Volume 86 Issue 48 | pp. 53-54
Issue Date: December 1, 2008

Broadening Perspectives

The Broad Institute catalyzes connections between disciplines
Department: Science & Technology
Gathering Place
The Broad Institute is located in the heart of Cambridge, Mass.
Credit: Anton Grassl
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Gathering Place
The Broad Institute is located in the heart of Cambridge, Mass.
Credit: Anton Grassl

THE MISSION at the Eli & Edythe L. Broad Institute is to bring the power of genomics to bear on understanding and creating treatments for disease. Figuring out how to best deliver on that promise is paramount in the minds of the Broad's founding members, who have chosen to take a collaborative approach. "The Broad has really been about creating a community," says Stuart L. Schreiber, director of chemical biology at the Broad, one of the institute's founding members, and professor of chemistry at Harvard University. That commitment has fostered lasting research connections in which chemists are playing increasingly important roles.

The Cambridge, Mass.-based Broad Institute evolved from talks among experts in the Massachusetts Institute of Technology and Harvard communities, including those at the Whitehead Institute/MIT Center for Genome Research and Harvard Medical School's Institute of Chemistry & Cell Biology. It was launched in 2004, and today the Broad—rhymes with road—community spans those institutions as well as 17 Harvard-affiliated teaching hospitals. In September, founders Eli and Edythe L. Broad gave an additional $400 million to permanently endow the institute (C&EN, Sept. 8, page 11). The endowment will enable the institute, which had been managed jointly by Harvard and MIT from its inception, to become an independent nonprofit organization. Beginning on July 1, 2009, the Broad will be governed by a board of directors that will include representation from the universities.

"The Broad Institute has benefited from its openness," says Gerald Rubin, director of Howard Hughes Medical Institute's Janelia Farm research campus, another institution that takes a collaborative approach to tackling big research questions. He characterizes the Broad as a synergistic marriage between technology experts and scientists addressing far-reaching biomedical problems—a far cry from the stereotype of the lone scientist toiling away in a lab. But like any marriage, the institute's culture requires a great deal of effort to maintain. "To get interdisciplinary science going, you must reward that kind of activity and set up structures that explicitly encourage it," Rubin says.

The Broad has several of those kinds of structures, and they influence the institute's organization, how some projects are funded, and even how day-to-day science gets done.

Scientists at the Broad coalesce around "programs" and "platforms," rather than traditional departments. A program is a scientific community dedicated to tackling a specific area, such as psychiatric disease or cancer. Program members include Broad staff scientists of all disciplines, as well as associate members, who are faculty based at one of the affiliated universities or hospitals. Platforms complement programs by developing state-of-the-art tools to help produce as well as analyze large amounts of data.

"I don't think the Broad could function as effectively as it does if it were a department at Harvard or MIT," Rubin says. To build a truly collaborative institute like Janelia Farm or the Broad, "you have to start from scratch, and never build any disciplinary walls," he says.

It would be tough to retrofit an existing department to function like the Broad does, Schreiber agrees. "The inertia of venerable institutions like Harvard is substantial," he says. Compared with traditional departments, the Broad's culture is less centered on individual researchers' contributions, which advance science in their own right but aren't necessarily the best approach to every scientific problem, he adds.

THE COLLABORATIVE culture at the Broad extends far beyond infrastructure. For instance, the institute holds annual retreats and biweekly program meetings attended by scientists from across the affiliate institutions. At these gatherings, presenters share new ideas and fresh results. "At a seminar in your department you might want to talk about things that are more complete stories, whereas at the Broad the attention is toward looking for connections with other parts of the Broad network," explains J. Christopher Love, a chemical engineer at MIT and associate member at the Broad. This type of meeting didn't necessarily originate at the Broad, but the institute "puts an interesting inter-institution spin on that model," says James E. Bradner, a physician-scientist at Dana-Farber Cancer Institute and a postdoctoral fellow in Schreiber's lab.

"Transitions from small to large are a way of life at the Broad. The Broad encourages you to think of projects on a big scale."

Attendees at the program meetings working in similar areas are expected to refrain from capitalizing on early data presented at the meetings, and Broad-affiliated scientists are confident that the system works. The meetings are "an opportunity to get incisive feedback" on new projects, Bradner says. "The opportunity to hear about a project as the concept is coming together far outweighs any risk of being scooped," he adds.

Bradner launched a fruitful collaboration after attending one such meeting at the Broad. He became part of a multi-institution team that recently pinpointed specific genome variations that can influence the success of bone marrow transplants. Bradner described those results at the American Society of Hematology's national meeting [Blood (ASH Annual Meeting Abstracts) 2007, 110, 37].

The Broad's Scientific Planning & Allocation of Resources Committee (SPARC) grant program is another catalyst for collaborations. SPARC gives pilot grants to sponsor multidisciplinary collaborative research within and among the Broad and its affiliates. The money for the SPARC grants comes exclusively from the Broads' gift, which is used to support higher risk projects, says Patrick Kleyn, director of scientific planning at the Broad. Those less restricted funds "help kick-start new ideas that might have difficulty getting funded through more traditional channels," explains Love, who has received a SPARC grant with MIT biologists Hidde Ploegh and Michael B. Yaffe to develop cost-effective processes to generate large libraries of new antibodies.

Helping Hand
A heavy-duty robot plays a big part in screening campaigns.
Credit: Carmen Drahl/C&EN
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Helping Hand
A heavy-duty robot plays a big part in screening campaigns.
Credit: Carmen Drahl/C&EN

Sometimes, the SPARC program establishes interdisciplinary links that extend far beyond the initial project. Chemical biologist Jon Clardy of Harvard Medical School and immunologist Dyann F. Wirth of the Harvard School of Public Health applied for SPARC funding to develop a high-throughput screen for testing potential antimalarial compounds on intact malaria parasites. With access to SPARC funds and the Broad's screening resources, they developed a robust screen that eliminated the radioactive reagent used in other malaria screens. It could also be run on a much larger number of compounds than ever before (Antimicrob. Agents Chemother. 2007, 51, 716). In collaboration with Ralph Mazitschek, a chemical biologist at Massachusetts General Hospital and in the Broad's chemical biology program, they analyzed their screening results and identified promising potential new targets for antimalarial drugs. That success allowed them to transition away from SPARC funding and toward grants from the Medicines for Malaria Venture, a Swiss nonprofit organization. The team also reached an agreement with Genzyme Corp. for developing hits.

Clardy and Wirth expect an announcement from Genzyme late in spring 2009 about whether an antimalarial compound stemming from their collaboration will advance into clinical trials. The entire process, from SPARC proposal to industry collaboration, took less than two years. "Transitions from small to large are a way of life at the Broad," Clardy says. "The Broad encourages you to think of projects on a big scale." In fact, the malaria project's approach has blossomed into a broader infectious disease initiative at the institutes.

Day-to-day chemistry within the Broad has also benefited from the institute's collaborative culture. Each of the roughly 60 synthetic organic chemists at the Broad—including graduate students, postdoctoral fellows, and staff scientists—has an electronic notebook for recording reagents, conditions, spectra, and general observations, and each chemist is privy to the details in every e-notebook.

That type of access came in handy when Broad chemists recently scaled up some enantioselective aldol reactions. The researchers hoped to use the aldol chemistry to make kilogram amounts of specific chiral building blocks for their specially designed compound library. The library, whose construction has been a long-term exercise for the Broad, is based on diversity-oriented synthesis (DOS), an approach that aims to construct libraries with richer stereochemical and structural variety than traditional combinatorial libraries (C&EN, Oct. 4, 2004, page 32).

The e-notebooks let the six chemists on the aldol scale-up team coordinate their efforts and ensure that the full range of conditions was tested, says Damian Young, an organic chemist and group leader in the Broad's chemical biology program. The team's scaled-up procedures were ultimately reliable enough for the Broad to outsource production of their aldol building blocks, freeing up the chemists to tackle other problems. "I doubt that we would be as far along on the chemistry side as we are today if we did not have open access to all the data that flow through the lab," Young says.

Tech Talk
Scientists discuss fresh ideas at Broad meetings.
Credit: Len Rubenstein
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Tech Talk
Scientists discuss fresh ideas at Broad meetings.
Credit: Len Rubenstein

THE BROAD'S COMMITMENT to collaboration continues beyond the chemistry that goes into building libraries and screening them. The institute has access to myriad assays, some developed internally and some externally. The goal is to use the assays to comb the library for compounds that might be, for example, the inspiration for a molecular probe for better understanding a disease or a drug for treating it. Structural and screening data for every compound in the Broad's libraries is posted in two public Web-based databases, PubChem and ChemBank. After that point, Broad scientists are encouraged to patent follow-up chemistry and biology from promising screening hits, Schreiber says.

In late October, the Broad's chemical biologists had just begun screening the first portion of their latest DOS library. Broad scientists have been screening compound collections for years, including a smaller collection of DOS compounds. The latest DOS library, however, is far larger and thus has required a great deal of up-front work, says Lisa Marcaurelle, an organic chemist and manager in the Broad's chemical biology platform. So far, the team has made 20,000 DOS compounds of the 300,000 they plan to have by 2011, she says. Young, who worked on DOS projects during his postdoctoral tenure in the Schreiber group, reiterates that this library is much larger and more diverse than previous DOS efforts, which were principally made by small groups of students or postdoctoral fellows.

It's only in recent weeks that this newest library has been put into a biological test, and it's too early to tell whether the library will open up new research directions. But institute scientists have high hopes for the new library's broad applicability to diverse questions in biology and medicine, as evidenced by the Broad's increased commitment to chemistry and chemical biology since its founding. In 2006, the Broad founded its latest platform, novel therapeutics, which is dedicated to exploring how the institute will translate chemical and genome data windfalls into innovations in the drug discovery process. The platform's director, Robert Gould, is a pharmacologist who came to the Broad after retiring from Merck Research Labs, where he was vice president for basic research and vice president for licensing and external research. "Chemistry plays a critical role in the novel therapeutics platform," he says. Since 2006, his platform together with the chemical biology platform has hired 35 organic chemists and approximately 30 screening and informatics specialists.

Furthermore, over the past four months, the institute was awarded two grants that require significant amounts of chemical legwork to achieve their objectives. The funding totals nearly $100 million over six years. One grant, from the National Institutes of Health, establishes the Broad as one of nine Molecular Libraries Probe Production Centers nationwide. This network of centers is charged with screening NIH's own chemical library and with using screening data to develop molecular probes of disease processes. The second grant, from NIH's National Institute of General Medical Sciences, renews the Broad's funding status as one of five Centers of Excellence in Chemical Methodologies & Library Development nationwide. The renewal funds further efforts toward expanding the repertoire of chemical strategies used for library building, to be carried out in collaboration with Eric N. Jacobsen, professor of chemistry at Harvard.

Those commitments are an investment in chemistry at the Broad, which will play an essential role in its future successes, Schreiber says. "I've heard chemists lament that as life science marches forward it seems to be leaving chemistry behind, but the Broad Institute is living proof that that's not true," he says.

 
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