The PerkinElmer Opera microscope allows investigators to automatically capture hundreds of thousands of images in a few hours.
Offering small-molecule compounds, siRNA collections, and high-throughput assay design and execution, the Yale Center for Molecular Discovery (YCMD) provides a service-oriented, results-driven approach to advance the scientific work of Yale investigators. The newly formed center, created in early 2012 by merging the Yale Small Molecule Discovery Center and the Yale Center for High Throughput Cell Biology, is poised to both expedite basic science discoveries and advance such breakthroughs to make them more attractive to industry.
The model for developing the next generation of drugs has changed completely during the last decade; pharmaceutical companies have abandoned the early-stage work they had historically undertaken, leaving it to academic centers to evaluate basic biology discoveries for potential drug development. “There’s a ‘valley of death’ and we’re trying to bridge that by pushing the discoveries at Yale further toward compounds that would be more attractive to pharma or maybe even a venture capitalist,” said Craig Crews, Ph.D., the center’s executive director.
Working closely with Yale’s Office of Cooperative Research and supporting that center’s mission of educating investigators and moving discoveries through the pipeline, YCMD also supports the goal of the National Center for Advancing Translational Sciences (NCATS) to speed the process of translating scientific discoveries into new therapies.
The Center, located on the West Campus, has recently become a core of the Yale Cancer Center and has expanded its staff—many of whom come from pharmaceutical companies—to include experts in computational and medicinal chemistry. YCMD focuses on small molecules, the precursors of what could become drugs; or small interfering RNA (siRNA), which allows researchers to knock out any gene in the genome, scaling assays and experiments into 384-well plates. This approach allows researchers to interrogate whatever they’re investigating with thousands of samples, but can also produce variable results.
“Part of what we do is create the robustness that allows us to have reproducibility,” said Michael Kinch, Ph.D., director of YCMD. Besides the experience of its staff, YCMD offers state-of-the-art instrumentation, including a new microscope capable of high-content, high-throughput imaging of multiwell plates. The PerkinElmer Opera is one of fewer than a dozen such microscopes being used by academic centers; it allows investigators to capture hundreds of thousands of images automatically in a few hours. YCMD also prides itself on identifying novel uses for its instrumentation, much of which came from Bayer when Yale acquired the West Campus. “We’ve been pushing it in directions maybe that it hasn’t been intended to go,” said Kinch.
One new area of emphasis is the collection of novel organisms, which springs out of work done by Yale investigators. For example, Yale has a rich collection of natural compounds culled from rainforests and other sources that researchers are encouraged to deposit in YCMD’s library. The scientists hope that screens run against these compounds will lead to the discovery of new drugs. “Because we are screening to industrial standards in an industrial setting with ex-industry staff, this isn’t just an academic exercise,” said Crews. “We have the capabilities and the expertise to bring to bear real-world pharmaceutical help to academic researchers.”
Richard Lifton, M.D.,Ph.D., right, with Craig Crews, Ph.D., center, and Michael Simons, M.D., director of the Yale Cardiovascular Research Center, left
Crews’ own successful research contributed to the creation of YCMD. His lab found that epoxomicin, a compound produced naturally by a microbial organism, could function as a highly potent selective inhibitor of the proteasome. This finding led to the development of Kyprolis (carfilzomib), a drug that was recently approved by the FDA for the treatment of multiple myeloma. Crews, who is the Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology and professor of chemistry and of pharmacology, set up YCMD’s infrastructure. He has been active in the Center’s efforts to buy chemical libraries; help investigators design assays to discover which compounds are active; and work with them to develop these compounds further.
Several years ago, Ronald Breaker, Ph.D., the Henry Ford II Professor and chair of the Department of Molecular, Cellular and Developmental Biology, was the first researcher to successfully complete a high-throughput screen using Yale’s chemical screening facility. His lab’s early work on bacterial riboswitches—portions of messenger RNA that control gene expression—recently led to the discovery of a new riboswitch that responds to fluoride. Fluoride is known to be toxic to bacteria, which may account for its role in preventing dental cavities, but until recently scientists did not know how bacteria counteract fluoride toxicity. Breaker and his colleagues discovered two protein channels that flush fluoride out of cells. They have spent the last year or so conducting high-throughput screens to identify compounds that plug those channels, thereby increasing fluoride’s toxicity to bacteria, including pathogens. The ultimate goal is to develop new and powerful antimicrobial agents. “Don’t ever think that you won’t do something like this in your scientific program, because there may come a time when you’ll have the ideal idea for a high-throughput screen,” said Breaker. “You don’t have to be an expert to successfully run one of these screens. The core is staffed with people who do this on a daily basis and are very good at it.”
One unique aspect of working with YCMD is that each investigator is paired with a staff member. “That way we can transfer from the lab the deep knowledge of the system and introduce the practicalities,” said Kinch. Last year, YCMD completed more than 80 projects, underwriting about $3 for every $1 contributed by investigators. The majority of projects undertaken by YCMD come from a request for proposals, such as a pilot program with Johnson & Johnson for projects aimed at target discovery and/or early proof-of-concept to identify molecules that alter key biological behaviors. The center also supports between 20 and 30 grant applications each year, writing sections and guiding investigators.
YCMD collaborates with researchers from anywhere within the University on a wide range of projects and is reaching out to other universities to establish strategic partnerships in which Yale investigators can exchange expertise with their counterparts in other institutions. “We want to make sure we’re a good citizen in a bigger community,” said Kinch.