Tobacco Documents Online

. .................................................................................................... .................................................................................................. tions, gene multiplications, and mat- ing-type switching in yeast. In the late 1980s, scientists studying cell growth in cultured mammalian cells-ovary cells from the Chinese hamster, to be exact, but they were used as a model for all mammalian cells-began examining gene amplification. When treated with x-rays, these cells would make extra copies of some of their genes, different genes in different cultures. A clever test was developed to assay this phenomenon. Certain drugs kill cells-unless those cells have extra copies of a specific gene. Although one cannot predict which genes will become amplified as part of the X ray dosage, if you zap enough cells, even- tually nearly any given gene will be- come amplified and the descendants of those cells will survive in the pres- ence of the drug. One such drug is called PALA. It inhibits an essential cellular en- zyme called aspartate trans-carbamy- lase (ATC). PALA competes for the active site on ATC; PALA will stick to the enzyme and gum up the works. The only cells that can survive in a medium containing PALA are those that produce so much ATC that it swamps out the PALA; these are cells that have generated extra copies of the ATC gene, and thus under- gone genomic instability. Scientists work with what are called "model systems." A model sys- tetn is an organism under a special set of conditions that makes it useful for answering certain types of scientific questions. The fruitfly Drosophila was inition of cancer. But it is an ex- tremely useful property for a model system to have. Most of the time immortality does not affect the outcome of mole- cular biology experiments; most of Narrowing in on cancer Scientists began studying this gene amplification phenomenon. How were the new copies of the gene made? Were they laid end-to-end? front-to-back? back-to-back? Eventu- ally, a scientist at the University of North Carolina at Chapel Hill named Thea Tlsty made an astonish- ing and embarrassingly simple obser- vation. `Wait a second,' she said. 'Never mind how these things are laid down-the interesting thing is that normal cells don't show gene amplification!' ........................................................ .... ..... Assaying genomic instability. Normal cells die when placed in a medium containing the drug PALA. If cells do grow in PALA, they must have multiple copies of the ATC gene and so be producing more enzyme. a model system in the 1910s and the enzymes and other biochemistry 1920s for mapping genes. Bacterio- of the cell still function normally. phage and bacteria were a model sys- But in this case, the immortalized tem in the 1940s and 1950s for un- cell line had an anomalous property. derstanding the gene. Cultured Tlsty noticed that primary cells- mammalian cells are one of several cells taken directly from the organ- model systems used today for under- ism-did not show the DNA amplifi- standing cancer. A model system is a cation seen in the cultured Chinese research tool, like a centrifuge or a hamster cells. The interesting ques- restriction enzyme. Scientists make tion, then, was not `How are the new model systems. By breeding countless gene copies arranged?' but rather, generations from one given strain `What is causing the cultured cells to that worked well, a model system be- amplify their DNA?' comes inbred and takes on qualities A few years later, that question the "wild type" never had. An impor- was answered. One of the hottest tant quality about cultured cells is genes in cancer biology today is that they are immortal. Being able to called p53. This gene is a tumor sup- divide indefinitely does not come pressor; in the normal state, it slows naturally; it is, in fact, part of the def- (continued on page 9) I I,trbur Trinscriht • Surnmer 1994 7

.................................................................................................... .................................................................................................... . A Newsletter of Cold Spring Harbor Laboratory Summer 1994 A. Inside this issue: Genetic Basis of Cancer CSHL on the Internet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genomic Instability: From Corn to Cancer One of the hottest topics in can- cer research today is "genomic instability." It refers to mutations that cause the chromosomes to go haywire; rearranging, expanding cer- tain regions, or deleting large tracts of DNA. Once begun, the damage can amplify with each cellular gen- eration and the genome becomes unstable. When this instability is passed on through generations of cells, genetic damage can spread, cellular growth control can be aban- doned, and cancer can result. But hot as it is, genomic insta- bility is an idea older than molecu- lar biology itself. Barbara McClin- tock, font of so many new disciplines in biology, began think- ing about genomic instability as ear- ly as the 1930s. Origins in corn genetics Since she was a graduate stu- dent at Cornell in the 1920s, Mc- Clintock was interested in what happened to chromosomes when they were disrupted. One might call her work a series of studies in "chro- mosomal behavior." How did the cell respond when a chromosome was broken? Did the chromosome "heal" itself? How did broken chro- mosomes recombine to form inver- sions and translocations? All of her most famous experi- ments can be seen in the context of how the genome (although she didn't have that word) responded to shock, what it did when it was made unstable. Her discovery in the 1930s of ring chromosomes in x-rayed (continued on page 6) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Game Golfers Garner Green One hundred twenty-five good sports, includ- ing some excellent shots, divoted their way into the Lab's heart by participat- ing in the First An- nual CSHL Golf Tournament, June 7 at the nearby Piping Rock Club. The tournament was a benefit for the DNA Learning Center. The sticky weather did not dampen the spirits of the enthusiastic Lab supporters, who vied individually or in teams of four for a variety of prizes. The tourna- ment was organized (continued on page 4) Is that Jack Nicklaus or Jack Richards? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . arbor iPanscript =~ printed on recyclzd paper recyclable

....: ..... .... ..................................................................... .............. ................................................ ............... Vol. 12, No. 2 Upcoming Events Harbor Transcript is published October 2, 1994 October 30, 1994 quarterly by the Public Affairs Sunday, 4:00 P.M. Sunday, tentative Department of Cold Spring Harbor Lecture by NASA Astronaut, Jim CSHLA lecture on Human Behavior. Laboratory, I Bungtown Rd., P.O. Newman. Children 10 & over wel- Call 367-8840 for info. Box 100, Cold Spring Harbor, NY come. Call 367-8840 for info. 11724-2213. Copies may be ob- November 16, 1994 tained by writing the above address October 15, 1994 Wednesday, 7:00 P.M. or by calling (516)367-8455. Saturday, 11:00 A.M. Huntington Hospital lecture. Subject Guided tour of Cold Spring Harbor to be announced. Cal1351-2647 for info. Editor, Susan Cooper Lab. Call 367-8455 for info. Assistant Editors, Lynn Hardin, December 4-5, 1994 Laura Hyman October 26, 1994 Sunday and Monday Writer, Nathaniel C. Comfort Wednesday, 7:00 P.M. Arts & Crafts Fair. Call 367-8350 for info. Art Director/Photographer, Huntington Hospital lecture. Subject Margot Bennett to be announced. Call 351-2647 for info. Planned Giving T he Laboratory is pleased to an- nounce the establishment of The Harbor Society. It is being formed to recognize and thank indi- viduals who have made or indicated their intention to make a planned gift to Cold Spring Harbor Laboratory. The Laboratory's Board of Trustees recently approved a new program, The Next 100 Years, with the goal of doubling our endowment, primarily through planned giving (see feature article in the previous Harbor Transcript). Excellence in sci- ence and financial strength go hand in hand; planned giving is thus of great importance to the future of the Lab's programs. The inaugural meet- ing of The Harbor Society is planned for early next year and members will be invited to a private reception at the President's House, the new home of Dr. and Mrs. James Watson. If you are interested in planned giving and would like more informa- tion about The Harbor Society, or would like to become a charter member, please contact Gordon Har- graves, Director of Planned Giving, at 367-8842. -Gordon Hargraves Research Notes Symposium LIX: Understanding Cancer H ow does cancer begin? Over 450 scientists gathered for an intense week of data and discussion on this old and difficult problem at this year's Cold Spring Harbor Symposium on Quantitative Biology. Understanding, diagnosing, and treating cancer is perhaps the primary raison d'etre for research biology to- day, at least in the eyes of the tax- paying public. This year's Sympo- sium, Molecular Genetics of Cancer, offered no major shifts in the way sci- entists think about cancer, but out of it did come some new focuses, new data, new themes. Former Cold Spring Harbor sci- entist Ed Harlow closed the meeting with a thoughtful summary. Harlow was encouraged that the genes that are emerging as important in causing cancer are not terribly surprising. This shows, Harlow, said, we are on the right track toward understanding the genetics of cancer. Harlow was discouraged, however, by the huge number of genes that seem to be in- volved. Long gone is any hope that cancer will be found to be caused by one or a few genes. A thousand or more genes may be involved. Estimates of the number of inde- pendent mutations needed to cause cancer range from 5 to 20, with the average around 10 or 12. Given the probability of spontaneous mutations, we don't have enough cells in our bodies ever to produce a tumor; something else must be vastly in- creasing the likelihood of getting or retaining a mutation. Environmental mutagens are certainly important in increasing overall mutation rates. Ge- netically, damage to the cell's system of DNA repair is emerging as an im- portant factor in many cancers. If the cell cannot repair genetic damage, mutations accumulate or even accel- erate, leading to cancer. Some new therapies were dis- cussed. Combination therapies, utiliz- ing both a "dumb" (i.e., non-specific) but powerful drug in conjunction with a "smart" (specific) drug that targets tumor cells, may hold promise. Also, Harlow pointed toward the control of angiogenesis, or creation of new blood vessels, in tumor tissue as a way to prevent tumors from metas- tasizing. Preventing a tumor from re- ceiving nourishment could kill the deadly cells. ~~~ ................................ .................................................................................................... .. :. ..................................... ...... ...... ...... ...... 2 1 arh or Transcript . Summer 1994

.................................................................................................... ............................................................................ Dorcas Cummings Lecture: The Genetic Basis of Cancer ((tV Je are living in strange times," says Harold Varmus, director of the National Institutes of Health. Varmus, who shared the 1989 Nobel Prize in Physiology or Medicine with Michael Bishop for his role in demonstrating that cellu- lar genes can cause cancer, be- came director of the NIH in 1993. He is thus a leader in set- ting national science policy. He is also an extraordinarily congenial, approachable man. Varmus gave this year's Dorcas Cummings lec- ture,. a public talk given on the Sunday evening of the annual Symposium. The title was, "Why is it important to understand the genetic basis of cancer?" What's so strange about these times? Cancer is one of the largest health concerns for Americans. Nearly one out of every two people, Varmus said, will have some form of cancer in their lifetime. Yet in these times of shrinking government bud- gets and environmental fears, one has to justify basic cancer re- mentation. Further, Varmus said, un- derstanding cancer has implications beyond cancer. In developing new ways to explore normal and abnormal cell growth, new techniques are de- veloped, and new and fundamental insights into biology are gained. Hnro41 Varmus search. A further paradox is that our understanding of cancer has ad- vanced enormously in the last 20 years, yet the numbers don't yet show much improvement. What we have learned is how complex cancer is, and how unlikely it is there will ever be a single cure. Does this mean basic research o the physiology and genetics of cell growth-i.e., basic cancer research- is useless. On the contrary, said Var- mus, it is increasingly important. Only through basic research will we discover the general principles un- derlying the complexities of cancer. It is these fundamentals that will leacV to new diagnoses, treatments, and cures. New therapies will require new knowledge, and new knowledge comes from exploration and experi- Varmus's "mantra" as a biologist is that a cancer is a genetic disease. This does not mean all cancers are inherited; rather, it means cancer re- sults from defects, inherited or ac- quired, in genes. Current wisdom is that it takes ten to twelve mutations, each in a different gene, to cause full- blown cancer. If you inherit one or more of these mutations, it means you are that much more likely to get cancer. A sinister thing about cancer is that it promotes itself. Since a tu- mor is a collection of cells that is growing out of control, tumor cells out-compete their neighbors, produc- ing many more tumor cells than healthy neighbors produce normal cells. Worse still, some kinds of mu- tations actually increase the likeli- hood of getting more mutations. An example is a defect in the cell's DNA-copying machinery. Such a mutation like this might increase the chance of getting more mutations from one in a million to one in a hundred. At this rate, a malignant tumor is much more likely. In chposing which avenues to pursue, Varmus tries to dis- tinguish between knowledge gaps and experimental opportu- nities. Knowledge gaps are a dime a dozen. In fact, close study seems to create them: the more you know about a subject, the more you realize there is to know. Experimental opportuni- ties, however, are more rare. They are knowledge gaps that have a good chance of being solved soon. This is why in gen- eral experimental, molecular ge- netic approaches are favored over exhaustive environmental, epidemiological studies. The ge- netic causes of cancer are not more important than environ- mental ones; they are just more easily addressed and solved. Out of basic cancer research will come new methods of assessing can- cer risk and the best course of treat- ment, and new, more effective thera- pies with reduced side effects. Varmus gave examples of all of these; no miracle cures, but several proinis- ing avenues. He emphasized that we are still treating cancer in crude ways, by cutting out the miscreant cells or poisoning all dividing cells in the body. Development of more sub- tle techniques will require a more subtle understanding of cancer and cell growth. What makes a cancer cell different from a healthy cell? How can we design drugs that attack only the cancer cells, leaving healthy dividing cells intact? These are some of the greatest challenges of modern medicine. A : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . : . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Harbor Transcript • Summer 1994 3

.................................................................................................... .................................................................................................... ........... Game Golfers Garner Green (continued from front page) by Rick Clark (Chairman), Morgan Browne, Douglas Fox, Arthur Her- man, Michael Vittorio, and Bill Keen. It was sponsored by JP Morgan & Co., with a brunch sponsored by Cablevision Systems Corp. and a cocktail party sponsored by Baxter Scientific Products. The Badge Agency and ITT Hartford sponsored a $30,000 hole-in-one opportunity on the 17th hole, which, alas, no one won. Twenty-six members of the Lab's Corporate Advisory Board were instrumental in raising a total of $48,400 in support of DNA education. The winning "low net" team, consisting of Rich Grabowski, Andy Ackerman, Richard Kleinman, and Arthur Rudolph, won Corbin blazers. The second place team, made up of Charles Peluso, Ben Parenti, Paul Farrell, and Bob Weinberg won deco- rative enameled trays, and the third place teams (there was a tie), Artie (l-r): James Childress, Dennis Dowd, Hank Kobrin (Second Place Individual Low Net), Sam Rozzi Third Place Team Low Net (l-r): Don Karlsen, Gerry Spitz, Artie Ventura, Vincent Adimando First Place Teant Lou, Net (1-r): Rich Grabowski, Arthur Rudolph, Andy Ackernutn, Richard Kleinman E E w m w First Individual Lou, Net: Glenn Vicari (I-r): Constance Denson (Closest to Pin), Robert Anderson, Terry Anderson, John J. O'Leary . .................................................................................................... .................................................................................................... ........

.................................................................................................... .................................................................................................... ............... : Ventura, Gerry Spitz, Vincent Adi- mando, and Don Karlsen, and Ron Spinelli, Stan Henry, Toni Rohr, and Michael Spinelli, won polo shirts. First place individual low net score was earned by Glenn Vicari, who won an Orrefors crystal vase, and second place was nabbed by Hank Kobrin, who won an Orrefors crystal bowl. Individual low gross scores were earned by Horst Saal- bach, Vincent Adimando, Joe Nidzyn, and Andy Ackerman. The longest drive award went to Alan Hock for the men and to Jane Morley for the women. Constance Denson managed to drive her ball closest to the pin on the par 3 eleventh hole. A team made up of three Lab staffers- Jack Richards, Art Brings, and John Maroney-and Bill Baldwin won the Highest Number of Strokes Award. They won golf lessons at the Town of Oyster Bay golf course in Syosset. ~: Second Place Team Low Net (l-r): Charles Peluso, Ben Parenti, Bob Weinberg, Paul Farrell First Individual Lou, Gross: Horst Saalbach Organizers Q-r): Morgan Broune, Douglas Fox. Richard Clark, Arthur Herman, William Keen (l-r): Alart Hock (Longest Drive), Jerry Williams, Joe Gioia, William Keen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . : Harhor Tramcripr • Sunnmrr 1994 5

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Genomic Instability (continued front front pctge) Normal Inversion [I] U_ Gene Deletion Expansion Chromosomal mutations. Large-scale mutational etents can dramatically alter a chromosome. In an in- version, the lower partion has been cut, rotated, and pasted back on upside-down. In a deletion, it has been lost altogether. In gene expansion, a region is copied nutny times, lengthening the chromosome and resulting in extra copies of genes within the region. maize turned out to be a special case of the phenomenon of broken chro- mosomes. The broken chromosome work led to McClintock's discovery of the breakage-fusion-bridge cycle, where broken chromosomes, or bro- ken parts of chromosomes, fused, forming a bridge-like structure when the cell began to divide and the two chromosomal parts were pulled in op- posite directions. The bridge breaks when at last the cell divides, forming more broken chromosomes that be- gin the cycle again. The BFB cycle is a sort of biological oscillation. The X rays were an initial perturbation that began the oscillation-the chromo- somal mutations they produced be- gan the BFB cycle. The best known of McClintock's work, transposable elements or "jumping genes," grew out of the BFB cycle work. An experiment she per- formed in the summer of 1944 at Cold Spring Harbor first suggested to her that the genome might respond in a unique and ttnified way to "stress," such as irradiation. Using the BFB cycle, she obtained plants in which a chromosome had broken. Now she grew up 450 of these plants. When she did, she observed in some of them bizarre traits that she attributed to altered gene expression. In other words, large-scale chromo- somal damage was affecting the pattern and timing of turning on individual genes. These discoveries led directly to McClintock's famous description of transposable elements, or "jumping genes." These small genetic ele- ments-McClintock did not call them genes-created instability whenever they left one chromosomal site and entered another. McClin- tock saw transposons as different from genes. Based on this discovery she suggested there were two kinds of genetic elements, genes and control- ling elements. The controlling ele- ments did not carry hereditary infor- mation but rather regulated the genome, controlling which genes were active or could be activated. Transposons were an internal source of instability, a perturbation con- tained within the genome. Generalizing the idea McClintock expressed these ideas most clearly in her 1983 Nobel lecture, "The Significance of Re- sponses of the Genome to Chal- lenge." In this article she traces the lineage of her transposon experi- ments and broadens their scope by comparing her maize work with chro- mosomal behavior in fruitflies and bacteria. She suggests-no, she says; Barbara didn't mince words when she was sure of something-the genome is "programmed" to respond to cer- tain kinds of challenge or shock. These include heat, radiation, chetn- ical insult, and others. What was novel about this idea-and what made it hard for other biologists to swallow-was that McClintock was saying the genome acted as a unit, that it had a behavior that could be observed on a higher level than that of single genes. The term "genomic instability" has gone through considerable evoiu- tion. In the 1980s, scientists used it in much the same way McClintock did. Many of these scientists were in fields related to McClintock's; they were corn geneticists, plant molecu- lar biologists. They were discovering the molecular mechanisms of the kinds of genomic instability McClin- tock found in maize. Looking at pig- mentation in corn kernels and cobs is a particularly easy way to assess ge- nomic instability. McClintock couid "screen" enormous numbers of cells by simply scanning an ear of corn. When she saw a strain with an un- usual pattern of pigmentation, she would prepare its cells for microscopy and examine the chromosomes for signs of rearrangements, deletions, or other damage. The term broadened in its use during the 1980s. Medical re- searchers and other scientists picked up on it to describe a wide variety of genetic phenomena, including trans- posable elements, polyploidy (the wholesale doubling or tripling of the genome), a local increase in the fre- quency of spontaneous point muta- :.......... ........................................... ...... ......................................................... ................... ................................................... ............ :

Cold Spring Harbor Laboratory Annual Fund Members of the Cold Spring Harbor Laboratory Association - contributors to the Annual Fund - form a unique support team that has the opportunity to meet international cientists and increase their own understanding of molecular biology through special publications, lectures, and workshops. The Annual Fund supports young scientists. Young scientists make important discoveries. Today's discoveries lead to tomorrow's cures.

The Laboratory considers education a primary function. Donors have the opportunity to participate in workshops, lectures, and special events.The following lists the categories of support and their benefits. Family Members - Donors of $50 or more receive the Laboratory's newsletter, Harbor Transcript, and invitations to general Lab lectures. Friends - Donors of $300 or more receive the above plus A Closer View and a CSHL bookmark Associates - Donors of $1,000 or more receive all of the above, as well as two children's science books and an invitation to a special annual event. Patrons - Donors of $3,000 or more receive all of the above plus invitations to special Lab events with scientists and a signed copy of The Double Helix. Benefactors - Donors of $ 10,000 or more receive all of the above as well as an invitation to dinner and a briefing by Drs. Watson or Stillman, and an illustrated science book. Enclosed is my tax-deductible check, payable to Cold Spring Harbor Laboratory, in the amount of $ ^ Please send me information about the Laboratory's Planned Giving program. Name Home Address Company Name Company Address Home Phone ( ) Office ( )

NO POSTAGE NECESSARY IF MAILED IN THE UNITED STATES Business Reply Mail FIRST CLASS PERMIT NO. 3 COLD SPRING HARBOR, N.Y. Postage will be paid by Cold Spring Harbor Laboratory Development Office Post Office Box 100, One Bungtown Rd. Cold Spring Harbor, New York 1 1 724-221 5