Researchers at the Broad Institute of Harvard and MIT have been chosen to receive a six-year, $86 million grant from the National Institutes of Health (NIH) to identify and develop molecular tools known as “small molecules,” which can probe proteins, signaling pathways, and cellular processes that are crucial to human health and disease.
The Broad Institute is among nine institutions to receive funding under the Molecular Libraries and Imaging Initiative, one of the NIH Roadmap Initiatives for Medical Research. These institutions together comprise a collaborative research network that will conduct high-throughput biological studies and chemical optimization of a diverse collection of small molecules, and openly share their data with the scientific community, yielding knowledge that may bolster the search for novel disease therapies.
“Small-molecule probe and drug discovery enables basic research to impact on human health, and the advances of chemical biology are transforming this discovery process,” said principal investigator Stuart Schreiber, director of the Chemical Biology Program at the Broad Institute. “Integrating chemical biology with genome biology, which is a founding principle of the Broad Institute, accelerates the march to new medicines in a magical way.”
The molecules of life come in a variety of shapes and sizes. At one end of the spectrum are large macromolecules such as DNA, RNA, and proteins. At the other end are a plethora of chemical compounds that exert effects on human biology by virtue of their relatively small size and their ability to interact directly with biological macromolecules. These so-called small molecules are readily transported through the body and include endogenous substances, such as hormones and neurotransmitters, as well as medicines like aspirin and penicillin.
The six-year NIH grant designates the Broad Institute as one of four Comprehensive Screening Centers in the Molecular Libraries Probe Production Centers Network (MLPCN), where vast collections, or “libraries,” of small molecules will be screened using high-throughput methods to identify compounds with interesting biological functions.
The NIH award reflects a new chapter in an already rich history of chemical biology and small-molecule screening at the Broad Institute, a chapter that began at the Harvard Institute of Chemistry and Chemical Biology (ICCB) in 1997. The ICCB, which became a founding asset of the Broad Institute when it was launched in 2003, created the first large-scale, public, small-molecule screening center and served as a model for future initiatives. “At the Broad, we are truly fortunate to have a group of individuals with world-class expertise in nearly all facets of professional, high-throughput, small-molecule science,” said Schreiber. “Indeed, we couldn’t undertake this work without them.”
The development of small-molecule probes is an intensive effort that involves more than high-throughput screening of molecular libraries. Before screens can be carried out, months of meticulous work are needed to lay the necessary scientific groundwork. Will chemicals be tested in test tubes or cells? How will the biological effects of small molecules be measured? At the Broad Institute, many of these questions can be addressed by leveraging the power of large-scale approaches such as global gene expression-based screening and high-content cellular imaging.
Once the preliminary work is complete and a screen begins, Broad researchers ensure that all of the data are captured digitally and deposited in public databases. The ICCB and the Broad Institute pioneered this type of public data sharing through their creation of ChemBank, and more recently researchers at the Broad have been contributing to a second public database, PubChem, which is associated with the Molecular Libraries and Imaging Initiative. Follow-up work, including further biological testing and small-molecule optimization, is then required to develop promising small molecules into bona fide molecular probes of human biology. This requires modern organic synthesis, a scientific endeavor that is an underpinning of the Broad Institute.
“The Molecular Libraries Program has cultivated an extremely high-quality collection of small molecules that are wonderfully complementary to the unique collection established at the Broad Institute,” said Schreiber. “We are eager to begin exploring the biomedical potential of these chemical compounds, in addition to our own, and to share our results with the global scientific community.”