A big experiment in big science

Broad Institute’s attack on disease brings answers, questions

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By Carolyn Y. Johnson
Globe Staff / January 2, 2011

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CAMBRIDGE — This is biology, super-sized.

Every hour of every day, hundreds of humming machines inside the Broad Institute decipher coils of DNA, screen thousands of chemicals for potential new drugs, and mine reams of raw data for insights into human biology and disease.

In a day, the Broad’s gene sequencers churn out 500 billion “letters’’ of DNA — the equivalent of 150 people’s genetic blueprints; in a year, the Kendall Square research center runs up an electricity bill of $6 million.

Ten years after scientists figured out the genetic makeup of a human being, the Broad Institute is perhaps the most visible example of how that achievement is changing science and medicine.

Since its founding in 2003, the Broad has exploded into a major research hub, with a team of 1,500 scientists and staff, deep pockets, and the goal of leveraging mind-boggling amounts of information to understand and abolish some of humanity’s most complicated and seemingly intractable diseases: diabetes, cancer, schizophrenia.

But with big ambitions come big risks. The Broad’s founders have made what amounts to a bet, with hundreds of millions of dollars from government and private donors: that this kind of large-scale biology will be the key to realizing the human genome project’s promise to transform human health and medicine.

There have been indisputable achievements: Broad scientists have found genes underpinning human diseases; have sequenced the genomes of more than 15 mammals, from dogs to horses; and are leaders in an international effort to compile the genomes of 1,000 people.

But even as discoveries raise the public’s hopes that new treatments are near, the research has so far illuminated not an easy path to curing disease, but immense complexity. In most cases, disease genes contribute in only a small way to the risk of illness, and some scientists have begun to question whether the big biology pursued at the Broad and elsewhere is drawing money from traditional research that might be more fruitful.

Broad scientists say they aren’t discouraged by complexity. Their aim is to pioneer a new, collaborative model for doing biomedical research that will allow researchers to tackle huge problems in human health and biology.

In the tried-and-true approach to research, scientists carefully design experiments to test a hypothesis — a possible explanation for a scientific observation. The Broad’s strategy is more sweeping, leaning heavily on new technologies to create a detailed catalog of all the biological components of disease and a library of chemicals that can be used to manipulate those components. The rich trove of data, they hope, will launch new research questions in hundreds of laboratories and ultimately improve human health.

Dr. David Altshuler, a founding member of the Broad, talks about it in terms of an old joke, in which a man is on his hands and knees under a streetlight at night. Asked if he’s looking in that spot because that’s where he dropped his keys, he says no — this is where the light is better.

“I don’t want to spend my life looking under the light,’’ Altshuler said.

But the alternative approach — scouring a city for a set of lost keys — is a daunting task that could turn up lots of irrelevant material, and might not succeed.

The Broad is also an experiment in the culture of science: Its scientists and staff are interwoven with researchers from across Cambridge and Boston. Junior scientists have flocked to the Broad because they are encouraged to pursue big questions with a combination of massive resources and a degree of independence not traditionally found in academia or industry.

“It’s like Disneyland for science,’’ said Alon Goren, 36, a postdoctoral researcher who splits his time between the Broad and Massachusetts General Hospital. “The entire way this is built is to give scientists the feeling that they’re important and valuable. . . . I feel as if I should dream more.’’

The Broad’s roots date to before the Human Genome Project. Its founding director, Eric S. Lander, was trained as a mathematician but learned biology in the 1980s and joined the Whitehead Institute for Biomedical Research in Cambridge in 1986. There, he built a conventional academic laboratory — starting with four MIT undergraduates who crafted algorithms to make genetic maps.

In such labs, young scientists are apprenticed to senior investigators, who seek funding to support their laboratories. They ask specific questions, come up with hypotheses, and design experiments to test their ideas.

But in the 1990s, Lander’s lab grew into a huge DNA sequencing center, the Whitehead/MIT Center for Genome Research, with a team of about 200 people. The center played a key role in the genome project, using massive amounts of equipment with names like “Genomatron’’ to create the first blueprint of a person.

Alan Fein, a former university administrator who was brought in to help organize the growing enterprise, said it was apparent that what was unfolding was unusual.

“It struck me as very similar to a political campaign. They took an incredibly hard problem at a sprint,’’ Fein said. “It was not about hierarchy; it was about teams.’’

As the effort to sequence the first human genome neared completion, Lander and others were thinking about how to preserve this spirit and model for doing science.

Separately, Harvard researchers had developed their own collaborative organization, the Institute of Chemistry and Cell Biology, which did exhaustive screening of chemicals that affect biology to speed the development of new drugs. The fundamental idea was the same: new technologies and cooperative approaches could allow scientists to tackle problems that would otherwise be impossibly big.

Stuart L. Schreiber, the chemist who co-led the institute, found that his thinking meshed with Lander’s when the scientists did a “nano-sabbatical’’ together in 1999 — the leading scientists apprenticed themselves as technicians to one of Schreiber’s top researchers. Schreiber decided to lease space from the Whitehead so that the chemical biologists of his growing institute could be in the same building as the genome biologists.

“It was so obvious this was electrifying,’’ Schreiber said. “We were seeing opportunities in cancer, infectious disease, metabolic disease; new projects got started in malaria, TB, and diabetes.’’

That exuberance was apparent not only to scientists. The Whitehead Institute had received a modest grant — $141,500 — from the Broad Foundation to investigate inflammatory bowel disease. When Eli and Edythe Broad came to Cambridge on a Saturday in October 2001, they stopped by.

“That started a conversation with Eric,’’ said Eli Broad, a Los Angeles philanthropist who founded two Fortune 500 companies. Broad asked Lander what he wanted to do next. Lander talked about creating an institute to leverage the type of teamwork, tools, and data generated by the genome project to tackle human disease.

“What would that take?’’ Broad asked. Lander said $800 million.

“Eric’s not a person of small plans,’’ Broad said. “We stayed in touch.’’

Now, seven years after the Broads made their first $100 million investment in a unique approach to improving human health, the big question is whether it will be the key to cracking diseases and major questions in human biology.

Scientists at the Broad and elsewhere have used ever-improving tools to comb the genomes of thousands of people and pinpoint genetic hot spots linked to diseases that range from diabetes to schizophrenia. The approach received a huge vote of confidence in 2009, when the Broads established a $400 million endowment that made the institute a fixture on the scientific landscape of Cambridge.

But the scientists acknowledge that they are still at the beginning. The genes that are involved in common diseases are breadcrumbs — guiding scientists to the beginning of a long trail that involves figuring out what those genes do, how their function might underlie disease, and how to alter their activity in ways that could help people.

Recent research by Broad scientists and collaborators demonstrates one example of how that process unfolds. Variation between the genomes of any two people can give rise to everything from different hair color to different risk for disease.

In a paper published in the journal Nature, researchers analyzed areas of genetic variation in more than 100,000 people and found 95 such areas linked to people’s cholesterol and trigylceride levels. The researchers then altered the activity of three genes in mice, finding that each affected cholesterol, thus proving the principle that such a broad survey can identify biologically meaningful genes.

Still, progress has been disappointing to some. Since the human genome was decoded, scientists have discovered increasing complexity, including unexpected ways in which segments of DNA that were once thought to be “junk’’ play a role in regulating genes.

Years of research and hundreds of millions of dollars have provided questions rather than clear answers about the underpinnings of disease, and some argue that the effectiveness of investing in this large-scale, technology-driven kind of science is due to be evaluated.

“When electron microscopes came out, people said they would really answer all the important questions in cell biology — and of course they didn’t. When DNA sequencing came out, the promise was that this would yield answers as to why we humans are human. But of course it hasn’t happened,’’ said Robert Weinberg, a leading cancer researcher at the Whitehead Institute.

Weinberg praises much of the work going on at the Broad. Yet he thinks there should be an assessment of whether large-scale science is being funded at the expense of time-tested hypothesis-driven science.

Large datasets of genes have been very useful in some cases, Weinberg said. “But if one were to step back and analyze the entire spectrum of things that have been done, in some cases advances have been incisive, and in many other cases they’ve been, to put it most charitably, modest.’’

One reason for the doubt about the large-scale approach is that complex diseases haven’t yielded as easily as hoped to a major tool, called a genome-wide association study, in which scientists scour portions of the DNA of thousands of people — some with a disease or trait and some without — to find genetic variations more common in those with the disease or trait.

Dr. Francis Collins, head of the National Institutes of Health, which provided about two-thirds of the Broad’s budget in fiscal 2009, said that so far the science has moved rapidly, with remarkable success at identifying genetic variants that underlie common diseases. As recently as 2004, he said, the scientific community did not know of common genetic variations that played a role in disease. Now, he said, there are about 1,000.

“That’s the good news,’’ Collins said. “The bad news, which we had no way of knowing ahead of time, is most of these variants have quite modest effects on risk, so as predictors of future illness they’re not as impressive for many diseases as people had hoped would emerge.’’

For example, in the recent work on the genetics of cholesterol and trigylcerides, the 95 areas that scientists identified account for only about 10 to 12 percent of the differences in people’s lipid levels.

But as technology has improved, scientists can more rapidly and cheaply examine more spots in the genome — even the full sequence of a person’s DNA — to seek the genetic causes of disease.

“There’s lots of missing heritability — the dark matter of the genome,’’ Collins said. “And that is also an opportunity.’’

Every day of the week, from MIT, Harvard, and hospitals across the Charles, scientists roll in — sometimes literally, on bikes and rollerblades — to work with Broad faculty and scientists to take advantage of that opportunity.

Scientists from different disciplines and institutions take part in “programs’’ — communities organized around common research themes, with weekly meetings. On Tuesdays, scientists working on cancer convene; on Thursdays, researchers meet to discuss how human genomic variation affects disease or drug reactions.

Piecing together the giant jigsaw puzzle of disease depends, the Broad’s founders say, on taking a different approach to science that is possible only in the scientific environment of Boston and Cambridge.

While Eli Broad had initially hoped that the institute could be located in Los Angeles, Lander made an impassioned case that it could only be done in Boston. Here, hundreds of scientists from independent labs at Harvard, MIT, or the hospitals spend part of their time at the Broad, developing and conducting experiments that could answer major questions in medicine.

The Broad has its own faculty and hundreds of scientists who work in what are called “platforms,’’ groups that specialize in technologies such as genome sequencing or screening vast chemical libraries. These scientists work together — bringing a powerful combination of cutting-edge tools and expertise to large-scale projects.

But the institute is also playful. Laboratories are filled with machines nicknamed after baseball players or cartoon pigs. Many of the walls can be written on, from floor to ceiling, and carry equations and other scientific scribblings.

“People come here because it is a playground for scientists. They have access to capabilities and expertise that they don’t necessarily have access to . . . in their own lab and maybe not even at their own institution,’’ said Steven Carr, a scientist who worked in industry for many years and now leads the Broad’s proteomics platform.

“People come here because the egos and weapons are left at the door,’’ Carr said. “The coin of the realm here is killing important scientific problems.’’

Carolyn Y. Johnson can be reached at

Correction: Due to a reporting error, an earlier version of this story said the Broad Institute sequences 500 billion "letters" of DNA per week. It should have said it sequences 500 billion "letters" of DNA per day. Also, because of an editing error, an earlier caption incorrectly described the formulas written on a glass wall. They were chemical formulas.