The Yeast Genetics Course at Cold Spring Harbor Laboratory: Thirty Years and Counting

IN the 1970 second edition of his classic textbook, The Molecular Biology of the Gene, James D. Watson wrote, "There are now many reasons to intensify work on organisms like yeast" (WATSON 1970 , p. 519). That same year, Watson followed his own advice by asking Gerald R. Fink—then at Cornell University—to start a course at Cold Spring Harbor Laboratory (CSHL) with another pioneer in yeast genetics, Fred Sherman, from the University of Rochester. Thus was born the Cold Spring Harbor Laboratory Yeast Genetics Course. The beginning of the Yeast Genetics Course in 1970 coincided with the end of the Phage Course, which had been given since 1945 and contributed in no small measure to the origins of molecular biology (SUSMAN 1995 ). Indeed, Watson was inspired to start the yeast course by the successes of the phage group and the Phage Course.

Watson and the participants of the Yeast Genetics Course he initiated thirty years ago at CSHL have led the way in establishing yeast as one of the most powerful model systems in eukaryotic molecular biology. Since its inception, nearly 500 scientists from around the world have taken the Cold Spring Harbor Yeast Genetics Course. Most of the outstanding yeast geneticists/molecular biologists of the past half-century have either taken the course, taught the course, or both.

To celebrate the great science and lifelong friendships that have resulted from the Yeast Genetics Course, a reunion for course participants was held at CSHL on August 11, 2000. The event brought together students and instructors of the course—from past to present—for two days of reminiscing and sharing of current research. The reunion clearly illustrated the influence that the course has had on its participants and the impact that these investigators have had in science. "It's hard to imagine where we'd be today without yeast," says Watson, who kicked off the reunion on a Friday evening with opening remarks.

Owing to the prodigious talents and dynamic, fun-loving personalities of Sherman and Fink, the Cold Spring Harbor Yeast Genetics Course rapidly became a classic. "I found Fred's deadpan sense of humor always hilarious and still do. I found Gerry's electric intellect and his love of yeast genetics to be energizing and still do," remarked Ira Herskowitz during the reunion. Herskowitz took the course in its second year, has made many important discoveries during his subsequent career in yeast, and eventually lectured in the course. Herskowitz's ties to Cold Spring Harbor run even deeper. His father, a Drosophila geneticist, worked at the Laboratory, and Ira lived on lab grounds in 1947 when he was a toddler.

Fink, who "willingly or unwillingly served as Fred's straight man" during the course describes how, with Sherman, "even the most innocent greeting turned into a comedy routine" (FINK 1993 , p. 438):

Sherman: How are you doing?

Student: Fine. How are you?

Sherman: Well I think I'm fantastic. But not everyone agrees with me.

Sherman, at the reunion: Things have changed a lot at Cold Spring Harbor. Back then, the milkman wouldn't deliver the milk unless it was paid for in advance.

Like Sherman, Fink can also entertain while explaining important biological concepts: "When yeast cells of opposite mating type encounter one another, they do not pause and reflect or look at the cracks on the wall—they MATE!" Sherman and Fink taught the course every summer (save one) for its first eighteen years, and one or both of them have lectured in it every year since then.

The Yeast Genetics Course is frequently a career-altering experience for its participants. Students learn that if they ask the right kind of questions, they have a chance to reveal new principles of nature, using the technically simple tools of yeast genetics. Instructors of the course also benefit. "After teaching the course, I would go back to my own lab at MIT bursting with ideas," says Chris Kaiser, who taught the course from 1992 to 1998.

Pam Silver, who at the reunion admitted to being an extreme pack rat, related how she actually saved her 1982 application to the course, her acceptance letter, and even her plane ticket to the course on the now defunct Eastern Airlines ("Round-trip, Boston to New York, $55"). "One of the highlights of the course for me was the invited speakers," says Silver, who would herself become an invited speaker for four subsequent courses. This sentiment was echoed by many of the celebrants including Mark Rose, who said of the course, "It's like being at the best of all possible meetings. You get to invite only the best speakers and listen to them without any distractions."

Rose, Aaron Mitchell, and Christopher Lawrence each taught the course for five years. Jim Hicks, an instructor in the course for seven years, was one of three in the infamous CSHL "yeast group"—along with Amar Klar and Jeff Strathern—who made outstanding discoveries about the mechanism of mating-type switching in yeast (HICKS et al. 1979 , HICKS et al. 1984 ; KLAR et al. 1980A , KLAR et al. 1980B , 1981a,b,c, 1982, 1983; ABRAHAM et al. 1983 , ABRAHAM et al. 1984 ). These three were directly and indirectly involved with the course, both as invited speakers and also as the CSHL scientists who relinquished their lab space to the course each summer. (Until the expansion of Delbrück Laboratory, the trio worked in a trailer for the duration of the course!)

Rose also related how David Botstein would enthusiastically declare, "Azoy! Mendel lives!" each time a participant in the course successfully dissected a yeast tetrad (a technically tricky task for beginners, but a snap for the experienced). Like Herskowitz, Botstein took the course in 1971, became a distinguished yeast geneticist/molecular biologist, and eventually lectured in the course. "The reason the yeast course remains vital is that young people are always ready and willing to pick up the baton as instructors," says Botstein. "In this way, the course is continually revitalized. I look forward to another thirty years."

Each year, the three-week course typically has sixteen students, three instructors, and several invited speakers. As expected, the instructors are experts in their particular subdisciplines. But they are also passionate about teaching the power of yeast genetics to the uninitiated. Together, the participants spend long hours each day in Delbrück (formerly Davenport) Laboratory, where students learn the technical "nuts and bolts" of doing yeast genetics, perform a wide variety of experiments, and hear about how genetic analysis in yeast can be used to understand any number of distinct biological phenomena. And they thoroughly enjoy themselves while working a grueling schedule. "There's a certain camaraderie that develops during the course that is unreal and mystical and wonderful," says Sherman, who would regularly lead the students into the nearby town of Huntington for evenings of dancing at Chelsey's, with music by Little Wilson. But Fink adds that no matter how late the work and play would go on, "all hands were on deck for the 9:00 [AM] lecture" (FINK 1993 , p. 441).

As every reader of GENETICS knows, many fundamental processes are similar in organisms as diverse as yeast and humans. Thus, lessons learned with yeast are frequently applicable in many settings. For example, much of what we know about the molecules that control cell division—and how this control is lost in human cancers—can be traced to genetic studies of yeast by Leland Hartwell and his colleagues in the late 1960s and early 1970s (HARTWELL 1967 , HARTWELL 1971A , HARTWELL 1971B ; HARTWELL et al. 1970 , HARTWELL et al. 1973 , HARTWELL et al. 1974 ; CULOTTI and HARTWELL 1971 ; HEREFORD and HARTWELL 1974 ; for a Perspectives article, see HARTWELL 1991 ). Hartwell was an invited speaker for nine of the first ten years of the Yeast Genetics Course.

In his closing remarks at the reunion, Bruce Stillman, the director of Cold Spring Harbor Laboratory, reminded the celebrants that CSHL scientist Michael Wigler identified one of the first human oncogenes (H-ras) and found that the yeast genome contains two genes (RAS1 and RAS2) that are very similar to the human ras genes (POWERS et al. 1984 ). Remarkably, Wigler and his colleagues discovered that despite the evolutionary divergence of yeast and mammals approximately 1 billion years ago, the human H-ras gene functions in yeast and can substitute for the yeast RAS genes (BIRCHMEIER et al. 1985 ; KATAOKA et al. 1985 ). Wigler was an invited speaker for nine years of the Yeast Genetics Course.

The last word about the power and joy of yeast genetics at Cold Spring Harbor Laboratory goes to Jeff Strathern. In his remarks about the course that were included in a delightful collection of photos, essays, and other memorabilia, Strathern wrote, "When I left Cold Spring Harbor I remember quoting from Elton John's record Crocodile Rock, `I never knew me a better time and I guess I never will.' The quote still applies."

View larger version (126K): In this window In a new window Download PPT slide   Jim Hicks (left) and Ira Herskowitz (center) passing the stack for the alumni team at the "Plate Race" following the 2000 Yeast Genetics Course. Hicks was Herskowitz's first graduate student at the University of Oregon. Chris Kaiser (right) is realigning the stack, a permitted move according to race rules. Photograph courtesy of Miriam Chua, Cold Spring Harbor Laboratory.

View larger version (100K): In this window In a new window Download PPT slide   Fred Sherman (left) and Gerry Fink on Bungtown Road, Cold Spring Harbor Laboratory, 1974. Osterhout Cottage is visible in the background (built circa 1800, reconstructed in 1969; WATSON 1991 ). In the 1890s, Osterhout was used first as a men's dormitory and later as a residence for the director of the Biological Laboratory, Charles Davenport, and his family. Alfred and Jill Hershey lived in Osterhout when they first came to Cold Spring Harbor in 1950, and in 1968, James and Elizabeth Watson chose Osterhout as their Cold Spring Harbor residence. For a Perspectives article about Hershey, see STAHL 1998 . Photograph courtesy of Gerry Fink, Whitehead Institute.

View larger version (135K): In this window In a new window Download PPT slide   The 1982 Yeast Genetics Course. Sherman and Fink have leapt the highest and the second highest, respectively. Pam Silver is at far left. Michael Rosbash is eighth from the left. Evelyn Witkin is second from the right. Photograph courtesy of Clare Bunce, Cold Spring Harbor Laboratory Archives.

View larger version (120K): In this window In a new window Download PPT slide   Sherman at the 1976 Yeast Genetics Course with a homemade apparatus for examining yeast cytochrome content. Sherman's inexpensive alternative to the Carey spectrophotometer (FINK 1993 ) and Hartree microspectroscope (SHERMAN 1964 ) consisted of a hand-held spectroscope, a cheap high-intensity lamp, and an aluminum cooking pot with a hole drilled in it, all mounted on a ring stand (FINK 1993 , p. 436). For a Perspectives article recounting studies of yeast cytochrome c, see SHERMAN 1990 . Photograph courtesy of Clare Bunce, Cold Spring Harbor Laboratory Archives.

	LITERATURE CITED

TOP LITERATURE CITED

ABRAHAM, J., J. FELDMAN, K. A. NASMYTH, J. N. STRATHERN, and A. J. S. KLAR et al., 1983  Sites required for position-effect regulation of mating-type information in yeast. Cold Spring Harbor Symp. Quant. Biol. 47:989-998.

ABRAHAM, J., K. A. NASMYTH, J. N. STRATHERN, A. J. S. KLAR, and J. B. HICKS, 1984  Regulation of mating-type information in yeast: negative control requiring sequences both 5' and 3' to the regulated region. J. Mol. Biol. 176:307-331[Medline].

BIRCHMEIER, C., D. BROEK, T. TODA, S. POWERS, and T. KATAOKA et al., 1985  Conservation and divergence of RAS protein function during evolution. Cold Spring Harbor Symp. Quant. Biol. 50:721-725[Abstract/Free Full Text].

CULOTTI, J. and L. H. HARTWELL, 1971  Genetic control of the cell division cycle in yeast. III. Seven genes controlling nuclear division. Exp. Cell Res. 67:389-401[Medline].

FINK, G. R., 1993 The double entendre, pp. 435–444 in The Early Days of Yeast Genetics, edited by M. N. HALL and P. LINDER. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

HARTWELL, L. H., 1967  Macromolecule synthesis in temperature-sensitive mutants of yeast. J. Bacteriol. 93:1662-1670[Abstract/Free Full Text].

HARTWELL, L. H., 1971a  Genetic control of the cell division cycle in yeast. II. Genes controlling DNA replication and its initiation. J. Mol. Biol. 59:183-194[Medline].

HARTWELL, L. H., 1971b  Genetic control of the cell division cycle in yeast. IV. Genes controlling bud emergence and cytokinesis. Exp. Cell Res. 69:265-276[Medline].

HARTWELL, L. H., 1991  Twenty-five years of cell cycle genetics. Genetics 129:975-980[Medline].

HARTWELL, L. H., J. CULOTTI, and B. J. REID, 1970  Genetic control of the cell division cycle in yeast. I. Detection of mutants. Proc. Natl. Acad. Sci. USA 66:352-359[Abstract/Free Full Text].

HARTWELL, L. H., R. K. MORTIMER, J. CULOTTI, and M. CULOTTI, 1973  Genetic control of the cell division cycle in yeast. V. Genetic analysis of mutants. Genetics 74:267-286[Abstract/Free Full Text].

HARTWELL, L. H., J. CULOTTI, J. R. PRINGLE, and B. J. REID, 1974  Genetic control of the cell division cycle in yeast. Science 183:46-51[Free Full Text].

HEREFORD, L. M. and L. H. HARTWELL, 1974  Sequential gene function in the initiation of Saccharomyces cerevisiae DNA synthesis. J. Mol. Biol. 84:445-461[Medline].

HICKS, J. B., J. N. STRATHERN, and A. J. S. KLAR, 1979  Transposable mating type genes in Saccharomyces cerevisiae.. Nature 282:478-483[Medline].

HICKS, J., J. N. STRATHERN, A. J. S. KLAR, S. ISMAIL, and J. R. BROACH, 1984  Structure of the SAD mutation and the location of control sites at silent mating type genes in Saccharomyces cerevisiae.. Mol. Cell. Biol. 4:1278-1285[Abstract/Free Full Text].

KATAOKA, T., S. POWERS, S. CAMERON, O. FASANO, and M. GOLDFARB et al., 1985  Functional homology of mammalian and yeast RAS genes. Cell 40:19-26[Medline].

KLAR, A. J. S., J. MCINDOO, J. N. STRATHERN, and J. B. HICKS, 1980a  Evidence for a physical interaction between the transposed and the substituted sequences during mating type gene transposition in yeast. Cell 22:291-298[Medline].

KLAR, A. J. S., J. MCINDOO, J. B. HICKS, and J. N. STRATHERN, 1980b  Precise mapping of the homothallism genes HML and HMR in Saccharomyces cerevisiae.. Genetics 96:315-320[Abstract/Free Full Text].

KLAR, A. J. S., J. N. STRATHERN, and J. B. HICKS, 1981a  A position-effect control for gene transposition: state of expression of yeast mating-type genes affects their ability to switch. Cell 25:517-524[Medline].

KLAR, A. J. S., J. N. STRATHERN, J. R. BROACH, and J. B. HICKS, 1981b  Regulation of transcription in expressed and unexpressed mating type cassettes of yeast. Nature 289:239-244[Medline].

KLAR, A. J. S., J. B. HICKS, and J. N. STRATHERN, 1981c  Irregular transpositions of mating-type genes in yeast. Cold Spring Harbor Symp. Quant. Biol. 45:983-990.

KLAR, A. J. S., J. B. HICKS, and J. N. STRATHERN, 1982  Directionality of yeast mating-type interconversion. Cell 28:551-561[Medline].

KLAR, A. J. S., J. N. STRATHERN, J. B. HICKS, and D. PRUDENTE, 1983  Efficient production of a ring derivative of chromosome III by the mating-type switching mechanism in Saccharomyces cerevisiae.. Mol. Cell Biol. 3:803-810[Abstract/Free Full Text].

POWERS, S., T. KATAOKA, O. FASANO, M. GOLDFARB, and J. N. STRATHERN et al., 1984  Genes in S. cerevisiae encoding proteins with domains homologous to the mammalian ras proteins. Cell 36:607-612[Medline].

SHERMAN, F., 1964  Mutants of yeast deficient in cytochrome c.. Genetics 49:39-48[Free Full Text].

SHERMAN, F., 1990  Studies of yeast cytochrome c: how and why they started and why they continue. Genetics 125:9-12[Medline].

STAHL, F. W., 1998  Hershey. Genetics 149:1-6[Free Full Text].

SUSMAN, M., 1995  The Cold Spring Harbor phage course (1945–1970): a 50th anniversary remembrance. Genetics 139:1101-1106[Medline].

WATSON, E. L., 1991 Houses for Science: A Pictorial History of Cold Spring Harbor Laboratory. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

WATSON, J. D., 1970 The Molecular Biology of the Gene, Ed. 2, p. 519. W. A. Benjamin, New York. ["There are now many reasons to intensify work on organisms like yeast. The very concentrated effort which has gone into the study of all aspects of E. coli is one of the major reasons why molecular biology has advanced so rapidly over the past two decades. Clearly, similar attention will soon be placed on one or more types of eucaryotic cells. For many reasons it is natural that much emphasis must go toward the study of several types of human cells. But at the same time, it may be wise to concentrate equally on the molecular biology of one or two of the simplest eucaryotes. Several reasons dictate this approach. One is that these microorganisms most certainly contain much less DNA than human cells. Only a five- to tenfold increase in genetic complexity is noticed in escalating to yeast or Aspergillus from E. coli. A second reason is economic: work with higher cells is at least an order of magnitude more expensive than with microorganisms. If a choice exists between solving the problem with human tissue culture cells or with yeast, common sense tells us to stick with the simpler system. A third, and perhaps the most important reason, is the ease with which detailed genetic analysis can be applied to many microorganisms. Despite the great advantages now brought about by the cell-fusion technique, detailed genetic analysis of human cells will be extraordinarily difficult to bring about. Thus, even if our primary interest is the human cell, this may be the time for many more biologists to work with organisms like yeasts."]

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