sign in sign up
<<
Home , Hugh Pelham, John Sulston, Maurice Wilkins

B UILDING ON THE DNA REVOLUTION

NEWS ECTION

S A Hothouse of

Green thumbs at a British lab helped cultivate the achievements of the won their prizes in 1962. Sanger claimed much-feted Watson and Crick and a slew of other luminaries. Can its one in 1958 and a second in 1980; Klug gar- PECIAL success be duplicated, or even sustained? nered the prize in 1982; Milstein and his S student, Georges Köhler, in 1984; and Shortly after learned that often budgets. The fiefdoms that plague uni- Walker in 1997. The most recent winners he and two former labmates had won the versity departments are absent. “All these are Brenner, Sulston, and Horvitz. 2002 , he received this e-mail elements add up to a strong formula for do- Can such stellar results continue? Big labs from a Chinese researcher: “I wish also to ing good science,” says LMB molecular bi- that churn out lots of data already threaten the win a Nobel Prize. Please tell me how to do ologist Matthew Freeman. lab’s preeminence. And the lab’s own expo- it.” The answer, Brenner announced at the Although Watson and Crick are perhaps nential growth threatens to dilute the intense award ceremony last December, is simple. the most famous, the list of 750 or so alum- interactions that have characterized the place. “First you must choose the right place … ni reads like a Fortune 500 of biology. Sci- But LMB’s current director, structural biolo- with generous sponsors to support you.” In entists there essentially created the field of gist Richard Henderson, feels confident it will addition, he urged, “choose excellent col- structural biology. Over the past 5 decades, still provide fertile soil. As Perutz once wrote, leagues.” For Brenner and “Well-run laboratories can a dozen other Nobel laure- foster [creativity in science]. ates, the right place was But discoveries cannot be Cambridge, U.K., and the planned; they pop up, like right people were their Puck, in unexpected corners.” peers at one of the world’s first laboratories devoted Roots in to molecular biology. LMB had it origins in the What started about 55 illustrious 19th century years ago as a pilot pro- , part of gram in at the the . University of Cambridge Cavendish scientists excelled eventually became the Lab- in physics. J. J. Thomson oratory of Molecular Biol- discovered the there, ogy (LMB), now home to and Ernest Rutherford about 300 researchers and smashed the atom. alma mater to hundreds of In 1915, Bragg, working molecular biology’s most with his father at the influential. Among the Cavendish, became the dozen Nobelists the lab has youngest person to win a spawned are Nobel Prize. The father-son and , who co- Prized moment. Francis Crick, , (Nobel laureate in team’s success set the stage discovered the structure of literature), James Watson, , and (left to right) all left Stock- for a new direction for the DNA there 50 years ago. holm with Nobel Prizes in hand. lab: biophysics. They had Watson has called LMB figured out how to use x-ray “the most productive center for biology in the they invented key technologies such as crystallography to probe the inner nature of .” DNA sequencing. And they have helped to crystals. In so doing, they created a window The lab’s recipe for success dates back to elucidate some of the most fundamental into the molecular structure of biological its early days, when leaders such as Max questions in biology: how carry the materials as well. Perutz had the luck and insight to pick the instructions for , for instance, and After World War II, Bragg was finally best and the brightest (among them some how a single cell develops into an animal. able to sneak biology through the lab’s back quite unorthodox choices) and secure them One great mind begat another, as the lin- door. Knowing that the Medical Research almost unlimited support, both financial and eage of Nobel laureates makes clear (see Council (MRC)—even then the United King- collegial. In the budding field of molecular graphic). Prize winner William Lawrence dom’s biggest research supporter—was keen biology, “his operation became known as the Bragg, director of the physics lab where on melding physics and biology, he con- place to be,” says , who shared LMB was conceived, brought in Max vinced it to create the MRC Unit for Re- last year’s Nobel Prize in or medi- Perutz, who in turn recruited John Kendrew search on the Molecular Structure of Biologi- cine with Brenner and H. Robert Horvitz. and Crick. Crick attracted Watson and cal Systems in 1947. Its two members were The lab welcomed researchers who wan- Brenner. Brenner’s protégés included Perutz, a chemist who wanted to try x-ray dered across disciplines and then encouraged Sulston and Horvitz. crystallography on proteins, and his student, them to interact closely. Even today, when in- When then-director Perutz moved the lab physical chemist Kendrew. For the next 10 terdisciplinary work has become de rigueur, to its own building in 1962, Frederick years, Perutz and Kendrew raced to identify LMB stands out for its cross-fertilization and Sanger and Aaron Klug came on board. the molecular makeup of two key blood pro- community spirit. Lab groups there remain Sanger brought in César Milstein and John teins, myoglobin and hemoglobin. They de-

small and flexible, sharing equipment and Walker. Perutz, Kendrew, Crick, and Watson vised better ways of doing x-ray crystallogra- CREDIT: AP PHOTO

278 11 APRIL 2003 VOL 300 SCIENCE www.sciencemag.org B UILDING ON THE DNA REVOLUTION S PECIAL Crick continued debating W. Cavendish Lab possible structures during al- most daily lunches, walks,

MRC Unit for Research on the Molecular teas, dinners, and even out- S Structure of Biological Systems ings on the Cam River. ECTION Max Perutz 1947 Only after of 1939–2002 the California Institute of Technology in Pasadena, seen as the lab’s fiercest rival, came up with an incorrect view of John Kendrew DNA did they get the go- Francis Crick 1946–1974 ahead to continue their work. 1950–1977 With the help of one of Frank- lin’s prize x-ray diffraction im- ages, they finally figured out how the components of DNA James Watson Sydney Brenner fit together. 1951–1958 1957–1992 On 28 February 1953, they began to build a paper- metal model demonstrating Laboratory of the pairing of the bases in Fred Sanger Molecular Biology this double helix. As the story Aaron Klug John Sulston Robert Horvitz 1962–1983 goes, at lunch that day in the Eagle Pub, Crick couldn’t 1962– 1969–1992 1974–1978 contain his excitement, an- nouncing, “We’ve found the John Walker César Milstein secret of life.” Nobel lineage. Many scientists at the Laboratory of But beyond the Eagle, Molecular Biology (orange) and its predecessor 1962–1983 1963–1995 their colleagues and the world (green), have received honors at Stockholm and, over didn’t take much notice. At the decades, attracted new talent destined to win prizes. (Dates reflect years spent at the lab.) Georges Köhler the time, “there was much 1974–1976 more excitement about the Slinky wire-frame spring walking down the stairs,” re- phy and faster ways of analyzing the reams of sessed with determining DNA’s structure. calls Michael Fuller, then a lab assistant and data generated—harnessing the mathematics They assumed that the structure would re- now the lab’s special projects coordinator. department’s primitive electronic digital com- veal how genetic information was passed Unraveling the mathematics of how this new puter for their calculations. from one generation to the next. Their first toy worked “seemed to excite [lab scientists] Perutz recruited allies from diverse back- attempts were a flop, however, and Perutz a lot more than the DNA model itself.” grounds: Crick was a physicist, Watson a zo- instructed the pair to leave DNA to Rosalind It took another decade for Crick and ologist, and Brenner a physician. Space was Franklin and Maurice Wilkins, who were others to work out some of the basic princi- tight. Crick and Watson—and, later, Crick using x-ray crystal- ples underlying and Brenner—sat back to back in one office. lography to study function, informa- “By 1956,” Perutz wrote, “the Unit had this molecule at tion that gradually grown so large, I spent my time scrounging King’s College in helped confirm his for a little bench space in a butterfly museum London. Ostensibly boast. Watson left here or the abandoned cyclotron room working on other the lab for Harvard there.” Together—closely—they began to projects, Watson and in 1958, where he turn biology on its ear. sought out the se- crets of a different Life’s secret nucleic acid, RNA. Watson and Crick shared a Brenner became common passion: to figure Crick’s closest col- out what genes were made of. laborator, working Crick, like many of his con- with bacterial virus- temporaries, thought genes es, or phages, to ver- were proteins; Watson be- ify Crick’s ideas. To- lieved they consisted of DNA. gether they helped Soon after Watson arrived crack the triplet na- in Cambridge in 1951, the Crowded spaces. When Max Perutz and ture of the DNA brash young American—he his budding molecular outgrew code and track the was 23 at the time—convinced their space in the Cavendish lab (right), path of information Crick that DNA was the stuff they moved into a hut behind this fa- from gene to pro-

CREDITS: OF MOLECULAR BIOLOGY; (BOTTOM, RIGHT) MRC LABORATORY LABORATORY, COMPUTER TO UNIVERSITY OF CAMBRIDGE LEFT of genes, and they became ob- mous physics center (above). tein. Molecular biol-

www.sciencemag.org SCIENCE VOL 300 11 APRIL 2003 279 B UILDING ON THE DNA REVOLUTION

ogy was gathering steam, and Perutz’s crew and Crick but also Perutz and Kendrew that was stoking its engines. they had won Nobel Prizes, the latter pair

ECTION for . The reputation of the lab S A very good year soared. By the late 1960s, American post- 1962 was a vintage year for LMB. By then, docs “were the engines that powered the Kendrew and Perutz had gotten their first lab,” says John White, one of those post- real look at the structures of myoglobin and docs, who is now at the University of Wis- PECIAL hemoglobin. Kendrew’s student Hugh Hux- consin, Madison. White calls the group “Jim S ley of University College London had begun Watson wannabees.” They were a stark con- his groundbreaking work demonstrating that trast to their British colleagues, who liked to sliding filaments powered muscle contrac- solve problems at tea instead of at the lab tion. And Watson and Crick’s model had in- bench. The synergy worked well. spired a slew of work on the gene-to- One transatlantic transplant from the Salk transition and the replication of DNA. Institute for Biological Studies in California That was also the year that Perutz’s crew was actually a Brit: Sulston. He was one of left the Cavendish and set up their own shop: the first dozens of young scientists who the official Laborato- would eventually come to ry of Molecular Bi- work with Brenner on his ology. They moved fondly named “worm proj- into a new six-story ect.” In 1974, Horvitz building on the out- made the trip from Har- Multitalented. While working on virus struc- skirts of town. Gone vard for the same reason. tures (modeled in photo), Aaron Klug devel- were the buttoned-up What lured them was oped new crystallographic methods. lab coats, required Brenner’s goal of using the attire at the Caven- nematode to help figure tron micrographs to work out three- dish. “Things be- out how genes affect devel- dimensional structures, earned Klug a No- came much freer, opment. “Most people bel in 1982. But he, too, was drawn to the lighter,” says Fuller. thought it was rather a unfinished business of RNA and DNA. Per Perutz’s order, joke,” Sulston recalls. Klug and his colleagues eventually worked there were no doors, True to the lab’s tradi- out the structures of transfer RNA, which no locked cabinets— tion, Sulston wasn’t given shuttles amino acids to where they can be no secrets among much space, not even a added to the nascent protein. In addition, scientists. desk. As far as Brenner Klug determined the structure of that Sanger, whose was concerned, “desks en- act as enzymes to cut up yet other RNA; he work at the Universi- couraged time-wasting,” also helped show how DNA is packaged as ty of Cambridge on Breaking through. John Kendrew stands says Sulston. Perched at a a chromosome (see p. 282). insulin had earned over a model of the structure of myo- lab bench, Sulston began him a Nobel in 1958, globin, the first protein structure to be the painstaking task of Quiet tenacity MPERIAL COLLEGE PRESS, LONDON (2002); OF MOLECULAR BIOLOGY; OF MOLECULAR BIOLOGY MRC LABORATORY MRC LABORATORY

helped open the solved and the beginning of a new era in watching the cells of the Sanger and some of his protégés were as ,I doors on the new lab. protein science. nematode embryo multiply quiet and unassuming as Watson, Brenner, Klug came, too, at- under a microscope and and Crick were outspoken. Sanger “was tracted to LMB’s shiny new space and col- then drawing what he saw. “When [Horvitz] not known to be spouting ideas at a 100 leagues interested in the structure and func- came and found me looking through the miles per hour like Francis Crick or Sid- tion of proteins. microscope, he didn’t think it was very sci- ney Brenner,” says Alan Coulson, a nema- Champagne corks flew that fall when entific,” Sulston recalls. Before long, “he tode who began his career as a telegrams arrived telling not just Watson started doing it with me.” technician for Sanger in the 1960s. Like Together, they tracked Perutz and Kendrew before him, however, how individual cells divide Sanger had tenacity. He spent day after and specialize to make the day for years trying to devise a way to se- adult worm. They noticed that quence DNA. Sanger eventually figured cells that had fulfilled their out a relatively efficient way to label the functions sometimes died, a different bases and their order, phenomenon they dubbed winning his second Nobel in 1980. ANDID SCIENCE II: BIOMEDICAL SCIENTISTS WITH FAMOUS CONVERSATIONS . By For several soon-to-be laureates, includ- C working out the of ing Walker and Milstein, Sanger was just the this process, Sulston and “right” person. At first, to check the accuracy Horvitz opened up a new of the sequencing, Walker determined the field in , earning sequence of those proteins encod- the 2002 Nobel. ed by the genes that Sanger was deciphering. One floor away, Klug was They began with the DNA of bacterial virus- chasing after the structure of es but later moved on to the mitochondria, Dynamic duo. César Milstein (left) and his student Georges viruses. The new imaging where Walker found the enzyme that became Köhler developed a method for making monoclonal antibodies, method he and his colleagues the focus of his career, ATP synthase.

now used all over the world. developed, which used elec- In keeping with the bare-bones bureauc- HARGITTAI, © ISTVAN CREDITS: BOTTOM) TO (TOP

280 11 APRIL 2003 VOL 300 SCIENCE www.sciencemag.org B UILDING ON THE DNA REVOLUTION S PECIAL racy of the place, Walker never needed to Right place, right people write a proposal about this new research di- A British newspaper once rection. At the time, MRC relied on the lab described LMB as a Nobel

chiefs to decide how to spend the money it factory. But Klug takes issue S allotted to the lab; they, in turn, trusted their with that characterization: ECTION colleagues to come up with good projects. “It’s more like a plantation, Thus, Sanger merely asked a few questions where you plant the seed.” before saying, “ ‘Why don’t you get on with The fertilizer came in many it?’ ” Walker recalls. forms—money, equipment, At the outset, the project did not garner collegiality, to name a few. much support. “Quite a number said I was a For about a decade follow- fool and that I was going to wreck my ca- ing World War II, MRC’s sci- reer,” says Walker. Instead, he shared the ence budget grew about 17% 1997 Nobel for determining the structure of annually. “Anything could be ATP synthase. He then went on to figure out done. There were no limits,” how this key membrane protein works. says Hugh Pelham, an LMB cell biologist. And to get those funds, all the researchers had to do was ask. After 30 years New generation. Laboratory of Molecular Biology director with MRC, Walker boasts, “To Richard Henderson (center) hopes his young researchers will this day, I have only ever writ- follow in their forerunners’ footsteps. ten one grant.” The support has been consistent, although modest at ease. Klug still maintains a lab, although he’s times; there was no money for wood-paneled officially retired. Image not offices or elegant oak desks, for example. The tight space only intensified the ca- Money flowed even without clear “re- maraderie. Rubin recalls being assigned the available for sults.” Perutz, for instance, spent decades lab bench between the pH meter and the online use. before his hemoglobin work panned out. balance—about a meter wide. Individual of- Similarly, the worm researchers were far fices, even for the top scientists, were out of from prolific during the project’s first 10 the question until more space was recently years. Even in today’s “publish or perish” added. “I think [crowding] was a good climate, that attitude still prevails: “It’s not thing,” says Brenner. Similarly, the lack of whether you have published a lot of papers, alternative dining options—then and now— it’s more whether you have done some fun- meant that everyone ate together, and con- damental work,” says LMB bioinformaticist versations and critiques were free-flowing. Sarah Teichmann. Ultimately, it was the people who made When LMB researchers needed a new the place. “The LMB was able to concen- Well covered. Nematode biology became so pop- instrument, Perutz made sure technicians trate in one place very exceptional scien- ular that LMB researchers were each assigned to and engineers were there to build it, a model tists,” says Pollard. Today, some of that tal- study just a small part of the organism. he learned at the Cavendish. “We were inter- ent would probably not make the first cut ested in topics that stretched the tech- for a university position, given the apparent Milstein also sought out Sanger’s leader- niques,” says Walker, explaining how the lab discrepancy between the scientist’s experi-

20 (1976); OF MOLECULAR BIOLOGY MRC LABORATORY ship, collaborating with him while a Cam- developed technologies such as x-ray crys- ence and the job description. Sulston, for in- , 4 bridge Ph.D. student. Later, when political tallography, DNA sequencing, and confocal stance, was a chemist working on the ori- unrest forced him to leave his native Ar- microscopes. gins of life when he came to study the gentina, he joined Sanger at LMB. Even That left researchers free to concentrate worm. “Max [Perutz] had this uncanny abil- more unassuming than his mentor, he didn’t on their work. “Your time was almost entire- ity to see something special, not necessarily strike his colleagues as Nobel material. ly devoted to research,” says LMB researcher K. J. Patel likens Milstein Thomas Pollard, a cell biolo- RADICAL SCIENCE JOURNAL to the seemingly bumbling—yet effective— gist at Yale University and TV detective Columbo. Sometimes Milstein LMB alum. Even senior sci- could be seen out in a nearby field pacing, entists worked at the tape recorder in hand. He’d walk through the bench—a tradition that con- halls distracted and oblivious. “But he was tinues today and goes far to really quite a deep thinker,” says Klug. explain the lab’s vitality, says When Milstein joined LMB, Sanger sug- Gerald Rubin of the Howard gested that he focus on antibodies instead of Hughes Medical Institute in enzymes. It turned out to be sage advice. Chevy Chase, Maryland, With Köhler, Milstein eventually developed who did his graduate work at a way to make unlimited amounts of mono- LMB. Perutz spent 90% of clonal antibodies, a uniform set of proteins his working time at the that all home in on the same target, paving bench until his death last the way for a Nobel Prize in physiology or year, focusing most recently Creative energy. Milstein, Klug, Walker, and Sanger each pushed

CREDITS: (TOP TO BOTTOM) MRC LABORATORY OF MOLECULAR BIOLOGY; MRC LABORATORY CREDITS: BOTTOM) TO (TOP in 1984. on neurodegenerative dis- molecular biology in a new direction with their achievements.

www.sciencemag.org SCIENCE VOL 300 11 APRIL 2003 281 B UILDING ON THE DNA REVOLUTION

academic ability, and to home in on that,” considerations are al- says Fuller. “There’s a history of people so gaining promi-

ECTION with no qualifications who are now senior.” nence. For instance,

S 25 years ago MRC Past as prologue didn’t bother to patent At the end of April, hundreds of former LMB Milstein’s technique researchers will converge on Cambridge to for making monoclon-

PECIAL celebrate the 50th anniversary of Watson and al antibodies, now a S Crick’s DNA paper. They include numerous fundamental tool in Nobel laureates whose prizewinning research many industries. The came after their time at LMB, as well as same was true of prominent department heads, institute direc- Sanger’s sequencing tors, and journal editors. There is no doubt in technology. Today, their minds that LMB is unique. “I don’t patenting is encour- think if you had put the same people in a U.S. aged, says Henderson, institution that they would have done as and several compa- well,” says Rubin. Biological incubator. Hundreds of budding molecular biologists got nies, such as Celltech, But can it continue to be so special? their start at the Laboratory of Molecular Biology, opened in 1962. are associated with Thirty years ago, “the field was much the lab. smaller. It was the place for U.S. postdocs to To keep pace with the burgeoning sci- Klug and Henderson suspect that the go, and the best went,” Rubin explains. entists and staff—about 400, more than place is good for at least a couple of more “Now there are many good places.” Al- twice the number 30 years ago—the build- Nobels. Even today, with universities, though funds still flow relatively freely, pa- ing has doubled in size every decade since medical foundations, and other organiza- perwork, regulations, and other constraints 1962. A new building is in the works. Says tions working to create hotbeds of scien- have crept in, Henderson notes. And while Klug, “I am worried that we will get too tific creativity, LMB still earns strong ku- he and his colleagues pride themselves on big and lose the ethos on which the lab has dos. Says Yale’s Joan Steitz: “There have their small labs, which range in size from 1 been built.” been very good research institutions that to 10 people, they worry that they will fall LMB now relies on a glossy annual re- have tried to capture the flavor and spirit, behind. “There’s so much more you can do port rather than word of mouth to publi- but they haven’t got it.”

with more manpower,” says Pelham. cize its accomplishments. Commercial –ELIZABETH PENNISI OF MOLECULAR BIOLOGY;AND SOCIETY MRC LABORATORY SCIENCE CREDITS: BOTTOM) TO (TOP LIBRARY PHOTO

NEWS DNA’s Cast of Thousands

Watson and Crick’s discovery revealed much, suggested more, but left many details unanswered. Ever since, researchers have been discovering the proteins that unlock DNA and the genetic code

When James Watson and Francis Crick with proteins. But rebuilt today, Watson and elucidated the structure of DNA, they dis- Crick’s bare-bones model would be draped covered an elegantly simple molecule. with proteins that kink and curl, repair, and With cardboard cutouts, metal, and wire, otherwise animate DNA. they showed how DNA’s two chains wound around each other, with the paired bases DNA ascendant inside, one full rotation every 10 bases. The age of DNA began well before Crick Their model immediately suggested how and Watson were born. In the 1860s, Image not DNA copied itself and enabled genetic Friedrich Miescher, a Swiss working in information to flow from one generation Tübingen, Germany, isolated a strange, available for to the next. They boasted that they had phosphorus-rich material from the cell nu- online use. found the “secret of life”—essentially, bi- cleus. Within decades, it was clear that this ology’s master molecule that controlled peculiar substance—later identified as nu- the fate of the cell and, consequently, of cleic acids—was fundamental to the cell’s the organism. chemistry. Somehow. Fifty years of research since then has Throughout the early part of the 20th shown that, despite its precision design, this century, biochemists argued about DNA’s molecule can’t dance without a team of cho- role. Some postulated that it was the stuff of reographers. Like a puppet, DNA comes genes; others insisted that proteins carried alive only when numerous proteins pull its “strings.” At the time of their discovery, Naked DNA. Watson and Crick’s first model of Watson and Crick had only the haziest of DNA didn’t begin to reveal the complex set of ideas about how this double helix interacted proteins the molecule needs to do its job.

282 11 APRIL 2003 VOL 300 SCIENCE www.sciencemag.org