JHJ-backhalf.finalPage 72 10/10/06 1:15 PM Page 72 JOHN HARVARD’S JOURNAL Bigger Biology of the “core” members whose labs are genes that may reveal how and why the based primarily at the Broad, leads the disease occurs and may also give scientists When a first draft of the human ge- medical and population genetics program, a guide for developing treatments. nome was sequenced in 2001, biology sud- which studies such genetic di≠erences. Psychiatric diseases, very few of which denly became much bigger. The genome— One of its key goals is to understand the have any known cause or mechanism, are three billion DNA “letters” long— genetic basis of complex diseases like dia- perfect candidates for genetic analysis. contains an incredible amount of data. But betes and heart disease. Altshuler, who Edward Scolnick, senior lecturer on ge- until recently, medical biology had been trained as a diabetes clinician, became netics, the former president of Merck Re- concerned with drilling down to the frustrated by the lack of knowledge about search Laboratories, has changed direc- finest details of how the body works. the disease’s origins. “So many of my pa- tion in his career to address this problem. With genomics, on the other hand, it is tients had parents and siblings and chil- Now, as director of the Broad’s psychi- now possible to get a wide-angle view of dren with type II diabetes, and we could- atric disease initiative, his goal is to human biology. “Fifteen years ago, we n’t explain it at all,” he says. “And it change the way such diseases are treated. thought of the human genome as this seemed to me amazing that in this era of The e≠ort focuses on schizophrenia and infinite, unbounded territory,” says Eric genetic information, we didn’t know what bipolar disorder, which seem the most Lander, a faculty member at MIT who is was causing it.” likely to be heritable. Scolnick says that also professor of systems biology at Har- Standard biology has been very good at knowledge of the biological basis of psy- vard Medical School and head of the explaining the so-called Mendelian ge- chiatric diseases is woefully lacking: Broad Institute at Harvard and MIT. “The netic diseases, in which inheriting a mu- “There is no chemical test or physical test Human Genome Project rendered it finite, tated gene leads something in the body to or biological test that allows you to make just big. So now you can ask questions go awry. Complex diseases, however, seem a diagnosis of these diseases.” The best like, ‘What are all the genes that confer to be a messy combination of genes and way to get at the biology is through ge- risk for diabetes? What are all the muta- environment. No one gene “causes” a dis- netic studies, he says. “To really under- tions that might give rise to cancer? What ease like diabetes, but several genes might stand function you have to understand are all the genes that are essential to make put a person at higher risk for developing how the genes a≠ect that function.” a cell infectable by HIV?’” it in the presence of certain behaviors or Genetic studies on this scale have be- The Broad (the name rhymes with road) environmental factors. To tease out risk come feasible only in the past year, and the is a joint venture among Harvard, MIT, genes, researchers collect DNA samples first papers are just being published. It is the Whitehead Institute for Biomedical and clinical information from large groups likely that genomics will quickly shed Research (also located in Cambridge), and of people with and without the disease light on some diseases, while others may the Harvard-a∞liated hospitals that aims and look for statistical di≠erences in their remain a muddle of data. But the Broad to answer some of those big-picture leaders insist that, whatever the questions. “We have a really clear The Broad Institute’s outcome, science will benefit from a hundreds of staff mission,” Lander says. “We want to scientists and wide-angle view of the relationship fulfill the power of genomics for technicians work on between genes and disease. medicine.” Announced in 2003 and genomics problems An ambitious application of that o∞cially launched in 2004, the best addressed by principle is the cancer genomics research teams. Broad focuses on interpreting the group, led by Broad core member information in the genome in a way Todd Golub, associate professor of that can be applied to human pediatrics. The group uses genomics health. It also serves as a kind of ser- to study and classify di≠erent types vice center for scientists at the two of cancers. This is not as simple as it schools who want to apply the tools sounds: part of what defines a can- of genomics and other large-scale cer cell is a genome that is irregular technologies to their own work. and unstable. Not all cancer re- Making the genome useful is a searchers believe it will be easy to much bigger task than sequencing make sense of erratic cancer it. The Human Genome Project pro- genomes, but Golub says that it’s duced a single DNA sequence, but important to try. “Most cancer re- in reality there is no “one” human search involves finding a gene in- genome. For genomics to be useful volved in some aspect of cancer and to medicine, it must tackle the studying it in great depth,” he says. di≠erences among people that lead Entire careers are spent cataloguing one person to get a disease and an- every aspect of a gene’s function. “If other to avoid it. David Altshuler, that’s the only approach you take, associate professor of genetics, one there’s the possibility you don’t get 72 November - December 2006 Photograph by Justin A. Knight JHJ-backhalf.final 10/10/06 1:15 PM Page 75 Page 75 the big picture. You see only the bits you and MIT access to its technical capabilities, lege of Cornell University—to further know about; there may be vast pieces of which are organized into “platforms”: facil- focus genomic technology on understand- information that remain.” ities specializing in techniques like genome ing and treating cancer.) sequencing, genetic analysis, and chemical The Broad currently has an operating By bringing together an impressive biology. Instead of relying solely on its budget of about $125 million, with most of array of technologies under one roof, the graduate students and postdocs for techni- its funding coming from the National In- Broad has created a new kind of resource cal skills, the Broad employs a dedicated stitutes of Health (NIH) and other federal for Boston’s biomedical community. Lan- sta≠ of research scientists to run its plat- sources. It has won major federal grants, der likens it to NASA’s Jet Propulsion Lab- forms. These scientists, who have no acade- including $14 million to identify common oratory in California, based at the Califor- mic duties, are wholly involved in collabo- genetic variations called single-nucleotide nia Institute of Technology. A grad student rative research with other researchers. polymorphisms (SNPs); $18 million to at Caltech may come up with an idea for Some scientists are concerned that cen- study heart, lung, blood, and sleep disor- sending something to Mars, but when it ters like the Broad promote a “bigger is ders; and $12.6 million to study cancer ge- comes time to build the rocket, she relies better” attitude that values massive data- nomics. About 5 percent of its budget on the expertise of the laboratory. “We sets and expensive techniques over de- haven’t got a tradition of that in biology,” tailed investigation. Although the Broad’s Lander says. “That’s what the Broad is. We studies are conducted on a scale beyond are trying to put jet rockets under smart what a single lab can accomplish, its lead- young faculty, postdocs, and grad stu- ers stress that they do not push “big sci- dents.” ence” over traditional investigator-led re- Until now, biology simply hasn’t had search. David Altshuler says that, “For many tools equivalent to jet rockets. But most kinds of research, the form that fol- in the past several years, the technology lows the function is probably what it’s al- available to biologists has become more ways been: the individual lab working powerful—and expensive. Genomic se- with the professor, because the problem quencers are the resource most people as- is best tackled in that way.” The Broad, he sociate with this kind of research, but said, is devoted to questions that are best other technologies also help to answer answered by teams working together. questions on a large scale: DNA “chips” can report which genes are turned on or Lander says that the vision for the Broad o≠ in a particular cell; RNA interference came from uno∞cial collaborations be- allows scientists to turn o≠ selectively tween scientists at Harvard and MIT that each of thousands of genes in a cell; and emerged while he headed the Whitehead “libraries” of chemicals let researchers Institute, a major center for sequencing quickly screen many di≠erent molecules the human genome. As the project came to to identify potential candidates for future a close, “this growing culture of collabora- Eric Lander drugs. With automation, machines can tion was so powerful, we felt we needed a RICK FRIEDMAN perform in hours or days tasks that might way to institutionalize it.” The idea took comes from the two universities.