American Philosophical Society
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202. Cellular and Developmental Biology[X]
1Name:  Dr. Robert Haselkorn
 Institution:  University of Chicago
 Year Elected:  2014
 Class:  2. Biological Sciences
 Subdivision:  202. Cellular and Developmental Biology
 Residency:  Resident
 Living? :   Living
 Birth Date:  1934
Robert Haselkorn bio for APS: I was born in Brooklyn, NY in 1934 in a house built by my mother’s father, a carpenter/contractor who had emigrated from Vilnius in Lithuania around the turn of the 20th century. My father’s father emigrated around the same time, from somewhere in Galicia. I attended PS 197 a short walk from home and moved on to James Madison High School, also walking distance from home. My mother was a math teacher at Madison before I was born. She moved to a different school, Midwood, when I was very young but many of her friends were still there when I started, so I was always comfortable there. A large cohort of friends from PS 197 accompanied me so that even though the school had 6,000 students (!) we enjoyed a substantial degree of security. Many of the teachers were superb, especially in math, English, French and history. Reviewing the facts of my history it seems to be filled with accidents that, in retrospect, have had very large consequences. The first one I recall is my choice of colleges. One afternoon, when I was a junior in high school, I watched a half-hour television program about Princeton. It described, in ten-minute segments, what it was like to study science, humanities or social studies at Princeton. That sealed it for me. I applied, was accepted, matriculated. The application required a choice of “interest”. I put down chemistry. That steered me to Clark Bricker as advisor during orientation week. His choice of courses made me a chem major. Driven into the arms of Arthur Tobolsky, a polymer chemist, and then Walter Kauzmann, the best teacher in the universe, I was guided firmly to Harvard and the laboratory of Paul Doty for graduate work. The Doty lab was a wonderful place to learn about the physical properties of proteins and nucleic acids. Best of all, my desk and workbench were placed between those of Helga Boedtker (Doty’s wife) and Ben Hall, an experienced graduate student who went on to become a star at the U of Washington. Ben developed cloning in yeast and holds the patent on production of hepatitis vaccine in yeast. In addition, Doty had persuaded Marianne Grunberg-Manago to spend a few months as a visitor. Marianne had discovered the enzyme polynucleotide phosphorylase, with which it was possible for me to synthesize polyA, polyU, polyC and polyI. My thesis described the physical characterization of those four polymers and their complexes. Those studies provided the basis for exploration of secondary structure in RNA, still being quoted nearly 50 years later, and related work by Noboru Sueoka leading to discovery of the dependence of the melting temperature of DNA on its content of GC base pairs. Another digression for accidents. When I started my graduate career at Harvard I registered for a room in one of the graduate dorms near the chem labs. I spent exactly one night there. The next day I encountered a friend from Princeton who had completed a year at Harvard Law School. He asked me where I was living. It turned out that he and other law students had secured a large house almost on the Harvard quadrangle that, by a quirk, had just obtained a free bedroom for which a new member of their cartel was needed. Was I interested? In less than an hour I was out of the noisy dorm and into the Lawyers House. This is just the first accident. The second occurred around January. This takes close watching of the chain of events. Another of the House Lawyers was engaged. His fiancée had a friend whose younger sister was a student at Wheelock College, across the river in Boston. Fiancee invited the sister of her friend to dinner. Fiancee asked the sister if she was interested in meeting a graduate student at Harvard, living in the House with her fiancée. Sister agreed. Information was transferred to me, a phone call was made, a date was arranged, and after suitable meetings etc we were married in June of 1957. Two children, four grandchildren and 57 years later Margot and I are still happily together. Some accident. Jim Watson joined the Harvard faculty about the time I started in the Doty lab. Jim became a very useful member of my thesis committee. When I was finishing the thesis, Doty advised me to write to Francis Crick about a postdoc, which I did. In about two weeks (no email then) Francis replied that they could not take me due to lack of space. I was crushed, Doty was abroad, so I took the letter to Jim. He said not to worry, that the Cavendish was too crowded anyway, why not write to Roy Markham at the plant virus lab in Cambridge. I did that and Roy replied immediately, with a full description of the facilities and the availability of plants and viruses and analytical equipment and colleagues. So I wrote a proposal to the American Cancer Society to determine the RNA sequences of plant viruses (successful), defended the thesis, and sailed for England with Margot and 9-month-old Deborah. We had rented, sight unseen, a house in the suburb of Chesterton belonging to an English biochemist, who was living in Seattle for a while. The adventures that filled our two years in Cambridge are a separate story. We enjoyed outstanding parties at the Markham house from beginning to end as well as outstanding science at the virus research unit with Roy himself, Maurice Rees, David Dunn, Graham Hills and visitors Bob Symons, David Lipton from Wash U in St. Louis and Mel Simpson still at Yale. I could take advantage of the proximity of downtown Cambridge, with Sydney Brenner, Francis Crick and Fred Sanger before they moved away to the far south end of town. My two accomplishments were simple: demonstration that the RNA prepared from turnip yellow mosaic virus was infectious in Chinese cabbage plants and that said RNA could serve as messenger RNA in a cell-free protein synthesizing system from E. coli. The latter experiments were carried out with Jim Ofengand in the Cavendish, in the spring of 1961. The timing was not great, because Marshall Nirenberg was doing similar experiments with TMV RNA at the NIH at the same time. He did a control experiment consisting of replacing the viral RNA with polyU, expecting to see nothing made. Instead, he saw polyphenylalanine, which he immediately realized opened the door to deciphering the genetic code. That was not the best time for me to be setting up a new lab, but that is what we had to do. Where? Time for another accident. The Doty lab produced a large number of scholars trained in the physical chemistry of nucleic acids. Two of them, Stuart Rice and Peter Geiduschek, had already achieved positions of responsibility at the University of Chicago. They knew me socially from meetings at Harvard. Stuart was on leave during the year 1960-61 and he spent that year as a visitor in Chemistry at Cambridge, England. One day I was cycling down the Kings Parade in Cambridge and I literally ran into Stuart. No harm. He asked me what I was doing and then what plans I had for the future. Then he described the program in biophysics in Chicago and arranged for a visit for me, including Peter Geiduschek. If not for the random collision with Stuart, I surely would have started my academic career somewhere else. As it happened, Ray Zirkle provided a fabulous offer in biophysics that placed me next to the labs of Ed Taylor and Peter Geiduschek, with outstanding students and superb equipment. Ed Taylor has been in the same department with me more or less continuously, missing only a few years he worked in London. Stuart Rice and Steve Berry have been in the Chemistry Dept for more than 50 years, as have I. And with my election to the APS, all four of us are members of the three societies: the National Academy, the American Academy and the APS. My career in Chicago started in the Committee on Biophysics, whose name was changed to Department of Biophysics, then merged with the Department of Theoretical Biology. In 1984 there was a major reorganization creating two new departments, Molecular Genetics & Cell Biology and Biochemistry & Molecular Biology. I was appointed in both, as well as in Chemistry. Graduate programs in biophysics rose and fell according to the whims of NIH. Ours thrived for my first 20 years in Chicago, then fell and disappeared in 1984, then was resurrected for another decade, then disappeared and finally came back under a new program in chemistry and biochemistry. Currently it is thriving. As my research program concentrated more on cellular differentiation in nitrogen-fixing cyanobacteria, I gravitated to microbiology and genomics. Much of my success in science has been due to the students, undergraduate, graduate and postdoc, who chose to work in my lab. To be sure, some of these choices were accidental. For example, my first graduate student, David DeRosier, apparently chose my lab as a result of a single lecture I gave in a biochemistry course, in which I described how the optical system worked in the analytical ultracentrifuge. Here is the accident: when I was a graduate student I took the Physiology course at the MBL in Woods Hole. That year, the course included a week of centrifugation taught by Howard Schachman, a spirited and thorough teacher. His example stayed with me and DeRosier was the beneficiary. So was I. DeRosier did his thesis on the structure of Turnip Yellow Mosaic Virus, which I brought with me from Cambridge. That project led to confirmation of an aspect of the model proposed by Don Caspar and Aaron Klug for the structures of spherical viruses. DeRosier proceeded to a postdoc with Klug and the invention of a method for reconstruction of structures from electron micrographs. Of great importance also, DeRosier brought into the lab his friend Bill Shipp, my second student, who produced a slender thesis with two chapters. The first described a double-stranded RNA intermediate in the replication of Tobacco Mosaic Virus in tobacco leaves. The second described DNA in tobacco chloroplasts, which Bill found accidentally as a contaminant in his RNA preparations. Bill’s work was followed closely by another student working on mitochondria in embryonic chicken liver, John Sinclair. Using our ultracentrifuge and Bill’s methods, John showed that the mitochondria contained DNA, readily differentiated from nuclear DNA. Plant viruses are difficult to study in one respect: the ratio of physical particles to lesions on plants is very high, so it is impossible to correlate physical properties with biological consequences. Frank Stahl urged me to take the phage course at Cold Spring Harbor, which I did, for two purposes. One was to learn how to handle RNA phages, which produced one plaque per physical particle. The other was to learn about the famous DNA phage T4, whose genetics was already extremely advanced. Back in Chicago I had some difficulty with the RNA phages but the T4 work focused on protein synthesis and was reasonably productive. This program was interrupted by a discovery made by Robert Safferman in Ohio: he found the first virus that grew on a cyanobacterial host. We obtained the phage from him and started a collaboration that introduced standard phage techniques into his studies, eventually yielding information about the structure, replication, assembly and contribution of these viruses to photosynthesis in the hosts. Graduate students Ron Luftig, Lou Sherman and Ken Adolph did this work between 1963 and 1970. Ken discovered his own phage in Lake Mendota, a significant discovery because the host organism was Anabaena, an organism that carried out nitrogen fixation, the conversion of N2 to ammonia. Much of our work post-1970 was with Anabaena. Ken’s thesis described a beautiful virus he discovered and named N-1. When Honoree Fleming joined the lab I thought she would continue work on virus development. But she wanted to study cellular development, specifically the development of heterocysts. This system involved the conversion of an oxygen-evolving cell carrying out green plant photosynthesis into an anaerobic factory carrying out nitrogen fixation. This differentiation involves controlling the expression of 1500 of the 7000 genes in the genome of Anabaena. Eventually this system was studied by students Jean Lang, Jim Orr, George Schneider, Christopher Bauer, Kristen Black , Kay Jones and Doug Rice as well as postdocs Barbara Mazur, Jim Golden, Steve Robinson, Nilgun Tumer, Stephanie Curtis, Sandra Nierzwickie-Bauer, Bianca Brahamsha, Brian Palenik, Martin Mulligan, Dulal Borthakur, Bill Belknap, Sean Callahan, Zi Ye, Amin Nasser and Bill Buikema. Jim Golden joined my lab as the spouse of Susan Golden, who had chosen to work with me after doing her graduate work with Lou Sherman at the U of Missouri on transformation of Synechococcus. Genetic systems had just been introduced to study photosynthesis, in the early 1980s. Among those systems were studies of the genes encoding components of the photochemical reaction centers, in particular those affected by herbicides. Susan Golden was able to show that one set of herbicides worked by binding to a protein component of the PSII reaction center. With grad student Judy Brusslan in Chicago she continued this work in her position at Texas A&M. At one point their results on transcription of the genes encoding the pabA protein did not agree. Sorting out their differences led to Susan’s discovery of the circadian clock in cyanobacteria. Jim Golden was also studying transcription in our lab. He worked out a method to extract RNA from heterocysts, the thick-walled cells in which nitrogen was reduced to ammonia. Among the RNA he found some DNA, which he examined with restriction enzymes and discovered that the region containing the genes encoding nitrogenase, the nif genes, was rearranged with respect to the same genes in vegetative cells. Further work showed that one of the nif genes was interrupted by a large DNA element that had to be excised, during heterocyst development, to allow proper transcription of that gene. In his own lab at Texas A&M, Golden went on to discover additional examples of DNA elements interrupting nif genes, that had to be excised during heterocyst development. This work was done in the early 1980s. Subsequently, Bill Buikema joined the lab and he set out to establish a system of genetic analysis in the cyanobacterium Anabaena. Following leads from Peter Wolk at Michigan State, Buikema succeeded in isolating a large number of mutants unable to differentiate nitrogen-fixing heterocysts. He succeeded in isolating DNA that contained the genes mutated in each mutant, then determined the DNA sequence of both the wild-type and the mutant gene. We still use his mutant collection to study transport mechanisms that send the sugar sucrose from vegetative cells into heterocysts to power nitrogen fixation and at the same time send arginine, a downstream product of nitrogen fixation, from the heterocysts into vegetative cells so the latter can grow and divide. Genetic studies of cyanobacteria did not get moving until the 1980s. Photosynthesis could be studied also in the purple bacteria, for some of whom there was a defective virus called GTA that could package and transfer DNA from one cell to another. These particles could carry genes, so they became the basis for a genetic system. We started with postdocs Rob Jones and Pablo Scolnik, grad student Peter Avtges, and then Robert Kranz. Kranz made major contributions, is now at Wash U in St. Louis. In the 1990s an exodus began from the USSR, with Michael Fonstein, Tanya Nikolskaya, Olga Zagnitko, Anna Lapidus and Yasha Kohen all contributing to the program to determine the genome sequence of Rhodobacter capsulatus. At the time, companies were being formed to determine bacterial genome sequences for clients who could and did pay $5 million for a complete DNA sequence. (Today that job takes a few days, at somewhat lower cost.) We purchased, with NSF funds, one of the first wave of ABI DNA sequenators. Part of the cost was covered by the U of Chicago, for which we provided a subsidized DNA sequencing service to others. Every attempt to get support for the Rhodobacter sequencing project from NSF or DOE was turned down. We established a collaboration with a team in Prague, headed by Vaclav Paces, who had been a postdoc with me in 1968. This worked well and we were able to publish together the first 189,000 base pairs of the sequence, which included all the genes required for the synthesis of cobalamin, a complex structure that comprised an important vitamin. But the complete chromosome contained 3,400,000 base pairs, so it was clear we had much to do. Without outside support it took almost 15 years! The final complete sequence was published just a few years ago with authors from the lab in Prague, my lab in Chicago, and a few scattered former employees of Integrated Genomics in Chicago. For the past 25 years we have been able to run three small programs at the same time. One was the study of the chromosome of Rhodobacter, the second the differentiation of heterocysts in cyanobacteria, focusing on transcription in heterocysts as well as the connections between heterocysts and vegetative cells, and the third a study of the enzyme acetyl-CoA carboxylase (ACC), which catalyzes the first step in fatty acid biosynthesis. The ACC program began with the idea that we could use herbicides that target the fatty acid pathway to analyze that pathway, similar to the use of antibiotics that target the ribosome to study protein synthesis. With postdoc Piotr Gornicki, we first examined the cyanobacterium Anabaena, discovering to our regret that Anabaena is resistant to the herbicide called haloxyfop and others that target ACC in plants. Much later we learned that all bacteria are resistant to these herbicides because all bacterial ACC are comprised of four separate subunits, none of which bind these herbicides. Indeed, as many others and we discovered, only grasses (monocots) were killed by the herbicides, while all dicots were resistant. This difference is due to the fact that all plants have a unique ACC in their chloroplasts. In the case of grasses the evolutionary path is via duplication of the gene for a multifunctional large protein. The ACC encoded by this gene is sensitive to haloxyfop. In dicots, the chloroplast ACC is encoded by four genes derived from bacteria and that enzyme is resistant to haloxyfop. Gornicki and his lab-mates worked all this out doing classical biochemistry, but attempts at doing genetic studies were stymied. Wheat was a suitable grass for biochemistry, but transformation experiments with DNA took about two years in wheat. We decided to transfer the whole system to yeast, which took some time to bring into the lab. Eventually, with help from Gela Tevzadze (an expert) and Marcin Joachimiak (a bright undergraduate) we were able to adapt yeast to analyse the ACC gene from any source: first the wheat chloroplast and cytoplasmic ACC genes, then the ACC genes of parasites such as Toxoplasma, Leishmania and others, and finally the human isoforms ACC1 and ACC2, the latter being one that controls fatty acid degradation in mitochondria, possibly a key to controlling obesity in humans.
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