The Nobel Prize in Physiology or Medicine 2009
Elizabeth H. Blackburn, Carol W. Greider, Jack W. Szostak
I was born in San Diego, California in 1961. My brother Mark was born in January of the previous year. My father Kenneth Greider was a physicist who had recently graduated with a Ph.D. from University of California at Berkeley. My mother Jean Foley Greider also had received her Ph.D. from UC Berkeley in Botany. My father worked in high-energy nuclear physics and my mother was a mycologist and a geneticist. After both parents completed postdoctoral fellowships in San Diego in 1962, my father took a faculty position in the Physics Department at Yale and so the family moved to New Haven, Connecticut. My mother took a postdoctoral position at Yale in the laboratory of Norman Giles, where she worked on Aspergillus as well as other fungal species. A few years later in 1965, my father took a faculty position in the Physics Department at UC Davis and so the family moved back to California. My mother first took a teaching position at a Sacramento community college and then later at American River College in nearby Sacramento.
Mark and I grew up in Davis, where we could walk to school. My parents built a house in a development in West Davis shortly after we moved to Davis. The street was conveniently located about a four block walk from the West Davis Elementary School (Grades K-4) and half a block from the new West Davis Intermediate School (Grades 5 and 6). Mark and I would walk to school together as kids, and later bike to high school, year-round. It gave us a sense of independence to come and go. The idea of parents driving their kids to school was one I had never heard of until moving to the east coast and becoming a parent myself. This early responsibility was something that shaped my sense of independence. For me school was something that was a kid’s responsibility. Parents were not really involved.
In December of 1967 my mother died when I was in first grade and Mark was in second. In retrospect, this event played a major role in my learning to do things on my own. Mark and I continued to get ourselves to school and to go on with our lives as best we could. School was not easy for me. I was put in remedial spelling classes because I could not sound words out. I remember a special teacher coming into the classroom every week to take me out for special spelling lessons. I was very embarrassed to be singled out and removed from class. As a kid, I thought of myself as "stupid" because I needed remedial help. It was not until much later that I figured out that I was dyslexic and that my trouble with spelling and sounding out words did not mean I was stupid, but early impressions stuck with me and colored my world for a time.
In 1971 my father was invited take his sabbatical at the Max Planck Institute for Nuclear Physics in Heidelberg, Germany. We moved to Germany for the year and Mark and I went to the Englisches Institut, a private school. Despite its name, it was a typical German Gymnasium and all of the instruction was in German. So for the first six months or so, we learned German by immersion. Mark and I took the city bus to school each day so we quickly learned to navigate the public transportation system, as well as navigate our way around a new school and new language and new culture. In Davis we had been used to getting to school on our own, so we welcomed this independence and developed an appreciation for how things were done in a very different culture.
I remember my grades were particularly poor in this school and especially so in the English class. The English teacher would give a dictation and we were supposed to write down what she said in English. It seemed too simple and pointless to me, but when I got my graded notebooks back, the scores were usually D’s or F’s because every other word was misspelled. Looking back over those notebooks later, I saw the pattern of backwards words and letters and gross misspellings that led me to suspect I was dyslexic. The other confusing thing about school for me was the "religion" class. You had to declare if you were Catholic or Protestant (as if those were the only choices) and then each group had their own class. Back home, my father was music director for the Unitarian Church, but as kids, we rarely went to church. It was too hard to translate what Unitarian meant to the Germans, so my father asked the school to excuse me from this religion class, and instead have a free period to do homework. This is how I met my friend Jiska, who was one of the few Jewish kids in the school and who was also excused from religion class. In my friendship with Jiska, both of us different from the rest, I began to develop an appreciation for people who were not like the others and who stood a bit outside the mainstream. This understanding of and affinity for people outside the mainstream served me well later in life. In high school and college I never felt the need to be part of a popular group, but rather sought out friends for their personal qualities. This appreciation may have also shaped many choices later in life; for example, working on the unusual organism Tetrahymena.
I spent a lot of time on my own in Heidelberg, playing down by the stream near our house or hiking the hill to the top of Boxberg. I took the bus into town on my own and learned to dress and speak like a German. There was a large American army base in town and I did not want to be mistaken as an army kid. I liked being more unusual: an American kid who understands German culture. By the middle of the year, I had learned German and became fluent in speaking and reading, but like all other written tasks, the writing and grammar eluded me. Mark and I had some German-American friends a few stories up in our apartment complex and we made up games like tapping out a code on the radiators and sending notes on string outside the kitchen windows to communicate. These games irritated the other apartment residents and resulted in the building manager coming to talk to my father. We were typical kids in that fashion, breaking some rules, where we could, but not going too far.
Davis – part II
When we returned from Germany I went into 6th grade, which was a transition year, the last in intermediate school before junior high school. I spent much of it readjusting to being back and making new friends. Unlike many scientists I know, I was not a kid who knew from early on that I wanted to be a scientist. I think one important thing I learned in my early years was to focus intently on the task at hand, such as learning German when we were in Heidelberg, to the exclusion of other things going on around me. This survival skill served me very well in later years. Focusing on certain goals and ignoring obstacles came naturally to me.
In junior high school I learned that I could be good at school. I remember liking the freedom to choose classes and the pleasure of learning and doing well. My perseverance and love of reading had somehow allowed me to overcome many disadvantages of dyslexia, and I read a lot of books for pleasure. I found I had to memorize words to spell them, as sounding them out did not work for me. This coping mechanism proved also to have an upside; memorization in biology and history was easy for me. My father encouraged us to do well in school and to do it for ourselves. He said that we should want to do well because it would "open doors" for us. He emphasized that being able to choose what you want to do in life is so important, and doing well early on will allow more possibilities in the future. I also discovered the pleasure of the outside reward of getting all A’s in classes, it made me feel good and I got positive feedback from people outside the family.
In high school I focused on doing well in my classes and finding a supportive group of friends. In junior high I had been attracted to outsiders, perhaps from my experience in Germany. But the outsider group I found myself with in junior high was not as interested in school as I was. I took the opportunity of the change in schools from Emerson Junior High to Davis Senior High as an opportunity to find a new group of friends. I met Lori Lopez and Resi Zapfel at an American Field Service (AFS) Club meeting in the first weeks of high school, and they quickly became friends. Resi was an exchange student from Austria and Lori was the AFS club president. Lori’s family and Resi’s host family the Robertsons became like a second family to me. I liked the foreign students in the ASF group, and the American kids who were a part of this group were not interested in mainstream popularity. I affiliated myself with the AFS student group throughout high school and was even president of the club my senior year. I did not focus particularly on science in high school, or join any science-related groups, although I continued to do well in all of my classes; I considered it a challenge to get all A’s. I never considered myself one of the smart kids, they seemed confident and driven. I just enjoyed learning and especially spending time with friends.
After my junior year at Davis High School, I knew I needed to think about where to go to college. I had done well in biology in school and was particularly captivated by my 12th grade biology class, where we learned a lot of physiology from a very motivated science teacher who had a Ph.D. I loved learning new material and being challenged, so I decided to major in biology in college. Many of my fellow high school graduates intended to go to nearby schools, either UC Davis or UC Berkeley. I did not want to go to either. I wanted to do something different from the norm, get out and have new experiences. My friend Alyssa Ingalls, whom I had known since 6th grade, was taking a trip to visit several University of California schools with her family Liz and Bob Young. I was happy to be invited along on this school tour. We visited UC Santa Cruz, UC Los Angeles and UC Santa Barbara.
I had a contact at UCSB, Beatrice Sweeney, who was a professor there and who had known and worked with my mother at Yale. My father put me in touch with Beazy, as she was known, and Alyssa and her family and I got a tour of the campus from her. Beazy was a cell biologist by profession but a naturalist at heart. She took us for a walk on the beach near her house and told us fascinating stories about the biology of all the marine animals and plants that we walked by. I was captivated by her and by the beautiful UCSB campus. I decided I wanted to study Marine Ecology at UCSB.
Beazy was on the faculty of the College of Creative Studies, a small college that is part of UCSB. The College of Creative Studies was founded by Marvin Mudrick, a professor in the English Department, to foster independent learning and interaction between disciplines. The requirements to get into CCS were significantly higher than to get into UCSB. My grades were very good, but my Scholestic Aptitude Test (SAT) scores were not. I never spent time practicing to take standardized tests and the dyslexia made them hard for me. I was very happy when CCS accepted me. So off I went in the fall to Santa Barbara.
The most important thing about UCSB and CCS was that Beazy [Professor Sweeney] encouraged me to begin working in a lab my freshman year. I was scared that I needed more time to adjust to college, but she said to start as soon as possible. I did a project first with Adrian Wenner studying sand crab populations in Santa Barbara. Though I thought I wanted to be a Marine Ecologist, this experience did not captivate my attention. The science was mostly statistics, which I did not understand or relate to. Beazy kept in close contact with me and saw I needed a different experience. So I then worked with a postdoc in Beazy’s lab studying the movements of chloroplasts during dark/light circadian cycles in Pyrocystis, a dinoflagellate. I enjoyed the work in the lab. I liked coming in to do my own experiments and was challenged when Beazy said I had to come up with a way to plot and describe my experiment on my own, with no set form. The simultaneous pain and joy of trying to create something that made sense to describe my observations was exhilarating.
I enjoyed watching cells and describing the circadian rhythms, but after a while I felt the work was too descriptive. So next Beezy took me to work in Les Wilson’s lab on microtubule dynamics. I am not sure if it was the topic or the personalities in the lab, though it was likely both, that captivated me. I worked first with Kevin Sullivan and later with David Asai studying microtubule associated proteins. The work in the lab was focused on understanding molecules and how they interact and behave. We would do experiments to examine how fast microtubules would assemble from the tubulin building blocks, then make a change to the tubulin preparation and see how that affected the results. Being able to manipulate molecules and understand the mechanics of how things worked fit my way of thinking. In addition, talking with both Kevin and David and the others in the lab was fun. People knew each other well, were playful, and would tease each other a lot. There were inside jokes and an easy way of laughing about experiments as well as everyday life that was infectious. I worked with Kevin for my sophomore year studying the assembly kinetics of chick brain microtubules under different conditions. The experience that Beezy and the CCS program provided me, to try out several different laboratory experiences, was instrumental in my finding how much I loved mechanistic thinking and biochemical experiments. By comparing several different labs, it became clear to me when I was having fun and when I was not. I saw that laboratory work was about people and interactions as well as about science. It could be playful and was appealing as a potential path I could enjoy.
My junior year in college I spent as a student at the University of Göttingen in Germany. Ever since my early experience in Heidelberg and visits to see Resi Zapfel (now Schmall) in Austria, I wanted to experience what it was like to live as a student in a foreign country. I took the opportunity to go to Germany for a year on the University of California’s Education Abroad Program (EAP). Before I left, Kevin Sullivan and Les Wilson encouraged me to continue lab work in Germany. They contacted Klaus Weber who had a lab at the Max Planck Institute for Biophysical Chemistry, and he agreed I could work there. I would split my time between classes at the University, such as Biochemistry and Genetics, and time at the Max Planck working on intermediate filaments in the Weber lab. In addition to lab work, I also became close friends with a number of Americans in Göttingen who were also on exchange programs.
At the beginning of the second semester I was looking for biology courses in the course catalogue and found one on chromosomes that looked interesting. When I showed up in the assigned room at the right time it turned out it was the regular lab meeting for Professor Ulrich Grossbach. Professor Grossbach had listed his lab meetings as a course so the graduate students could get credit. I was very embarrassed to walk into a private lab meeting, but the researchers in the group were all very nice and they asked me to stay. Michel Robert-Nicoud, a research associate in the group, took me under his wing and asked if I wanted to help in a study of polytene chromosomes of Chironomus, a diptera distantly related to Drosophila. I enjoyed learning how to do the preparations. It was satisfying to prepare the salivary glands just right and see the giant polytene chromosome under the microscope. I finished the work I had begun in the Weber lab and moved to work with Michel in the Grossbach lab.
Michel collaborated with Tom and Donna Jovin, who were also at the Max Planck Institute for Biophysical Chemistry, on an unusual left handed helical form of DNA called Z-DNA. Tom and Donna had studied the biophysics of sequences that could form this unusual DNA structure. To understand if Z-DNA is found in natural chromosomes and where it might be located, they developed antibodies to Z-DNA. They were collaborating with Michel Robert-Nicoud to locate the Z-DNA by staining the giant Chironomus polytene with their Z-DNA antibody. There were controversies about whether Z-DNA might be located in bands or interband regions of the chromosome. There was also discussion about whether the regions that stained with the antibody normally had Z-DNA or if the binding of the antibody itself induced Z-DNA where it might not normally be. There was a lot of excitement in the lab about this project and Donna Jovin was preparing to submit a paper on these findings. It was thrilling to know that my work staining chromosomes was of use for real experiments and not just as make-work, and might be part of a publication. This experience with Chironomus polytene chromosomes gave me an appreciation for the beauty of chromosomes. It may be that I gained an affection for chromosomes that I brought with me several years later when I first met Liz Blackburn.
Santa Barbara – part II
When I returned to Santa Barbara for my senior year I wanted to go back to work in the Wilson lab. Kevin Sullivan was writing his thesis and planning to move to a postdoctoral position. Kevin suggested I work with David Asai who was a research associate in the Wilson lab. Kevin was very excited about his future studying the genes for tubulin, because he said genes and DNA were the most exciting work going on. Talking to Kevin and David helped me decide that I wanted to go to graduate school. I enjoyed the camaraderie in the lab and liked the challenge to think creatively. I worked hard my senior year, and CCS made it possible for me graduate in 4 years by their flexibility about transferring credit from my course work in Germany.
For graduate school entrance I took the Graduate Recorded Exam (GRE) exams and, as with the SATs, did not do well. I applied for admission to eight different graduate programs, but did not make it through the numerical cut off for grades + GRE’s. I got many rejection letters. However, two schools did decide to interview me. I may have seemed like an interesting case to those people who actually read the applications, rather than pre-screening with a numerical cut-off. I had a 3.9 GPA and A+’s in O-Chem, P- Chem and pharmacology, a lot of lab experience, but poor GRE scores. California Institute of Technology interviewed me and each of the 10 professors with whom I talked asked me why my GREs were low. I talked science with all of them and also explained the dyslexia and poor scores on standardized tests. After the interview I was accepted to Cal Tech. UC Berkeley also accepted me and asked me to come for an interview. It was during that interview that I met Elizabeth (Liz) Blackburn. I felt her enthusiasm for chromosomes and telomeres was infectious. I wanted to talk to her more after the allotted interview time so I made plans to come back again the next week to talk in more depth about her telomere work. After that interview, I decided I wanted to go to Berkeley and work with Liz.
Both of my advisors at UCSB, Bea Sweeney and David Asai encouraged me to go to Cal Tech instead. David had done his Ph.D. there and felt it was a special place to he wanted me go there too; Beazy did not want me to go to Berkeley "just because my parents had gone there." Somehow my interest in potentially working with Liz was great enough to for me to go against the recommendations of two mentors. So I signed up as a Ph.D. student in the Department of Molecular Biology at Berkeley.
When I got to Berkeley I had missed the week of orientation for new students, because I decided to attend the wedding of my friends Monica and Chris Morakis whom I had met in Göttingen. My first few weeks at Berkeley felt overwhelming. Although I had done biochemistry, I had not taken any molecular biology courses and had never worked with DNA. My classmates were an impressive bunch with a strong background in molecular biology and it seemed they were all clearly smarter and better prepared than I was. It was thrilling to be part of such an impressive group of interesting people, and soon we all became very close friends.
Although I had come to Berkeley to work with Liz Blackburn, all first year students had to do three laboratory "rotation projects" for 2–3 months each before decisions were made about which lab to join. My first rotation was with Richard Calendar studying phage P2 and P4 interactions. I was very fortunate that that year, two of us first year students were both assigned to Rich’s lab at the same time. My fellow ‘roton’, Jeff Reynolds, was very smart, very friendly and it seemed he knew everything about DNA. So I could lean on Jeff and his knowledge to get me started at Berkeley. From those first days, Jeff became, and still is, one of my best friends.
My second rotation project was in Liz Blackburn’s lab. There was a certain amount of anxiety among the first year students as we could not choose our rotation labs; assignments were made by the Department chair, Nickolas Cozarelli. I was very happy to get assigned to Liz’s lab because of my strong interest in working with her. For the rotation I worked on a project to clone telomeres from trypanosomes and the related species Leishmania. By the time I arrived in the lab, Liz and Jack Szostak had already shown that telomeres from Tetrahymena would function as telomeres in yeast. This was incredible because Tetrahymena and yeast are in different kingdoms phylogenetically. They had shown that when Tetrahymena telomeres were ligated to both ends of a plasmid, they allowed that plasmid to be grown as a linear chromosome in yeast. By removing one Tetrahymena telomere they were able to clone a functional yeast telomere. I was using this same technique to try to capture telomere fragments from Leishmania. I enjoyed the laboratory environment and by talking to people I got a sense of what projects I found most interesting; I was intrigued by the question of how telomeres get elongated.
In the second quarter, I also took a graduate course on chromosomes taught by Liz in which students were assigned papers that they then presented to the entire class. I was assigned the Szostak and Blackburn 1982 Cell paper that identified yeast telomeres. I was petrified, having never presented a paper in front of a large group before. I studied the paper inside and out. I was scared, but I was energized and got a thrill out of presenting that paper. I found it satisfying to convey the excitement I had about telomeres to my fellow students.
Janice Shampay, a student in Liz’s lab had recently published an important follow-up paper to the Cell paper. They showed that Tetrahymena telomeres had yeast sequences added to them as the linear plasmid was maintained in yeast. The excitement grew with the idea that these telomere sequences must be somehow added to chromosome ends. A previous rotation student and friend of mine, Jim Bliska, had done his first rotation in Liz’s lab. He had been testing ways to find an activity that might elongate telomeres. From what I knew about telomeres, I thought this project was exciting because it directly approached the heart of the biggest question: How are telomeres elongated?
I had to wait until after my third rotation before I could ask Liz about working with her, according to the graduate program rules. Toward the end of the 3rd rotation, I made an appointment to talk to Liz. As I went into her office I was both scared and excited. I asked her first if I could work in her lab, and second, whether I could work on the telomere elongation project. I was thrilled when she said "yes" to both. I think the conversation lasted all of a minute, but it was a very momentous minute for both of us.
The Blackburn Lab
I joined Liz’s lab in May of 1984 and I set out to see if I could find biochemical evidence for telomere elongation in Tetrahymena. Liz had first sequenced telomeres in Tetrahymena and she reasoned that this single celled ciliate would be a good source for a telomere elongation activity. Each cell has over 40,000 telomeres and perhaps more importantly, there is a stage of its life cycle where new telomeres are added onto fragmented chromosomes. I made extracts from Tetrahymena cells and examined whether artificial telomeres could be elongated by enzymes present in the extracts. These experiments are described in detail in the accompanying published lecture.
After about nine months of trying variations on experiments, we found our first strong evidence for telomere elongation. An 18 nucleotide telomere "seed" was elongated with a repeated sequence that was six bases long – precisely the length of the TTGGGG telomere repeat in Tetrahymena. Now we had a biochemical assay that we could use to determine if this was a new telomere elongation mechanism. We set out to critically examine whether the 6 base pattern we were seeing was indeed due to a new activity or perhaps instead was a well known polymerase fooling us. Liz and I worked very well together. We would talk most every day and each of us would assert what we thought should be done next. Often we agreed but sometimes we did not, and we would try to convince the other of our reasoning. I remember for one experiment we talked for a long time and neither of us would give up our stance. It was an impasse. The next day when I came in to the lab and we talked, we had both shifted sides. I decided to do her proposed experiment first. We both laughed that we had each convinced each other.
I learned many important lessons that first year after the initial telomerase discovery. Mostly, I learned the importance of questioning your own assumptions. We did not set out to prove we had a new enzyme, rather we imagined all the ways our own thinking could be deceiving us and allowing us to interpret our results in a way that favored our bias. I learned that getting the correct answer is more important than getting an answer you might hope for. I learned to step aside from myself and view my data through the eyes of a skeptic. We worked for a year before we convinced ourselves that the telomere terminal transferase was indeed a unique activity. The initial discovery was in December of 1984 and the paper was published in Cell in December 1985.
Stanley Hall Cold Room – UC Berkeley
We first called the activity we identified "telomere terminal transferase" because it transferred telomere sequences onto termini, but later shortened it to "Telomerase". My friend and fellow student Claire Wyman and I would joke around in the lab a lot. Claire pointed out telomere terminal transferase was too long and suggested various humorous names as alternatives. Names were further discussed later that night over a few beers and telomerase was one Claire had proposed initially as a joke. She thought it was funny, but Liz and I both liked it.
The next most exciting question was – where does the information for the TTGGGG repeat addition come from? I wondered if there might be an RNA component that specifies the TTGGGG sequences added. I set out to do an experiment to pre-treat the Tetrahymena extract with either DNase or RNase or nothing and see if that affected the activity. I remember that day Tom Cech was visiting Berkeley for a seminar. Tom had a long-standing interest in both telomeres and in RNA biology. Liz and I met with Tom in the morning and I told him about my idea of testing to see if the activity was RNase-sensitive. He agreed that was an interesting experiment. Throughout the day, as he was being walked around the department from appointment to appointment, Tom would stop by the lab and see how the experiment was going. I was flattered that he was so interested.
The RNase experiments indicated that activity was eliminated when RNA was degraded, implying there was an RNA component. Liz and I felt that the best way to really show that an RNA was involved was to find the actual RNA. So I went into the cold room to try to purify the enzyme. I read as many books on biochemical purifications as I could, and set out to purify telomerase. As a complete amateur, I spent an inordinate amount of time in the cold room setting up and running columns to purify telomerase. My friends would come to find me to go get coffee at Café Roma, and I would have on my puffy down jacket covered over with an extra-large white lab coat. They joked that I looked like the Pillsbury Doughboy.
The friends in Stanley Hall were a very close group. We would walk to get a latte at least once every day. We would talk science, tell jokes, tease each other and complain to each other about experiments that did not work. There were a lot of practical jokes that we played on each other. I was having trouble with experiments one afternoon and complained to Jeff that I was "bored". So late that night Jeff filled my umbrella with home made confetti with the word bored on each piece. The next day I was leaving genetics class, it was raining so I opened my umbrella and thousands of pieces of paper fell out. I knew I had to retaliate. The next day I got into the lab very early. I went to Jeff’s lab bench; he had 40 bottles of different chemical reagents for his experiments lined up on the shelf above his bench. They were all glass bottles filled with clear liquid, I removed the labels that were taped on for every one of them (I marked each with a number underneath and kept a paper key). When Jeff came in to work in the morning, he started his experiment for the day, reached up for his TE buffer and found 40 identical unlabeled bottles. He was shocked at first, then, being clever, he saw the small numbers on the bottom and realized what I had done. He came into our lab and said "OK so where is the key?" I pretended to not know what he was talking about, but was glad when he admitted I had gotten him back. These kinds of jokes were common in Stanley Hall. Often they involved dry ice inside plastic tubes, which would burst and sounds like a bomb when placed in a metal garbage can.
We found every excuse imaginable to have parties at one of our graduate student houses. One party invitation flyer copied a Departmental memo that said "Emergency water outage-Party time" we decided this was a good reason for a time for a party at Jeff’s house. Some of our parties involved making up skits for the "follies" where we would roast our professors and fellow students. We all worked very hard and we played hard too. The creativity was not just at the lab bench, but spilled over to our daily life together at work; being creative in all aspects of our lives in the lab and out was wonderful. Spending time with people who understood me and what I was doing and who loved to laugh and play was extremely rewarding.
After four years in graduate school, my thesis committee members encouraged me to finish up and look for a post-doctoral position. I remember Jasper Rine specifically telling me it would be good to finish the thesis in four years, because I had enough material and it looked good to finish quickly, so why not try? Mike Botchan, who was on my committee, strongly encouraged me to apply for postdoctoral fellowship positions at Cold Spring Harbor Laboratory, where he had been for a number of years before coming to Berkeley. So I sent letters inquiring about positions to four people at CSH, Bruce Stillman, Yasha Gluzman, Doug Hanahan and Mike Wigler, and was asked to go there for an interview.
Cold Spring Harbor Laboratory
I think there may have been only eight or ten people in the audience for my interview talk at CSH. I gave a talk on telomerase activity in the James library. All four lab heads with whom I had applied to work were there, as well as Jim Watson whom I had never met before. It was a cold and rainy day, and afterwards Jim Watson wanted to take me to lunch. I was both excited and terrified at lunch and did not know what to say, but he was clearly interested in telomerase. Several days after the interview when I was back in Berkeley, I got a call from Bruce Stillman, he said that he would be happy to have me as a postdoc in the lab if I wanted to come, but that there was also an opportunity to have an independent position as a Cold Spring Harbor Fellow and work on whatever I wanted. I had not heard of or applied to an independent fellowship position so I was a bit surprised. I later found that Mike Botchan from Berkeley had quietly nominated me for this without my knowing. When Bruce called, I first said that I would just work with him as a postdoc; but then I thought it over for a week and realized there were so many interesting questions I still wanted to ask about telomerase that I would love to keep working on it. So I called Bruce back and told him that I would like to accept the independent Fellow position. So I filed my thesis in November of 1987 and continued to work on trying to identify and sequence the RNA that co-purified with telomerase for a few months. January 1, 1988 I started as a Cold Spring Harbor Fellow.
My main goal in my new lab at CSHL was to clone the gene for the telomerase RNA. I had already obtained several partial sequences through direct RNA sequencing using specific RNases. I made short oligonucleotides to the regions of RNA sequence and used them to probe genomic libraries from Tetrahymena. After searching through many libraries, I found one clone where the sequence matched the partial RNA sequence AND also contained CAACCCCAA, the complement to the TTGGGG telomere sequence. I was excited and told my friends in the building about the sequence. I was very surprised to hear later at lunch in Blackford Hall that many other people knew of the result. A few hours later Bruce Stillman stopped me on the street to say he heard I got a great result. News traveled fast at CSH and people really cared about what other people were doing. It was fun to again be with people who cared about each other and who kept up with what science people around them were doing; it was a very exciting time.
Having a clone with a telomere repeat was tantalizing, but how could I show that it was required for telomerase activity? I devised a series of experiments using antisense oligonucleotides and RNase H to show that this RNA was indeed required for telomerase activity. I wrote a draft of a paper and sent it to Liz since I had initiated the sequencing efforts while working in her lab. I presented my work in Bruce Stillman’s lab meeting and he encouraged me to propose a model for how I thought the enzyme might work in the paper. This model, drawn crudely on a Macintosh SE, has stood the test of time. It turned out what I conceived of as a possible mechanism is indeed the way telomere repeats are made by copying the RNA template. I sent Liz the clone encoding the RNA component before our paper was published, and she and her student Gou-Liang Yu were able to express a telomerase RNA with a change in the template sequence in Tetrahymena and show that change was incorporated into the telomere repeats. This was definitive evidence for the templating model proposed.
Having success in cloning telomerase soon after arriving at CSH was a great start. I soon had my first graduate student, Lea Harrington, and was rapidly promoted through the different scientific staff positions to the position of "Rolling 5". We continued to pursue our curiosity about the function of telomerase and role of telomerase in cells that are discussed in more detail in the Nobel lecture. In 1993 I married Nathaniel Comfort, whom I met when he was the science writer in the Public Affairs office at CSHL. In 1996 our son Charles Comfort was born in Huntington, New York. Nathan completed his Ph.D. in history of science at the University at Stony Brook in 1997 and was offered a position on the faculty at George Washington University. I was concurrently offered a position in Tom Kelly’s department of Molecular Biology and Genetics at Johns Hopkins University. So when Charles was one year old, we moved to Baltimore to start new lives.
Johns Hopkins University School of Medicine
I was very fortunate to come to Johns Hopkins to a very interactive and cohesive department. Although the institution as a whole is much bigger than CSH, the department of Molecular Biology and Genetics felt as small and homey as CSH. I was fortunate to have outstanding graduate students and postdocs come to work with me. I was able to branch out into both yeast genetics and mouse genetics and follow my interests in what happens to cells when they don’t have telomerase. I enjoy having smart people around to talk to who are excited by the work on telomeres. The different directions the lab has gone have been driven not just by my own interests but by the interests of the students in the lab. Finding something new that nobody knew before is exhilarating, and discussing ideas with students and postdocs and helping them to pursue their most interesting questions leads to new insights.
Two years after I moved to Johns Hopkins, my daughter Gwendolyn was born. Having two kids and a full time job in the lab is a challenge, but having Charles and Gwendolyn is the best thing that has ever happened to me. My lab knows that I am a mom first, and the flexibility that academic science provides makes having a career and a family possible. I can go home when needed, or to a school play in the middle of the day, then come back and finish my work-day; or work from home on the computer. The main thing is to find the time to get things done, it is not the hours at work but the overall productivity that counts. Having flexibility takes a huge amount of pressure off.
In 2002 Tom Kelly, the Department Director (the Hopkins name for Chairman) told me he was leaving Hopkins to take a position at Memorial Sloan-Kettering Cancer Center in New York. I kept the note that my assistant left on my desk that day that said "Tom Kelly wanted to talk to me" – and marked it as a Black Day; I actually cried when he told me he was leaving. Tom was an ideal director for the department. He cared about everybody and worked hard to help create the collegial environment that attracted so many top scientists. After a two-year search process, I was appointed as the Daniel Nathans Professor and Department Director for Molecular Biology and Genetics. I am extremely honored to hold the Daniel Nathans Chair, as it was Dan who created the department and established the interactive environment that Tom Kelly helped build. Dan Nathans, who died in 1999, personified thoughtfulness, caring and above all integrity, traits that we all strive to show the way that Dan did.
I know that I cannot fill the shoes of either Tom Kelly or Dan Nathans, but I try to bring my own style of leadership to the department. Being director is made easy by the terrific faculty in the department; the science is outstanding and everybody talks and cares about the other faculty. The flat structure of the department that was established early on makes it clear that everyone has a voice. Decisions are made by discussion and consensus and not in a top-down fashion. I have been able to learn about leadership in a hands-on fashion and the faculty have all helped me tremendously in that.
Mentors, friends and lessons
One of the lessons I have learned in the different stages of my career is that science is not done alone. It is through talking with others and sharing that progress is made. Work done today, of course, builds on the past work of many others, but in addition, experiments are often suggested by friends and colleagues either directly or indirectly. The ideas generated are not always the result of one person’s thoughts but of the interaction between people; new ideas quickly become part of collective consciousness. This is how science moves forward and we generate new knowledge.
I am grateful to the many scientists who have influenced and helped me in my journey from Davis to Baltimore: Bea Sweeney, Michel Robert, Kevin Sullivan, David Asai, Les Wilson, Elizabeth Blackburn, Jasper Rine, Mike Botchan, Bruce Stillman, Rich Roberts, Dan Nathans, Tom Kelly. These colleagues and many others have helped me move from one stage to the next and taught me many essential lessons along the way. I would not have been able to do the science that I have done without the students, postdocs and wonderful technicians who brought their energy and great ideas to the lab. Finally, the close friends I have made in Davis, Berkeley, CSHL and Baltimore are my constant support group. I value them above all else.
From Les Prix Nobel. The Nobel Prizes 2009, Editor Karl Grandin, [Nobel Foundation], Stockholm, 2010
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 2009
Try to save some patients and learn about human blood types!
All you want to know about the Medicine Prize!
Read more about the Medicine Prize during the past century