recollect whether I was successful in the lab, but I suspect I was not. In fact, I have only a few memories from that time. Paul insisted that everyone take a break at three in the afternoon. I remember all of us going dutifully as a group to the cafeteria, but I also remember being disappointed that the usual topic of conversation during these breaks was not science, but property taxes. I also remember trying to enliven the lab by putting a quote of the day on the lab blackboard (most were fairly silly).
My first real research project came during the next summer, and that led to my dropping out of science. I wanted to do research for a senior thesis and had arranged to work for Klaus Weber at Harvard. Klaus wanted me to analyze the active site of the enzyme aspartate transcarbamylase by chemically modifying different amino acids within it, and gave me a bench in a student lab. I was alone in this lab and had no idea what I was doing. Looking back on this period in my life, I believe that I was too afraid to ask for help, thinking that I should be able to do everything by myself. I should have asked more questions and sought more guidance. In any case I tried doing experiments all summer, but nothing worked. At the end of August I went to Klaus and asked him what I should do next. He said I should try the experiment one more time and if it did not work, I should abandon the project. I tried one more time and still failed. I did not enjoy failing and decided that a career in science was not for me. I spent my senior year taking non-science courses (except for one remaining Physics course that I needed for my major) and loving them.
My undergraduate education was both good and bad. On the one hand I felt intimidated by the many astonishingly smart people that I met at Harvard, and this made me less confident. I suspect that many people entering Harvard have a hard time living up to what they imagine is expected of them. I did reasonably well in my classes, but not great (my worst grades were in chemistry and physics). More importantly, I felt that I had to do everything on my own, because asking for help was a sign that I was not intelligent enough. I now see how destructive this attitude was, but then I assumed that this was what I had to do. On the other hand, the courses I took were challenging and stimulating, and they taught me to think about and draw conclusions from data. Useful skills for what I do now.
And Harvard provided the spark that eventually led me back into a career in biology. During my junior year, I took Cell Physiology from Woody Hastings. Woody, a pioneer in bioluminescence research and one of the early researchers studying GFP, who was a new and especially kind faculty member. One day I went to his office and asked if I could have a key to the biology library so I could study late at night. He immediately got up from his desk and walked down four flights of stairs to the main office and instructed the people there to give me a key. No one had gone out of his or her way like that for me before. I was very impressed.
I had entered the Cell Physiology course a week late and so could not take the lab. I wrote a term paper instead. The paper was on the role of cyclic AMP in the activation of sodium transport in the toad bladder, the transport being measured with Ussing chambers. I received a B– (I still have a copy of the paper) and didn't think about the subject until three years later.
My college years (1965–1969) were a time of considerable student activism and experimentation. I was not immune to the changes that were going on around me. I was strongly for civil rights, against the Vietnam War, and owned a pair of black and red striped pants. I was not, however, much of an activist (I would have been classified as a liberal). Nonetheless, during my last semester at Harvard, I and virtually all of my friends went on strike after the University had allowed the Cambridge police to come onto campus and beat the student protestors. The initial confrontation had made the national news, so when I decided to boycott my classes, I called my parents to tell them my reasons. My parents were sympathetic, but did not want me to get in trouble (the fears of what had happened during the Red Scare of the 1950s made them caution me against joining any political organizations). Our conversation lasted more than an hour. At the end, my parents reluctantly agreed with my actions. Not willing to end our conversation at that point and trying to get a rise out of my parents, I said, "Mom, Dad. Be sure to watch the news tomorrow night, because if there is another confrontation, I'm going to be right there on the front lines" (something that I would not have done). My mother replied, "Marty. If I ever find out that you were anywhere where there was violence, I'll murder you." Our mutual laughter finished the conversation (Figure 4).
|Figure 4. Graduation from Harvard in 1969. From the left are my brothers Alan and Ed, my mother, me, and my father. I am wearing a red armband on my left sleeve because of the strike.|
After college I had no idea what I was going to do with myself. At first I had the horribly naïve, arrogant, and totally wrong view that if I could not do well in science, then a social science would be a snap. As a result I had taken an introductory social science class during my senior year and intended to enroll in Harvard as a special student to study sociology. I soon learned that scholarship in sociology was not as easy as I imagined. I left the program after one semester with a much healthier respect for other academic disciplines. Still unsure what I should do, I had a series of short-term jobs: I interviewed people in hospitals to find out how they repaired their electronic equipment for a Department of Education study, substituted for my father selling dresses, did some draft counseling, and set up summer rock concerts in the parks of Cambridge, Massachusetts.
One year out of college I was hired to teach high school at Hamden Hall Country Day School in Hamden, Connecticut. I taught a broad range of classes in the two years I was at the school: chemistry, first-year algebra, and an introductory social science course. When the first school year ended, one of my fellow teachers, Barbara Beitch, who had a biology Ph.D., suggested that I talk with a friend of hers who had a lab at Yale Medical School about a summer job. I went to her friend, José Zadunaisky, and heard about his work. He explained that he was interested in active chloride transport in the frog retina and that he was studying the transport with a Ussing chamber. Remembering the Ussing chamber from the paper I had written for Woody Hasting's class (but forgetting all the other details – which, of course, did not correspond), I asked if cyclic AMP was involved. He didn't know, but remarked that someone else had asked him the same question the day before. He hired me, assigned me a different project, and then left for the summer to do his own research in France. With him gone, and enamored by my own idea, I hunted down the other person who had asked José about cyclic AMP, Arthur Neufeld, asked him how I could test for the involvement of cyclic AMP, and proceeded to do that experiment and not the one that I had been assigned. He suggested adding epinephrine (adrenaline) to the preparation to raise cyclic AMP levels. I set up the apparatus with a great deal of help from Stephen Klyce and Maurico Lande, two postdocs in the lab, added epinephrine, and the short-circuit current (a measure of the chloride transport) took off (Figure 5). I was elated. The experiment had worked. To me, the big difference between this experience and my disastrous summer at Harvard was that I had finally learned to ask for help. I continued to do experiments over the summer and also found considerable satisfaction in finding pertinent references in the library (the one skill I thought I could bring to these studies). José returned at the end of the summer and asked for the results of my experiments (we had not corresponded over the summer). I told him that I had not done the assigned work (much to his surprise), but I was able to show him what I had done. Fortunately, he liked the results, and this research led to my first scientific publications.
|Figure 5. My first successful result. Taken with permission from the copyright holder, the Association for Research in Vision and Ophthalmology. Chalfie, M., Neufeld, A. H., and Zadunaisky, J. A. (1972) Action of epinephrine and other cyclic AMP-mediated agents on the chloride transport of the frog cornea. Invest. Ophthalmol. 11: 644–650.|
Having an experiment succeed really increased my confidence and my enjoyment of science. At the same time I was becoming disillusioned with teaching, not because I did not enjoy working with students, which I did, but because I felt I was ignored and dismissed by the school administration. I remember being told by a school administrator at a faculty meeting, "That is a good idea Marty, but we are not going to do that here." I also found ironic that, contrary to common expectations, the scientists I knew were much more communicative and interactive than the teachers. The teachers were friendly people, but, perhaps because they talked all day in their classes, they were silent in the faculty room during their breaks. In contrast, the scientists in José's lab, perhaps because they had spent long hours quietly working on their experiments, always seemed to be willing to take time to chat when someone came by. Perhaps I had just found a supportive home. In any event, these considerations and the naïve feeling that having a Ph.D. would be prestigious, led me to apply to graduate school. I was accepted into the Physiology Department at Harvard (I had applied to the Biology Department but they had transferred my application).
As a beginning graduate student, I was assigned a desk in a faculty member's lab. Fortunately for me that faculty member was Bob Perlman (Figure 6). Bob had recently come from the National Institutes of Health, where he and Ira Pastan had discovered the role of cyclic AMP in catabolite repression in E. coli. At Harvard he was interested in catecholamine biosynthesis and secretion, particularly from the adrenal gland. My work on the effect of epinephrine on the cornea probably resulted in my assignment to his lab. I was given a desk right outside his office, and his door was almost always open. During my first year, when I was taking classes and had not yet started working in the lab, I spent a lot of time in the library reading reviews and other articles. Whenever I got an idea for an experiment, I would barge in on Bob to tell him about what I hoped would be a thesis project. Several times Bob would say that the idea was a good one and that coincidently he had just read an article in which the authors had already done the experiment. I was greatly discouraged by this turn of events, but Bob would tell me that I should be happy to have thought of a reasonable experiment. Somehow that was never quite as satisfying.
|Figure 6. Bob Perlman in a characteristic pose in his office at Harvard.|
When it came time to choose a laboratory for my research, I rotated in two other labs, those of Tom Wilson and Sue Leeman. I learned much from both of them because both took a real enjoyment in their research, but Bob's support was very important to me and I decided to do my thesis in his lab. Bob had learned that another Harvard researcher, Shields Warren, had generated an adrenal tumor (pheochromocytoma) in rats that only made norepinephrine. My project was to test a hypothesis of Richard Wurtman at MIT that cells of the adrenal medulla made epinephrine because they were bathed in high levels of glucocorticoids from the adrenal cortex and this induced the production of the enzyme that converted norepinephrine into epinephrine. I obtained a rat with the tumor from Warren's technician, Rosanna Chute (who, because of her red hair, liked to be called Rusty Chute), transferred the tumor into new rats, and injected the rats with dexamethasone. The rats wasted away, but the tumors never made epinephrine. Another failed experiment. Fortunately for me, Bob suggested that I make cell suspensions from the tumors and study norepinephrine synthesis and secretion. Making the cell suspensions turned out to be quite easy (the tumors fell apart when pushed through a mesh), and the experiments proceeded fairly well.
Bob was constantly interested in our experiments and insisted that all his students and postdocs call him in the evening to tell him our results. I always enjoyed these conversations; Bob made me feel more like a collaborator than his student. This companionship extended to the writing of our papers. Every time we sent off a manuscript or had a manuscript accepted for publication, I would go into Bob's office and we would each have a small beaker (5 or 10 ml) of Scotch whiskey in celebration. I learned much about writing from Bob, but when he wanted me to begin writing my thesis, he clearly thought that I had more to learn. To let me know it was time to start writing, he gave me a copy of Strunk and White's Elements of Style and told me to read it from cover to cover. I still have the book above my desk.
My time in graduate school confirmed my opinion that the lab is a haven. I had many friends in the lab, especially Buddy Ullman, Jay Slater, Michele Carvotta, Debbie Hoadley, Jacqui Kitabgi, Lorna Role, and Karen Vaccaro. I also became friendly with a terrific group of faculty, students, technicians, and animal caretakers that got together almost every Tuesday afternoon when the weather was nice to play a very relaxed game of softball. This was really an excuse to have a beer; almost everyone had a can of beer at his or her position. Because most of these people worked in the Sex Lab (our name for the building called the Laboratory of Reproduction and Reproductive Biology), Bill Moyle and Jack Senier, the leaders of this group, insisted that the team be called the Nads so that we could cheer on our teammates by yelling, "Go Nads." They even made a team t-shirt, which I still have.
Despite the fun and games of graduate school, I had to think about what I wanted to do for my postdoc. At first I considered going to another lab working on catecholamines, but I was not sure that I would learn much more in the area and I had no pressing ideas for experiments I wanted to do. Fortunately, I had a visit from Bob Horvitz, who at the time was doing a postdoc with Sydney Brenner at the MRC Laboratory of Molecular Biology (LMB) in Cambridge, England. Bob and I had been friends in high school in Skokie and remained in touch through college and grad school. During this visit he wanted to talk with me about dopamine because he was interested in studying its action in the nematode Caenorhabditis elegans. I knew something about C. elegans because one of my roommates, Paul St. John, was a technician with Sam Ward, a former Brenner postdoc who established one of the first C. elegans labs in the United States. I liked hearing about Bob's work with John Sulston elucidating the postembryonic lineage of the animal and the idea of spending some time in England, so I asked Bob if he thought Sydney would take me on as a postdoc. He suggested that I write Sydney. I was also encouraged by Bob Perlman, who said that he liked the idea that I would be working on a completely new system and that I would be working for Sydney, someone he himself had wanted to work with. Although Sydney's brief reply said something about my working with John White, another staff member at the lab, I assumed that I was accepted and proceeded to apply for fellowships. I was fortunate to get a British American Research Fellowship given jointly by the American Heart Association and the British Heart Foundation, and I was particularly delighted with its acronym.
Since I had a few months free before I was to go to the LMB, Sam Ward kindly offered me a temporary place in his lab, which he referred to as the farm team. I looked at C. elegans for the first time at a tall biochemistry bench at which people usually stood to do their experiments. I sat rather unsteadily on an elevated chair, staring down a microscope for hours as I looked at the tiny worms moving on their Petri dishes. I was somewhat tense, because I wanted to do well. I worked intently, so much so that at night before falling to sleep I would close my eyes and see plates of moving worms. After a few days of this, I woke in the middle of the night from a dream in which I was writhing about saying, "Help – I'm a mutant," to find myself with a debilitating muscle cramp that extended across my shoulders and down my arms to the elbows. I was unable to return to the lab for a couple of weeks, but finally came back and learned to grow C. elegans. (I now lecture everyone in my lab on the importance of how to properly view the animals.)
I had intended to work on neurotransmitters in C. elegans, but before I left the United States I went to the first international C. elegans meeting at Woods Hole and I acquired a new research project. I drove to the meeting with Bob Horvitz, and on the way he encouraged me to look at the work that John Sulston was doing on touch-insensitive mutants and to think about continuing that project. John had come to the meeting expecting to give a slide presentation about this work, but found on his arrival that he had been scheduled to present a poster. As a result the first picture I saw of John's mutants was the 35 mm slide that he had taped to the window at Swope Hall. He was not going to continue the project, and it was too good to be abandoned. I was grateful to have the chance to continue the work.
Before I left Harvard another member of the faculty, excited about my going to Sydney's lab, told me I was going to have a wonderful time. He also told me, however, that Sydney judged people very quickly and if he decided you were not worth talking with, you were finished. I arrived in Cambridge and went to see Sydney. I told him that I was interested in working on the genetics of touch and he thought that this was a good project. When he asked me if I had any questions, I asked him for an explanation of some part of his 1974 paper describing the genetics of C. elegans (something I always did with Bob Perlman). He looked a bit annoyed and didn't really answer the question. I thought over what I heard at Harvard, suspected that I had done the unthinkable, and decided that my career in science was over. Fortunately, my initial fears were unfounded.
The LMB was an amazing place to do science, and, as many people have remarked before me, a postdoc is the very best time to do science. The lab was organized so as to optimize people's research. In fact, the facilities were so good that you knew that the only limitation on research was your own imagination. I remember once going to the stock room to get an ultraviolet lamp that I needed for a chemical conversion and being asked by Mike Fuller, who ran the stock room, "Which wavelength?" In addition, postdocs were expected to find their own projects; their postdoctoral advisors never assigned a project. We talked a lot about experiments and made suggestions (as Bob had to me), but everyone was on their own to design what they did. As a consequence Sydney never put his name on any paper that did not contain experimental work he had done. As a result, Sydney is a coauthor on only one of the seven research papers that came from my time in his lab.
The most astonishing aspect of the LMB to me, however, was how everyone was deeply concerned about science. People talked about experiments at coffee, lunch, and tea and in our coffee room at all hours. And although molecular biology was considered the most important part of biology, people's interests were more general. One day someone mentioned at morning coffee that the Cambridge astronomy department was going to show pictures taken by one of the Voyager probes, and about 35 people left to go see the film. People also made a point of reading and discussing scientific books (I particularly remember conversations about Stephen Jay Gould's Ontogeny and Phylogeny and The Mismeasure of Man). I would often see friends from the lab Saturday afternoon at Heffers, the great Cambridge bookstore, looking for the latest books (although I should admit that our tastes were rather broad and not restricted to science).
Despite the terrific atmosphere at the LMB, it did lack one commodity: space. When I arrived at the LMB, I was given three feet of bench space next to a cubbyhole that contained our Nomarski microscope (later, when Bob Horvitz left for his faculty job at MIT, I was able to move to the slightly larger desk he used next to the window). I began by familiarizing myself with various mutant phenotypes using a demonstration collection that Bob had prepared for me. In the course of this introduction I actually found that a strain with a muscle mutation that caused twitching was also touch insensitive (presumably because it had habituated). I also started my first mutagenesis and began looking for touch-insensitive mutants.
One of the remarkable projects taking place in the lab at that time was the complete reconstruction of the C. elegans nervous system. Sydney had hired a spectacularly gifted electron microscopist, Nichol Thomson, who could cut and collect the thousands of serial section needed to trace the wiring of the nervous system, which was done by John White and Eileen Southgate. A separate room one floor below us housed this mammoth collection of serial electron micrographs. One day, thinking that I should see what the touch sensing cells looked like in these micrographs, I announced to everyone in the lab that I was going to look at "my cells" and would be down in the anatomy room. John Sulston had already found that these cells had unique bundles of very prominent microtubules (the cells were originally called the microtubule cells), so they were very easy to see in the micrographs. Having made this announcement, however, I had a problem, because once I looked at the pictures for a couple of minutes, I realized that I did not know what I should do with them. Too embarrassed to go back to my bench so quickly, I did the only thing I could think of: I counted the microtubules in each section and recorded the number. Then I graphed the number versus the position along the neuronal process. The graph was a jagged line that had many peaks and valleys. Having decided that I had spent enough time in the anatomy room, I returned upstairs to the lab where Jonathan Hodgkin, a new staff member, asked what I had been doing. I showed him the graph and he asked, "Is that what the microtubules are supposed to do?" I had no idea, but I soon found out that they were not supposed to act in this way. The common view was that microtubules all began at the cell body; the graph should have simply shown a decrease in microtubule number as one looked further from the cell body. Since the number of microtubules in the touch-sensing cells repeatedly increased and decreased along the process length, all were not likely to start in the cell body. Working with Nichol Thomson, who cut several new series of sections for me, I was able to show that microtubules did begin and end within the process, and was able to submit my first C. elegans paper. I was quite proud of the fact that the one skill I brought to this work was the ability to count to fifty.
When I was a graduate student Bob Perlman had ordered at least one hundred reprints of every paper, so when my microtubule paper was accepted, I asked Jonathan how many reprints I should order. He told me that at the LMB no one ordered reprints, but since I wanted some for future fellowship applications, I ordered the minimal number. Jonathan apparently thought that my action was hilarious, and began to make arrangements with Mariana Wolfner, a friend of his who was a graduate student at Stanford. Suddenly I started getting reprint requests for my paper, with a surprising number of them coming from Stanford. I even got a request card from Linus Pauling. I eventually learned that Mariana was the source of all these requests and had stolen the reprint request postcards from various professors. Unfortunately, Jonathan did not tell me about his prank until I had sent out many of the reprints. I imagine that Linus Pauling and the others were quite surprised to be getting reprints about worm microtubules.
I thrived at the LMB, and the experiments went well. Ironically, I had entered the C. elegans world just as Sydney was leaving it (he had several other interests he wanted to pursue). As a result, I had very few conversations with him about my work, but I always felt that he was supportive. The person I learned most from was John Sulston, who at that time was elucidating the lineage of male larvae and the embryo. John was an astonishing experimentalist, who always seemed to work out scientific ideas from first principles, all those ideas that are taught in introductory chemistry and physics classes. John is also one of the most moral and fairest people I have ever met. For example, I believe his later success in the C. elegans genome project stems directly from his desire to engage the entire worm community in an enterprise that emphasized sharing and openness. In addition to John, I collaborated with John White (who also taught me English slang, although I think he made up some of the terms), Nichol Thomson, Bob Horvitz, and Peter Evans (a friend from graduate school who had move to the Zoology Department in Cambridge). Together we worked on a wide range of problems. I isolated touch mutants, worked on microtubule structure, studied lineage mutants, investigated neural circuitry, and even did some work on neurotransmitters. I found the freedom to wander off into any direction very stimulating.
I made many friends at the LMB (Figure 7). In addition to the two Johns, Nichol, and Jonathan, who were staff members, we had a remarkable group of postdocs, many of whom still work on C. elegans. This group included Donna Albertson, Phil Anderson, Ed Hedgecock, Bob Horvitz (for six months), Jon Karn, Judith Kimble, Cynthia Kenyon, Sandy McLeod, Barbara Meyer, Tony Otsuka, Bill Sharrock, Kevin Struhl (for a short time), and, eventually, Andy Fire and Jim Priess. These people were brilliant, and I often felt that I had to play catch up to understand their conversations. I learned a lot from each of them.
|Figure 7. Friends at the LMB. Two of the photos deserve comment. First, the picture of Nichol was taken while punting on the Cam, a great escape from the lab because we would end up at the Green Man in Grantchester. Second, the picture of Bob and Jonathan was taken inside the Blue Grotto on Capri. They were smiling when the picture was taken, but not after they realized that the flash prevented them from seeing anything.|
I do not want to give the impression that all we did was work. The Frank Lee Center (with its pub, swimming pool, and squash courts) near the LMB, the Cambridge Arts Theatre and Arts Cinema, and several pubs (the Green Man in Grantchester and the de Freville Arms in Great Shelford – where I learned to play bar billiards) all helped make my five years in Cambridge very enjoyable. I swam at the Frank Lee with Jon Karn and Sandy McLeod and then much later with Bob Holmgren, a postdoc working on Drosophila. Jon, Sandy, and I realized we were one person short of a medley relay, and Jon tried to convince Sydney to make sure that the next worm postdoc was a backstoker, but that never happened. In my last years at the LMB, Bill Sharrock and I used to play our guitars in various folk clubs (all in pubs) around Cambridge. Folk clubs were still popular in England in the early 1980s, and we could play several times a week if we wanted. A typical session at a folk club would include a performance by an invited guest performer and then the rest of us would play. Having a voice that was capable of clearing the club, I usually played instrumental pieces.
During my last year in Cambridge, when I no longer had a postdoctoral fellowship, Sydney kindly made me a staff member. I really loved being in Cambridge and felt that I was working on exciting projects. Nonetheless, I realized that I could not stay there forever, and applied for faculty jobs, mainly in the United States. I was amazed when two visitors to the lab, Joel Rosenbaum from Yale and Ron Morris from Rutgers, offered to write letters on my behalf. They taught me a valuable lesson: that faculty members have an obligation to help their younger colleagues, not just the people from their labs. I am still grateful for their generosity and friendship.
Their letters and Sydney's recommendation clearly worked because I was offered a position at Columbia University. I joined the faculty in 1982 and have remained there. Cy Levinthal was chair when I was hired, but I suspect that several members of the neurogroup (John Hildebrand, Darcy Kelley, Steve Schuetze, and, particularly, Eduardo Macagno) were helpful in getting me hired. At first I was a bit reluctant about living in New York, and during the first months as a faculty member, I complained to friends that I had made a horrible mistake. By six months, however, I told these same people that I could not imagine living anywhere else.
I continued to work on the C. elegans touch system, initially by amassing a much larger collection of touch-insensitive mutants. I was well funded and several people joined the lab. These talented students and postdocs and all the ones that followed were the real reason for the lab's success. I find it difficult not to acknowledge all the contributions the people in my lab have made, but this biography is already too long. I hope they accept my apology for not naming them and my gratitude for all that they have done.
Unfortunately, I had acquired the habit, common to worm researchers in Cambridge, of not publishing partial stories, a habit that meshed well with my strong inclination to procrastinate. Since I was characterizing a very large collection of mutants, I did a great deal of research but did not publish my results for six years. My lack of publications was a great concern for the senior faculty, because they were worried about my chances for tenure. Eventually, I submitted manuscripts for most of the work, and the publications were considered sufficient for tenure in 1989. I remember with amusement a conversation I had with Cy during this time. He had gotten quite ill and was confined to his home. One day I visited him to tell him about a series of lectures that Sydney had just given in the department. Cy interrupted my recounting of the lectures to tell me that the letters had arrived for my tenure review and that he was "surprised, but delighted, that they were so good."
By 1989 we were well on our way toward cloning the genes needed for touch sensitivity. Of course, as I have related in my Nobel lecture, this was also the time that I first heard about GFP. The story of our GFP experiments is told there. That work was very exciting, but actually took up a relatively small amount of our time. Over the subsequent years, we continued to work on touch, and I was fortunate to have several more people push the work forward, especially the identification of the mechanosensory transducer.
The year 1989 was also the beginning of the best part of my life: my marriage with Tulle Hazelrigg and the eventual birth of our daughter Sarah. Since this is supposed to be a scientific biography, I will let this part of my life remain private. I do want to say, however, that I am grateful for all the love, humor, and music that have filled our lives. Well, maybe not always the humor; April Fool's Day remains the most important holiday of the year and sometimes things get rough.
Writing an autobiography seems to call for a summing up of the lessons of one's life. Other than saying that, so far, my life has been a rather undirected and surprising trip, I don't feel I have much to say. As to the future, there are more experiments to do, music to play, people to enjoy, and surprises to catch me unaware.
I am grateful to Tulle Hazelrigg, Ed Chalfie, Alan Chalfie, Jonathan Hodgkin for comments on this manuscript and for making me honest.
From Les Prix Nobel. The Nobel Prizes 2008, Editor Karl Grandin, [Nobel Foundation], Stockholm, 2009
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/Nobel Lectures. The information is sometimes updated with an addendum submitted by the Laureate.Copyright © The Nobel Foundation 2008
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