Large-scale, collaborative, translational research is the very foundation of the Broad Institute, and is one of the reasons it counts among the world’s foremost research institutes.
Founded a decade ago as a collaboration between MIT, Harvard University and Harvard-affiliated hospitals, “it was created as a place where scientists from different labs, disciplines and institutions could work together on large scale projects,” said Issi Rozen, Director of Strategic Alliances at the Broad Institute. Today, its team is composed of more than 200 faculty members with primary appointments at one of the founding institutions and a large community of about 2,000 scientists, “many of whom are Broad staff scientists,” Rozen added.
Issi Rozen, Director of Strategic Alliances at the Broad Institute
Challenge the impossible
The mission at the Broad is to collaboratively tackle large projects that none of the labs can accomplish alone, often in partnership with pharmaceutical and biotech companies. These projects are categorized as either programs or platforms. Programs are, essentially, scientific communities that coalesce around a research area. Active programs are underway in oncology, chemical biology, cell circuits, epigenomics, genome sequencing and analysis, health research, infectious disease, metabolism, population genetics and psychiatric research. Each of those groups meets regularly. For example, Rozen said, “our cancer program has about 200 researchers who meet weekly to discuss new and ongoing research.”
Another example, published in June, details the largest study of its kind for diabetes risk factors in Latin America. Studying 4,000 people, this US–Mexico collaboration with the Carlos Slim Foundation revealed a strong genetic risk factor for type 2 diabetes (the HNF1A gene) that affects 2% of the Mexican population but is rare in other populations.
In contrast to such programs, platforms focus on industrial scale capabilities like genetic sequencing and proteomics. Individuals in these platforms work collaboratively with faculty researchers to design research projects. These groups, together with the faculty, also advance the tools and technologies necessary to advance the science, and it also works with the medical researchers to help leverage the best technologies and approaches to deliver the results they need.
Current platforms are focused on therapeutics, genomics, imaging, metabolite profiling, proteomics and RNAi. The Therapeutics Projects Group and Broad Technology Labs round out the platforms.
In practice, working with the platform side of the Broad helps researchers do what they want to do in their projects rather than merely what they think is possible. By removing preconceived notions of the technological limitations—and often the limitations themselves— these collaborations can help scientists design their research plans to leverage the advantages of the latest technological breakthroughs.
For example, researchers from the Broad Institute and MIT recently created a new mouse model that simplifies use of the CRISPR-Cas9 system for in vivo genome editing by allowing the genes to be perturbed more easily. This new Cas9 mouse was used to model the lethal lung adenocarcinoma, among other cell types.
The Broad Technology Labs offers another good example of how platform research works. In these labs, deep expertise in molecular biology, lab automation, microfluidics and computational biology are combined to help bridge the gap between proof of principle and fully-integrated, large scale processes. This approach makes innovative technology available to users earlier than may otherwise be possible. The goal, as with each of its programs and platforms, is to advance science to improve patients’ lives.
“This is a very unique way to think about working,” Rozen said. With these collaborations across disciplines and institutions, “you see a lot of engagement, and a lot of new technology developed around a platform.”
Focus on relevant models
Perhaps the hallmark of the Broad’s approach is its insistence on working only with relevant models. “We’re strong believers that you should only work on projects where the targets emerge from human biology and genomics,” Rozen said.
For example, “a drug may show activity in a mouse model but, to be effective, the target must be based on human genetics and the mechanism of action on human biology. This eliminates a lot of the risk during drug development.”
In practical terms, that may mean looking for clues in nature and genetics regarding the protective or deleterious effects of mutations and launching a research program based upon those findings. One example would be a program to determine why people with multiple risk factors for a particular disease do not develop that disease.
Throughout the Broad’s programs, an overarching goal is to develop new screens, new chemistries or new technologies to drug targets that currently are considered undruggable.
The L1000™ Expression Method has resulted from this approach, Rozen said. “It allows high throughput screening of gene expression. Researchers can measure the expression levels of only 1,000 genes and use the L1000 to develop a computational model that approximates the measurements of thousands more genes.” Genometry, which commercialized the device, says it measures 80% of the gene-expression levels of all twenty thousand transcripts at about 5% of the cost, in about three days.
Working with the Broad Institute
To work with industry, “we set up collaborations in areas of mutual interest. We can’t bring products to market ourselves, so we look for the right partner to provide complementary expertise,” Rozen said. “When we find a molecule, for instance, pharma can take it in-house and develop a drug.”
Consequently, the Broad itself is not engaged in clinical trials. Collaborators do have access to its researchers, however, many of whom are practicing physicians at many of the world’s foremost hospitals.
In addition to its Harvard-affiliated hospitals, the Broad also has formed some specialty centers. These include the Joint Center for Translational Medicine at Caltech and UCLA, funded in 2009.
Rozen said the main benefits of working with the Broad is its expertise in genetics, biology and early stage lead generation. “Also, we may have technologies and resources—including chemical libraries—our partners may not have.” Industry partners bring expertise in optimization, clinical development, regulatory issues, etc.
In selecting those partners, “we look for people who share our scientific vision,” Rozen said. That extends to identifying the activities that are necessary to move a project forward and the willingness to commit resources and the dogged determination to ensure the projects are successful. “We want a commitment to seeing a successful project.”
Company size is not a factor, Rozen says. Although financial resources are part of the commitment, “smaller companies with targets they care deeply about also work with the Broad.” To be successful, companies need a unique and critical capability that can move a project forward.
The Broad prefers to work with companies early, even before the target selection or validation stage, looking at the genetics to see what target emerges.
“We can’t move forward without biopharmaceutical collaborations. There are great ideas coming from the biomedical community, so we always look for new partners to enhance our current partnerships,” Rozen said, pointing out that geographic location is irrelevant. “We work with companies globally.”
The Broad Institute’s interests are wide ranging and are narrowed only slightly by Rozen’s comment that it is “seeking programs that translate genetics and biological insights into drugs.” That said, the Broad will not embark on projects without faculty expertise. “Sometimes companies propose projects, but if we have no biological expertise in that niche already on the faculty, we decline,” he said.
“Our key commitment is to drugging targets that emerge from human biology and developing comprehensive approaches to seeing it translated into therapeutics that help patients,” Rozen said. “We really care about advancing the field to propel the understanding and treatment of diseases.”
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