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Home , Bert Vogelstein, Biology, Francis Crick, Horace Freeland Judson, Icarus (journal), Jacques Monod

09 04

THE PRESIDENT’S REPORT OF THE SALK INSTITUTE FOR BIOLOGICAL STUDIES INSIDE SALK “He will forever be with us in spirit as a great man and as a role model of how to do and live .” –HEINER WESTPHAL

Francis Harry Compton Crick 1916-2004 REPRINTED FROM

units of DNA, encoding all the biological information , needed to generate and maintain a living person — has been deciphered. Co-Discoverer of DNA, Dr. Crick was a with a thirst to understand and a talent for productive friendships. It was his two-year collabo- Dies at 88 ration with Dr. Watson that made possible the discovery of BY the of DNA, a feat that each has said he would not have accomplished without the other. After Dr. Watson Francis H. C. Crick, co-discoverer of the structure of DNA, returned to the , Dr. Crick’s close collaborator the genetic blueprint for , and the leading molecular for many years was , with whom he solved the of his age, died on Wednesday night in a hospital in of the genetic . . He was 88. Dr. Crick occupied a rarely paralleled position of He died after a long battle with colon , said Andrew intellectual leadership in the early years of molecular Porterfield, a spokesman for the Salk Institute, where he worked. . In intense efforts to explore beyond the door opened Dr. Crick laid the foundations of in a by the dis-covery of DNA, from to Pasadena, sustained burst of creativity that began in 1953 with the were drawn into a pursuit that at every stage was shaped by discovery of the structure of DNA, the hereditary material, in Francis Crick. , , and ended about 13 years later with the “By , wit, vigor of personality, strength of voice, subject’s primary problems solved, most of them either by intellectual charm and scorn, a lot of travel, and ceaseless Dr. Crick or by in his circle. letter-writing, Crick coordinated the of many other The discovery of the structure of DNA resolved long- biologists, disciplined their thinking, arbitrated their standing questions about the nature of the hereditary conflicts, communicated and explained their results,’’ the material and the manner in which it is copied as one genera- historian wrote in “The Eighth Day tion succeeds another. The proposal for the structure, almost of Creation.’’ immediately accepted, was electrifying to scientists not only The French biologist told Mr. Judson: because of its inherent elegance but also because it showed “No one man discovered or created molecular biology. But how biology, and the nature of life itself could ulti- one man dominates intellectually the whole field, because he mately be explained in terms of and . knows the most and understands the most. Francis Crick.’’ Indeed, the desire to replace religious with rational explana- A unforgettable portrait of Francis Crick was drawn by Dr. tions of life was a principal motivation of Dr. Crick’s career. Watson in “The ,’’ his best-selling account of So central is DNA to biology that the of Francis their discovery. Mr. Crick was unknown at the , pursuing H.C. Crick and James D. Watson, his American colleague in his Ph.D. at the advanced age of 35. But the lack of this the discovery, may be remembered as long as those of Darwin credential did not diminish his confidence in his own abilities. and Mendel, the architects of the two pillars of modern biology, “I have never seen Francis Crick in a modest mood,’’ the of evolution and the laws of . Dr. Watson wrote in the first sentence of his book. Some consequences of understanding the structure of He described Mr. Crick’s animated conversation, his DNA are already familiar, from linking suspects to crime manic laughter, his , infuriating to colleagues, of scene evidence to manipulating it to make genetically engi- pumping them for their data and showing them what it meant. neered . But these are just foretastes of a -based “Conversation with Crick,’’ Dr. Watson wrote, “frequently medical revolution that is expected to unfold in the years upset Sir ,’’ the director of the Cavendish ahead now that the — about three billion in Cambridge, where Mr. Crick then worked,

2 “Dr. Crick was a scientist with a thirst to understand and a talent for productive friendships.”

“and the sound of his voice was often sufficient to make were already understood to be the ’s working Bragg move to a safer room.’’ parts, and Mr. Crick began with studying the structure of Yet Dr. Watson’s vivid portrait held elements of caricature. , the -carrying of the . He Mr. Crick’s immodesty did not extend beyond the realm of worked in a branch of the Cavendish, the intellectual argument. Council unit, headed by Dr. Max F. Perutz. Well before his “Rather than believe that Watson and Crick made the was finished, however, he realized that a far more DNA structure, I would rather that the structure made interesting problem was the structure of deoxyribonucleic Watson and Crick,’’ Dr. Crick wrote diffidently in a memoir, , or DNA. A classic of 1944 had pointed to “What Mad Pursuit.’’ DNA as the genetic material. But biologists had made almost On the day of the discovery, Dr. Watson asserted, “Francis no progress since then in understanding how DNA might winged into the Eagle,’’ the dingy Cambridge where they store hereditary information and few were actively working lunched every day, “to tell everyone within hearing distance on the problem. that we had found the secret of life.’’ Mr. Crick’s life was changed one day in October 1951 Dr. Crick did not remember that incident, he has written, when a Dr. Watson, a 23-year old American biologist, walked but he did recall going home and telling his wife, Odile, that into his life. Dr. Watson also understood that the structure of he seemed to have made a big discovery. Years later, he DNA was the key to everything. Neither was supposed to be continued, Odile told him that she had not believed a word of working on DNA, but they at once fell into discussing how it, saying, “You were always coming home and saying things the problem might be approached, in conversations so like that, so naturally I nothing of it.’’ sustained that the pair were given their own small office at the so their voices would not disturb REJECTED TENURED POSITION everyone else. Francis Harry Compton Crick was born on , 1916, in “Jim and I hit it off immediately,’’ Dr. Crick later wrote, , England, where his father and uncle ran a “partly because our interests were astonishingly similar and boot and shoe factory founded by their father. He studied partly, I suspect, because a certain youthful arrogance, a physics at University College, , and after a short ruthlessness and an impatience with sloppy thinking came researching the of under high naturally to both of us.’’ pressure (in his view “the dullest problem imaginable’’), he Their approach, copied from the great Linus was drawn by World War II into military research, working Pauling, then at the Institute of , was on the design of magnetic and acoustic mines. He did so to build exact models of the DNA that would be well at this job that after the war, Dr. R. V. Jones, the head of compatible with the limited information available from X-ray Britain’s wartime scientific intelligence, wanted Mr. Crick to , a method of probing a chemical’s structure succeed him. But Mr. Crick chose research. with X-rays. A political difficulty was that the problem of “Looking back, it was absurd because I had a tenured DNA’s structure had been assigned to another scientist, job,’’ he said in a recent interview. Finding himself at loose Maurice H. F. Wilkins of King’s College, London. Under the ends after the war, he decided the most interesting research etiquette of British science, to Dr. Watson’s amazement, no problem lay in trying to understand the physical basis of life, one else was supposed to muscle in on it. the between the living and the nonliving. The choice But Dr. Wilkins, a wartime friend of Mr. Crick’s, said he eventually drew him to the Cavendish Laboratory in did not object to his trying a model. Dr. Watson and Mr. Cambridge, one of the world’s leading centers for studying Crick soon had one ready. It was based, in part, on X-ray the structure of proteins by X-ray analysis. At 35, he started data about DNA obtained by Dr. Wilkins’s colleague, Dr. working for his Ph.D. on the structure of proteins. . Dr. Watson had heard Dr. Franklin

3 Francis in 2000

Francis (pictured left) and during a walk in Cambridge

describe these data in a public lecture but had misunder- INGREDIENTS IN PLACE stood them. From , an experienced American chemist who For their model, Mr. Crick and Dr. Watson constructed the happened then to be sharing their office, Mr. Crick and Dr. backbone of the DNA in the form of a spiral, or Watson also learned the true chemical of the DNA helix, with the winding chains held together in the middle by bases and the fact that the structures shown in current text- metal . The bases, the four chemical subunits that spell books were incorrect. out the genetic information, pointed outward from the chains The ingredients for the discovery were now all in place. because the two researchers could see no way that the neces- With the right structures in hand, Dr. Watson was one day sarily irregular sequence of bases would match together playing with cardboard cutouts of the four bases when he neatly if they pointed inward. noticed that an A-T pair on his small desk was identical in With the model completed, Mr. Crick invited Dr. Wilkins shape with a G-C pair. He immediately perceived how the and Dr. Franklin to Cambridge to inspect their progress. Dr. bases could point inward, holding the spiral staircase together Franklin instantly recognized a glaring , and a few days with steps of always equal width, provided that later Dr. Bragg, embarrassed by the debacle, ordered Mr. always paired with , and with . Crick to do no more on DNA. The pairing rule at once explained the equivalences of Nonetheless, Mr. Crick and Dr. Watson kept thinking Chargaff’s rules and, more critically, how one DNA chain could about the problem and a few months later were able to serve as the template for building another, the essential require- reverse Dr. Bragg’s prohibition. The precipitating event was ment for any molecule that embodied hereditary information. the announcement by , who was Dr. Bragg’s “That morning,’’ Mr. Judson wrote in “The Eighth Day of peer and rival, that he had found the to the structure Creation,’’ “Watson and Crick knew, although still in of DNA. Mr. Crick and Dr. Watson knew that Pauling’s only, the entire structure: it had emerged from the shadow of solution was wrong, but believed it might be only days before billions of years, absolute and simple, and was seen and Pauling realized his error and seized on the solution. understood for the first time.’’ In their second attempt, Mr. Crick and Dr. Watson picked In his memoir, Dr. Crick said: “It’s true that by blundering up several important clues. As part of a reporting system about we stumbled on gold, but the fact remains that we were designed to share information among supported looking for gold. Both of us had decided, quite independently by the British Medical Research Council, Mr. Crick came to of each other, that the central problem in molecular biology see a correct version of the X-ray data that Dr. Franklin had was the chemical structure of the gene.’’ No other scientists reported at the lecture attended by Dr. Watson. Although Dr. were pursuing the structure with such single-mindedness. Franklin had insisted that these data proved DNA could not It took only a few days to build the model dictated by their be a helix, Mr. Crick understood that they proved the new concepts. This time it convinced everyone because it opposite and that the two chains were antiparallel, in other explained everything. words that the head of one was always laid against the tail of “It has not escaped our notice,’’ Mr. Crick wrote in a the other. lapidary conclusion to their report of , 1953, in the The two biologists had also belatedly learned of Chargaff’s journal Nature, “that the specific pairing we have postulated rules, named for , a longtime student of DNA immediately suggests a possible copying for the at Columbia University. The four bases that occur in DNA genetic material.’’ are known as adenine, guanine, thymine and cytosine, or A, After making the discovery and completing the require- G, T and C for short. Chargaff had discovered that from ments for his Ph.D., Dr. Crick plunged into the problems now whatever DNA was isolated, A and T were found in made accessible by the new structure. How did the sequence roughly equal quantities, as were G and C. of bases in DNA determine the sequence of amino in

4 “It’s true that by blundering about we stumbled on gold, but the fact remains that we were looking for gold.”

the ribbon-like structure of each molecule? How was outside the cell, thus excluding the Lamarckian thesis that the information copied from DNA and transferred to the cell’s acquired characteristics could be inherited. protein-synthesizing centers? Though many scientists played important roles in solving NOBEL PRIZES FOR THREE this array of problems, the guiding intelligence at almost all In 1962, Dr. Crick, Dr. Watson and points was Dr. Crick’s. It was he, for example, who first realized received the in for their work on DNA. there could be only a specific number of amino acids, the Dr. Wilkins and Dr. Franklin had contributed the X-ray data building blocks of proteins. Scanning the confused biochemical that suggested and confirmed the structure of DNA, but Dr. literature, he drew up the canonical list of the 20 acids. Franklin died of in 1958. With his colleague Sydney Brenner, Dr. Crick eventually The discovery of DNA brought unwelcome attention, too. proved, in an experiment of remarkable elegance, that the In 1967 Dr. Crick read a draft of Dr. Watson’s account of was a comma-less, triplet code in which a set of their discovery, “.’’ The memoir, which three bases determines an unit and a string of then bore the working title “Honest Jim,’’ was a startling triplets thereby specifies the full sequence of amino acids in departure from the usual staid accounts of laboratory life. a protein chain. The Crick-Brenner experiment essentially After its opening declaration about Dr. Crick’s lack of consisted of deleting bases, one by one, in the DNA of modesty it adroitly portrayed the participants’ feelings as the and showing that only after three bases had been helter-skelter pursuit of DNA wound to its resolution. Dr. eliminated in close proximity did the DNA-transcribing Crick viewed the gossipy narrative as a betrayal of their system come back into correct phase. friendship, a violation of his privacy and a distortion of their In a conversation in 1960 with the French biologist methods and motives. He was unsuccessful in efforts to Francois Jacob, Dr. Crick and Dr. Brenner recognized the prevent the book’s publication. long-puzzling identity of the messenger chemical, now known Dr. Crick later came to terms with his colleague’s account. as messenger RNA, that distributes copies of the genetic “In those days there was a different convention, at least in information in the cell’s nucleus to the protein-making Britain, about writing about your friends,’’ he said in an apparatus in the cell’s periphery. interview in 2003. “But I came out of the book quite well, In another insight of remarkable power, Dr. Crick in his apart from the first sentence. As said, the “adaptor ,’’ divined that there must exist both a person who comes out worst is Jim.’’ of carrier that recognize triplets of bases on One of the problems caused by the book was Dr. Watson’s the messenger and adaptor that link each kind of implication that the pair of them had obtained Dr. Franklin’s data amino acid to its appropriate carrier. ridiculed on DNA surreptitiously and hence had deprived her of due credit the idea, saying that if the adaptor enzymes existed, they for the DNA discovery. Dr. Crick believed he obtained the data would already have found them. But both the transfer fairly since she had presented it at a public lecture, to which he RNA’s and the adaptor enzymes proved to exist, as Dr. had been invited. Though Dr. Watson had misreported a vital Crick had predicted. figure from the lecture, a correct version reached Dr. Crick Dr. Crick derived several sweeping that have through the Medical Research Council report. If Dr. Franklin stood the of time. He assumed from the start that the felt Dr. Crick had treated her unfairly, she never gave any sign of genetic code was universal to all forms of life, as indeed with it. She became friends with both Dr. Crick and Dr. Watson and trivial exceptions it has proved to be. His “central dogma’’ spent her last remission from cancer in Dr. Crick’s house. formulated the view that once genetic information had passed Dr. Crick gave his younger colleague no cause into protein, it could not get out again. The dogma meant that for complaint. Dr. Watson acknowledged the selflessness of the genetic message was impenetrable by information from Dr. Crick’s motives.

5 “The most important thing is to be there when the picture is painted.”

“Francis was always so kind to me,’’ he said in an inter- Dr. Crick’s style of practicing science was unusual. Most view in 1998. “He never tried to promote himself. He was biologists do ; he did so very rarely, being one of just interested in solving problems.’’ biology’s few theoreticians. He did not take graduate students, By 1966, the first era of biology at the molecular level was preferring instead to work with a single colleague. His complete. Though many details of enormous interest remained scientific interlocutors were, after Dr. Watson, Dr. Brenner to be discovered, the foundations had been well and truly laid. during the Golden Age of molecular biology, and Dr. Christof Dr. Crick and Dr. Brenner decided to move on to another vast Koch, for his work on the brain. of biology, the manner in which a whole organism develops “Francis essentially works alone but likes to have a from the fertilized . colleague to play against, so to speak,’’ Dr. Brenner said In 1977 Dr. Crick left Cambridge, and his well-known house recently. on Portugal Place, with its golden helix above the front door, Dr. Crick wrote little about his own life and, despite his where he and Odile had held many high-spirited parties. The fame, remained a surprisingly private person. His first Cricks moved to the Salk Institute in San Diego. There he marriage, to Ruth Doreen Dodd, ended in divorce in 1947. took on another challenging unsolved problem of biology: He is survived by his wife, the former Odile Speed, an artist; the nature of . a son from his first marriage, Michael F. C. Crick of Seattle; He had little expectation of producing any radically new ideas and by two daughters from his second marriage, Gabrielle A. at age 72, he wrote in 1988, “but at my time of life I had a Crick and Jacqueline M-T Crick Nichols, both of England; right to do things for my own amusement.’’ Never one to let his and four grandchildren. mind fallow, Dr. Crick produced a stream of papers about What is the nature of scientific genius? Dr. Crick was aspects of the brain and a well-regarded popular book in 1994, perhaps offering an answer in his response to a different “The Astonishing Hypothesis,’’ which summarized his ideas. question, that of whether he enjoyed his life. Another diversion that Dr. Crick allowed himself was a “I cannot do better,’’ he said, than to quote from a lecture bold speculation about the origin of life. Only the most by the painter John Minton “in which he said of his own eminent and secure of scientists would dare flirt with the artistic creations, ‘The important thing is to be there when idea that may have been seeded with life by a rocket the picture is painted.’ And this, it seems to me, is partly a ship from another planet. But that possibility, a thesis Dr. of luck and partly good judgment, inspiration and Crick termed “Directed ,’’ was aired in an article persistent application.’’ he published in the journal (1973) with his Salk © 2004 The Company. Reprinted with Permission. Institute colleague Leslie E. Orgel and in a popular book by Dr. Crick alone, “Life Itself’’ (1981). Dr. Crick in no way rejected the orthodox scientific thesis that life evolved in some way, yet to be specified, from the chemicals present on the . But he was impressed by the unexplained universality of the genetic code and uncomfortable with the narrow window of time between the date the earth cooled enough to be habitable and the first appearance of life in the fossil record. With “,’’ he prepared, in effect, an intellectual escape hatch, an alternative explanation for life should scientists in fact find it too hard to account plausibly for the remarkably rapid of earth’s first life forms. Jim and LIz Watson with Odile and Francis Crick

6 INSIDE SALK Research News

of the Proceedings of the Turning Treachery National Academy of . are to Triumph difficult to study, not only for safety reasons but Cells infected with viruses proven what until now was because living cell systems such as HIV actively only suspected — that are incredibly complex, promote their own chemical factors within the with thousands of chemical infectivity, according to a cell itself actively assist reactions happening fascinating new study by with the uncoating process. simultaneously. The Salk Salk scientists. Using a These treacherous scientists found a way to unique cell-free system that ‘chemical concierges’ were separate out the viral closely mimics real life, the first, dramatic discovery just after they John Young and to emerge from a entered the cell, colleagues have shown that revolutionary new technique placing them in a cell-free chemical ‘double agents’ devised by the Salk team system where each chemical inside cells help invading for studying invasions. reaction could be studied in Cvirus particles strip for The results were published isolation. The prototype action before they begin in the May 18, 2004 issue system used a virus called >> taking over the cell’s crucial machinery. “If we can manipulate these molecules we may be able to produce a new therapy for AIDS,” says John Young. We now know that several distinct steps are needed for viruses such as HIV to take over a healthy cell. The virus must first attach to the outer membrane of the host cell, then fuse with it, allowing the deadly virus particles to enter the cell. These viral particles then start to generate copies of the virus’ own DNA, which rapidly takes over the cell, crippling and eventually destroying it. However, in between entering the cell and starting work, the viral particles must have their protein ‘coat’ removed. Young’s team has now

7 INSIDE SALK Research News

Turning continued We’ve Got Rhythm avian sarcoma and leukosis Ever tried thinking about your feet as you walk down stairs? You’re virus (ASLV). This virus likely to end up at the bottom a lot faster than intended. This simple, makes a good experimental if hazardous, experiment demonstrates the role of the central pattern generators (CPGs) — complexes of in the that model because it is in the control locomotion independently of the brain. In essence, the CPGs same as HIV mean you don’t have to think about walking: you just do it. Although (retroviruses) and is known CPGs are central to our , their extreme means they to be stable in a laboratory remain mysterious and difficult to study. Now Salk neurobiologists, setting. headed by associate professor Martyn Goulding, have harnessed the The new cell-free power of genetics to pinpoint a crucial part of the circuitry that keeps us moving. system has the potential to CPGs, found in the stretch of spinal cord below the ribs, consist revolutionize the treatment of complexes of ‘controller’ cells called interneurons. In a study of retroviruses important to published in on May 13, the Salk team focused on interneurons, human . Current a useful group of nerve cells to study because their existence therapies for HIV inhibit appears to be determined by a single gene, Dbx1. Goulding’s team viral DNA production or showed that genetically engineered mice that lack Dbx1 fail to develop interneurons. Importantly, the stop the virus fusing with spinal cords of these mice were no longer able to the , but the produce coordinated movement. Instead of regular virus quickly becomes ‘left-right’ firing of the motor nerves to the flexor resistant to these muscles — the muscles that bend limbs — the two approaches. Viral uncoating sides of the spinal cord often fired together. is an entirely new avenue for The team discovered that interneurons normally work as inhibitors, holding back nerve impulses to researchers. “This technique the right flexor muscle to allow the left flexor muscle shows us what happens after to contract, and vice versa. Without these interneu- the virus first steps in the ron ‘metronomes,’ the two sides of the spinal cord door and allows us to identify were slightly out of phase, just like two pendulums the molecules involved,” swinging at different speeds. As in the pendulum said Young. “If we can example, occasionally the two sides of the spinal column fired at exactly the same time, before drifting Martyn Goulding manipulate these molecules apart again. we may be able to produce a This study is one of the first to demonstrate the simple but elegant new therapy for AIDS.” interneuron circuitry that coordinates movement in warm-blooded The treacherous chemical such as ourselves. “Until recently, the only known cells in the concierge may, after all, circuit were motor ,” said Goulding. “By identifying the hold the key to beating this that are used to produce particular types of interneurons in this simple neuronal circuit, we have been able to determine their role devastating . in important behaviours such as walking.” He said that the valuable new technique holds out hope for people with spinal cord injuries, offering the prospect of more effective treatments for these challenging disabilities.

8 A SALK TEAM HAS DEMONSTRATED THAT OUR PERCEPTION OF BRIGHTNESS NOT

ONLY DEPENDS ON THE OBJECT’S RELATIONSHIP TO OTHER OBJECTS IN ,

BUT ALSO IN TIME. In the Eye of the Beholder

Pilots, artists, film makers and magicians are only too aware of the simple truth that we see with our , not with our eyes. Visual illusions are a way of life for these people and, although we are mostly unaware of them, for all of us. Illusions may be hazardous, in the case of night flying for instance, or a source of entertainment as employed in special effects, but to Salk scientists like and his colleagues, illusions provide a valuable window into the mysterious world of information processing by the human brain. If our eyes were simply cameras and our brains the film, illusions could not exist. The reason they do exist is that the brain does more than just process points of light from the and build up a dot picture of our world. It is increasingly clear that, to create images, the human brain mixes information from the retina with a host of other inputs, using its previous experience to fill in gaps and ignore signals that remain constant. PMost of the time this works pretty well, but sometimes, as shown by Sejnowski’s team, the brain slips up and reveals its amazing inner workings. Illusions involving brightness — our perception of how much light an object is emitting — are common. A cream purse lying on a dark tablecloth will appear brighter than the same purse lying on a white tablecloth. However, the Salk team has now demonstrated that our perception of brightness not only depends on the object’s relationship to other objects in space, but also in time. The team discovered their novel illusion, published in the April 22 issue of Nature, during an experimental set up that involved exposing subjects to two flashes of light, one short and one long, and asking the subjects which appeared brighter. When the two flashes of light started at the same time, the brief flash (a mere 56 milliseconds long) looked dimmer than the longer flash (278 milliseconds long). However, when the brief flash ended at the same time as the long flash, the reverse was true: the shorter flash appeared brighter than the longer flash. Importantly, nothing had changed but the timing. The shorter flash appeared brighter to subjects because it happened at the end of the long flash. This “temporal context effect” was unexpected and had never been shown before. The study implies that at least two distinct types of neurons are involved in how we perceive brightness. One type of neuron ‘adapts’ Terry Sejnowski to a that stays constant over time and ceases firing, while the other fires continuously, however long the stimulus continues. “These two encodings are multiplexed to produce our perception of brightness,” Sejnowski said. A short pulse at the end of a long pulse appears brighter because it freshly triggers the ‘adapting neurons.’ It appears that in the business of perception, as in show business and aviation, timing is everything.

9 SALK IN THE NEWS

Ron Evans Fred H. Gage Joseph Noel

Some of Salk’s faculty Sydney (Australia) Morning The San Diego Union-Tribune Leslie Orgel was interviewed recognized by the media this Herald, the Straits Times of discussed a new experimental for the April issue of Current spring include Nobel Prize winner, , the Los Angeles surgical procedure for Alzheimer's Biology. In the article he traces his laureate and distinguished Times, Sun and patients involving genetically mod- career, from his undergraduate professor Sydney Brenner, who Chicago Tribune. ified cells. The article also days at Oxford University, to his was interviewed in the April issue cites earlier experiments current research, which involves of Discover magazine. Brenner Professor Ron Evans was completed by Professor Fred H. understanding how complex mol- discussed his views on genetics interviewed by Forbes magazine Gage and his colleagues, who ecules like RNA evolved on earth. and advances in biology over the in a June 21 article on “Silencing have done research on gene past 50 years, including his Syndrome X,” the mysterious therapy in the brains of mice. The unique architecture of the current projects involving puffer disorder marked by high choles- Salk Institute was covered in a fish, which are helping to unearth terol and blood , inflamed Professor Joseph Noel’s work lengthy story in the May 9 Boston nearly 1,000 new human genes. arteries and other symptoms that was mentioned in an article in the Globe, which explored the pose high risks for disease April issue of the trade journal Bio correlation between innovative Professor Terry Sejnowski and . Evans’ work on relay Space. Noel also elaborated on laboratory architecture and was asked to comment on a switches in cells called PPARs the appointment of the new CEO innovative science. The story study conducted by the National has increased understanding of for the biotech company Allylix, compared the designs of labora- Institute of Mental Health. The how , and sugar which is based in Louisville, tories nationwide, including two study focused on a suppressed are regulated; Kentucky, and conducts research designed by Louis I. Kahn: the gene that encouraged monkeys pharmaceutical companies are to produce natural products for Richards Medical Research to complete tasks more efficiently. now trying to develop drugs that the pharmaceutical, nutraceutical, Laboratory at the University of The news story appeared in control high levels of these agricultural and cosmetics Pennsylvania, and the Salk. media worldwide, including the significant risk factors for disease. industries. The products are in part based on the research of Noel’s laboratory and he is one of the company’s founders.

10 INSIDE SALK Awards & Honors

Professor Tony Hunter Professor was recently named one of has received the Kumho four winners of the 2004 Science International Award Prince of Asturias Award for in Molecular Biology Scientific and Technical and from the Research, Spain’s most Kumho Cultural Foundation prestigious award for in South Korea. The scientific achievement. award recognizes Chory’s Hunter and four other contributions to furthering researchers: Judah the understanding of how Folkman, , light and influence Robert Weinberg and Joan . She has Massagué, are being also made significant recognized for their advancements in using annual award to recognize significant contribution to to an outstanding scientist research in the fight against and chaired by H.R.H. accelerate biological who has made notable cancer. The awards will be Don Felipe de Borbón, the discovery. The Kumho contributions to the field presented in a ceremony Prince of Asturias and heir Group and Kumho Cultural of plant molecular biology this fall, in Oviedo, Spain, to the Spanish throne. Foundation established this and biotechnology.

Distinguished research Foundation Inc. ARCS is a Professor Marguerite Vogt professor Sydney Brenner national women’s volunteer is featured in “California’s was named the 2004 organization dedicated to Remarkable Women,” an Scientist of the Year by the helping the best and exhibit in the state’s History San Diego Chapter of the brightest U. S. graduate and Museum that salutes the Achievement Rewards for undergraduate students by accomplishments of California Research Scientists (ARCS) providing scholarships in women throughout history. natural sciences, medicine The 91-year-old working and . Each year, molecular biologist is featured to reinforce the ARCS alongside more than 200 Foundation’s interest in women ranging from to scientific excellence, the San athletes to artists. The exhibit Diego Chapter recognizes an was initiated by California’s for his or her First Lady, Maria Shriver. outstanding achievement in Vogt is widely known for her the scientific arena. Brenner pioneering work with Salk Nobel Prize winner on was honored for his major the polio virus and her early work on genes that cause cancer, or contributions to biology that . During her scientific tenure, which has spanned more have spanned a half century, than 75 years, Vogt has educated or helped train scores of including winning the Nobel scientists, young postdoctoral and graduate students. Prize for Medicine in 2002. This list includes five researchers who have won the Nobel Prize.

11 INSIDE SALK On Campus

High-Tech High |carrying out original research in Walk Salk’s Halls the field of . The program was sparked by a This summer, six students from contribution made by Howard the innovative High-Tech High Newman, a Salk Board of School joined forces with the Salk Trustees member, who with his Institute to enhance their science wife Maryam wanted to support and . The the Institute’s initiatives in the eight-week program concluded use of computers in biological successfully in late August. research. Students developed their The group will powers of by learning also work closely with the Crick- about the intricacies of working in Jacobs Center for Computational a laboratory. They also familiarized and Theoretical Biology, helping to themselves with the components unravel the complex structures of biomedical research-including and functions of the brain. The the business and technical support Center was established last year that ensures its sustenance. The through a donation made by Irwin High-Tech High and other San Diego students spend eight weeks in Salk program marked the beginning of and Joan Jacobs. laboratories, learning about science first-hand. a partnership with High-Tech High Salk’s Vice President of School that reflects the Salk’s worked in labs-one student was Manning Heads New Academic Affairs, Bruce intent to expand its programs to working in the legal department Bioinformatics Effort Stevenson, is confident this new educate the about and another in information group will make great contribu- scientific research. technology.” She concluded, Gerard Manning, an expert in tions. “By combining various The Institute’s scientists were “We want to show that just bioinformatics and computational fields in biology with advances the course instructors and students because you’re in biotechnology, biology, has joined the Salk in database management and conducted their own experiments you shouldn’t ignore the business Institute as a senior staff scientist computer technology, scientists in the laboratories and various or technology support aspects and director of the newly formed will be able to address more facilities. The recruits learned |of the field. We want to get bioinformatics program. complex issues, like understand- about technology transfer, the students to be life-long learners, The program evolved in ing the functional diversity of role of Human , how and we’re excited about this response to the challenges proteins produced in our cells.” to apply for a grant and other real-world opportunity.” posed by the deluge of data from Manning comes to the Salk from important aspects of a career in High Tech High was started the project and the biotechnology company science. The portrayal of science in 2000 by a consortium of high-throughput experimental Sugen, where he, collaborated in popular culture was examined technology firms in San Diego to . Manning’s discipline closely with Salk professor Tony as the young apprentices, help correct a gnawing problem has been increasingly helpful in Hunter on a project to map and together with faculty, watched in high school education: the harnessing this data to help computationally analyze all and discussed movies exploring shortage of students prepared guide experiments and provide human kinases — proteins similar disciplines. The program for jobs in engineering, science results in the search for new critical to the regulation of culminated with a presentation of and other high-technology fields ways to treat or prevent disease, cellular signaling pathways, and conclusions to colleagues, like telecommunications, as well as in answering funda- frequently implicated in cancer. parents and teachers. biotechnology, biomedical mental questions in human Before Sugen, he was a scientist Rebecca Haddock, High-Tech research and development, biology. His group will provide at Molecular Applications Group. High’s associate principal for computer software and - bioinformatics tools and support He received his Ph.D. in devel- Student Affairs, is excited about ics manufacturing. The school to researchers, and will work opmental genetics from the partnership with the Salk and has 400 students, who spend alongside other scientists to , and his supports the students’ wide much of their time engaged in apply advanced computational bachelor’s degree in exposure to all aspects of science major projects, internship and technologies to a variety of from University College Cork, related activity. “Our students self-paced studies. research problems, as well as Ireland.

12 Nathaniel LandauGeoffrey Boynton Sascha du Lac Richard Krauzlis DEVELOPMENT NEWS Academic Appointments Applauding our Donors Congratulations to four faculty “For who would set a limit to the mind of man? members whose achievements Who would dare assert that we know all there is in advancing basic biologic to be known?” GALILEO research were recognized at the No limits. The words of Galileo are a potent annual faculty meeting in April. reminder of what the Salk stands for. At the June 8 Geoffrey Boynton, Sascha du donor appreciation dinner, Board Trustee and Chair Lac and Richard Krauzlis were of the Advancement Committee Ted Cranston promoted to the rank of associate invoked the achievements of history’s heavy- professor and Nathaniel Landau weights-Galileo Galilei, Christopher Columbus and underwriting support through major gifts, and con- to professor. Leonardo da Vinci-and likened their explorations to tributing to the annual fund throughout the year. Geoffrey Boynton works Salk’s continuing pursuit to discover many of life’s This donor support helps sustain the continuing in the systems neurobiology intricacies including how the works, and innovative studies of distinguished scientists laboratory, using MRI to examine grow, children develop and the brain operates. such as Professor Ronald Evans, an authority on how the brain processes vision — The Salk has probed and challenged scientific cellular changes that occur in obesity. After the conducting studies on norms from its inception. This ongoing quest has evening’s meal, with the guests settled comfortably and — to deepen our resulted in many extraordinary accomplishments. into the wide foyer under the East building, understanding of how the brain During the evening, President Richard Murphy Professor Evans spoke about his study’s latest perceives objects and what announced a 14-month commemoration of Salk advances, focusing on hormones in our cells that happens to perception during dis- milestones that will begin on October 28 (which control the body’s metabolism. Professor Evans eased, normal and resting states. would have been Dr. ’s 90th birthday). has made some fascinating discoveries about the Sascha du Lac’s research Some of the upcoming milestones include the 50th family of these hormones. They bind with receptors is also focused on the neural anniversary of Dr. Salk’s development of the polio that help control sugar, fat, and salt levels mechanisms of learning. Her and the 40th anniversary of the Salk in the body. When activated, these receptors are laboratory studies the visual Institute. Dr. Murphy thanked all donors, saying that able to protect against obesity. However, if the system as a way to observe none of these milestones would have been possible genes that programmed the are mutated, how nerve cells interact to without their generosity. the receptor is not as active and obesity occurs. create the phenomenon of Approximately 40 per cent of the Salk’s generated The research comes at a time of acute concern learning and . revenue comes from private contributions. Last year, over obesity in the United States, where the disease Richard Krauzlis, another more than $30 million was raised through philanthropy. is now considered an epidemic. About 65 per cent member of the systems neuro- A special group of benefactors, the President’s Club of Americans are considered overweight, and some biology laboratory, specializes in (gifts of $1,000 or more to the Salk’s annual fund), states report obesity rates of more than 20 per cent how eye movements are co-ordi- donated a record $1.9 million toward the Salk’s of their . Obesity is strongly linked to nated by the brain, and in isolating priorities of greatest need. Dr. Murphy recognized leading causes of death such as high blood pressure, the nerve cell pathways that the laudable contributions of , foundations heart disease and diabetes. Professor Evans’ control those movements. and donor groups. These contributions, designated and passion were tangible, as he shared the Nathaniel Landau works in to the endowment fund, the annual fund and new developments of his research and updated the the infectious disease laboratory and existing research programs are invaluable as audience on some of the Salk’s other endeavors. and his research is focused on the they assist both current and newly-recruited faculty Ultimately, it was a night of donor appreciation AIDS virus. Recently he has made with ongoing research support. — the first of an annual affair of thanks — and by discoveries that show — on a Donors who attended the evening, sponsored by evening’s end, the relationship between scientist molecular level — why the virus Northern Trust Bank of California, were recognized and donor was once again underlined. The Salk specifically attacks humans and is in one or more giving categories: achieving a level relies on, and is grateful for, its donors and philan- not infectious to other animals. of lifetime giving support, participating in Partners in thropists. It is a powerful partnership based on a Research (which recognizes gifts through estates shared vision: to pursue breakthroughs and and bequests), supporting research priorities and continue surging forward without limits.

13 INSIDE SALK Outreach

Royalty Headline Fay Joins Institute Symphony at Salk Board of Trustees

The Romeros, the Del Mar David Fay, the executive based family of guitar virtuosos, director of the United States Golf were guest performers at the ninth Association (USGA), has been annual Symphony at Salk, Aug. selected to the Salk Institute’s 21, 2004. A veritable institution in Board of Trustees. the world of classical music, the Romeros are touted as the “Royal Family of the Guitar.” They accompanied the San Diego Symphony on two of the evening’s musical works, and both interpre- tations were dynamic. The concert’s program featured five musical pieces, including together since 1957, when dynasty continues to thrive as Mozart’s Impresario Overture, patriarch Celedonio Romero a quartet with the inclusion of Vivaldi’s Concerto in B Minor, immigrated with his family to the grandson Celino, son of Celin. Rimsky-Korsakov’s Capriccio United States from Spain. Sons Symphony at Salk has Espagnol, Massenet’s Le Cid Celin, Pepe and Angel each become one of San Diego’s and Rodrigo’s Concerto Andaluz. made their debut as members of premier cultural events. Widely known for their the quartet while they were in Proceeds from the evening influence on modern classical their teens. Although Celedonio benefit biological research David Fay guitar, members of the Romero passed away in San Diego in impacting the study of human Having played a role in the family have been performing 1996, the legendary family health and disease. USGA, golf’s national govern- ing body since 1978, Fay has served as its executive director Walk America since 1989. He’s known as an articulate leader whose insights have helped the organization resolve complex and intricate questions surrounding this competitive sport. His duties include coordinating a series of major golf tournaments, includ- ing the U.S. Open. Fay is a native of New York; he and his wife, Joan, live in Summit, New Jersey.

About 30 walkers from the Salk Institute contributed more than $15,000 to the March of Dimes “WalkAmerica” fundraiser to support research on birth defects. For total contributions, Tony Basurto led the Salk team, by raising more than $7,400.

14 F ROM THE P RESIDENT

Francis Crick was a remarkable human being. We will research discipline. Francis argued that, in the right hands, always remember him, and his accomplishments will impact computers could be used to convert vast amounts of information humanity forever. about the brain into models of brain that could be When Francis and Jim Watson solved the structure of DNA tested in our laboratories. And so began the thinking behind in 1953, they revealed for the first time what a gene might be, the Crick-Jacobs Center for Computational and Theoretical how genes might mutate, and how genes could be copied from Biology, one of Francis’ many legacies to the Institute. one to the next. That work began a revolution in Because of his cancer, Francis knew he wouldn’t be alive to molecular biology in which Francis and others figured out how see the Center completed. Nonetheless, he participated in DNA leads to the production of RNA and subsequently to numerous debates about the kind of research the Center should protein — the so-called central dogma of biology. This work pursue. One memorable debate was with Nobel laureate ensured Francis’s everlasting reputation as one of the true Sydney Brenner. Francis argued that the Center should pursue giants of biology. studies aimed at analyzing the neural networks that mediate In the late 1950s, Jonas Salk chose Francis as one of the Salk , while Sydney felt it should pursue the study of key Institute’s original nonresident fellows to help him shape the molecules within single cells. Francis told Sydney, “Your approach Institute and set its high standard of scientific quality. That began will never work,” to which Sydney replied, “Francis, you’ve a 45-year relationship with the Institute that became permanent been saying that to me for 30 years!” Clearly, these two giants in 1976 when Francis and moved to . of biology, the best of friends, were comfortable disagreeing It was then that Francis turned to studying the brain and the with one other. Nonetheless, within two weeks, each was biological basis of consciousness, work he pursued for almost defending the position of the other. And as a result, the Crick- 30 years. Francis’ interest was pivotal in convincing the Institute Jacobs Center will pursue computational biology from both to expand its expertise in , which has become one perspectives, analyzing molecules as well as neural networks. of the Institute’s academic strengths. Even in his last moments, Francis was thinking about the Despite his fame, Francis was always accessible to the new center. Several months ago he wrote a position paper sug- Institute and to its people; he agreed to serve as president and gesting that the Center focus its work on the claustrum, a part was always willing to be, in his words, “trotted out” to meet of the brain amenable to both molecular and cellular analysis. visitors. “I’m happy to do whatever is good for the Institute,” Because the claustrum is not well understood, he set out to he would say. write a review paper on it, and he was working on the document Francis was beloved by his Salk colleagues. He was a pure literally hours before his death. Francis wrote that paper for us scientist with high standards. He was brilliant, hard working, and for our research, not for himself. Also, the work he started creative, fun loving, articulate, and focused on his work. on the brain will be a key project in the center. He welcomed new ideas and the give and take of scientific We are privileged to have known Francis. We can describe debates, and he dealt respectfully with everyone, even those him, but we can never fully capture him. He was beloved, and with whom he disagreed. he gave an enormous amount to science, to humanity, and to the These strengths converged during the last three years, when Salk Institute. We will miss him deeply. he became convinced that computational biology, validated experimentally, would be important to the future of neuroscience. How he advocated for this idea illustrates his style and commitment. Richard Murphy Francis and Terry Sejnowski suggested at a faculty retreat Crick Memorial Service that the Institute develop computational biology as a new August 3, 2004 15 INSIDE SALK

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OCTOBER 15 Nobel Lecture Speaker: Robert Cone, Vollum Institute, Oregon Health and Science University Salk Institute Paintings, drawings and other artwork by members of the San Diego biotechnology community (including Salk artists) OCTOBER 20–22 were on display earlier this spring at the Institute's first Art Third International Conference on Show, part of the Society of Research Fellows' SalkFest. Development and Learning Salk Institute

OCTOBER 23–26 Salk Institute

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