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The Yale Center for Molecular DiscoveryA Core Research Facility at Yale’s West Campus

“This is one-stop shopping for scientists who are lookingto take the next step in advancing their research.”Scott Strobel, vice president for West Campusplanning and program development

Making sense of life’s complexityThe adult human body contains more than 60 trillion cells, organizedinto 300 distinct cell types that carry out the many processes of life—replicating DNA, distributing new proteins, controlling cell division, orenabling cell-to-cell communication. Yet within this complexity, a singlemolecule can have a profound impact. Scientists have long known thatmutations in specific genes can cause devastating diseases like sicklecell anemia, hemophilia, or cystic fibrosis. Equally important, smallmolecules can attach to the surface of a cell or even pass through membranes to impact the cell’s inner workings, with profound implicationsfor human development and health.This is the province of the Yale Center for Molecular Discovery (YCMD).A core facility on Yale’s West Campus, the Center is uniquely equipped tostudy how chemical compounds drive cellular machinery and to ask whathappens to the cell when specific genes are switched o . The answers notonly expand our basic knowledge of biology, but also may lead to newtreatments in the fight against hereditary diseases, drug-resistant bacteria,and cancer.Accelerating the pace of discoveryAt the heart of the Center is the ability to scale up a laboratory investigation,moving from a handful of samples per day—typical for academic laboratories—to tens of thousands per day, a level once associated only with bigpharmaceutical companies. This scale-up, so critical to the translation ofbasic research into new medicines, requires an innovative organizationalmodel as well as state-of-the-art equipment.The YCMD is sta ed with experts drawn from both academic laboratories and biopharmaceutical companies, bringing in-depth knowledge oftools and techniques not usually found in a university setting. Further,the Center is the only core service facility of its kind to select its projectsthrough a peer-review process, ensuring that the most promising ideas aregiven top priority. Once a project is selected, the Yale faculty researcher ispaired with a YCMD sta member, and research proceeds collaboratively.The team uses a suite of automated liquid dispensers, plate readers, andmicroscopes to rapidly process large numbers of samples, while retainingthe high level of quality that is the hallmark of Yale’s scientific research.Taken together, the capabilities of the YCMD open an extraordinarywindow into the living cell, with implications across the areas of naturalscience, human health, and the discovery of novel medical treatments. Onlya handful of universities around the world have access to this gySciencesThe 136-acre West Campus is hometo an integrated cluster of researchinstitutes in the areas of chemicalbiology, cancer, nanobiology, systemsbiology, microbial diversity, and energysciences. Supporting this work arefour core facilities shared by Yale’sscience faculty: Yale Center for Molecular Discovery Yale Center for Genome Analysis High Performance ComputingCenter West Campus AnalyticalChemistry CoreThese interrelated institutes and corefacilities sustain a multidisciplinaryapproach to today’s most pressingquestions of human sustainability —health, the environment, and energy— and advance Yale University asa national leader in scientific teaching and research.

of expertise and technology, and at West Campus, Yale is determinedto sustain and expand the YCMD at the absolute cutting edge. Donorsupport will play an essential role in this mission, not only enablingnew discoveries but also distinguishing Yale in the top echelon ofresearch institutions.A focus on tomorrow’s drug pipelineWhat makes a good candidate for drug research and development? Yale’sCenter for Molecular Discovery has been designed to answer this question, with tools to not only find active compounds, but also map out howthey work, so that the most promising can be advanced to clinical trials.The Yale Center for Molecular Discoveryhas a major educational mission, preparing undergraduates, graduatestudents, and postdoctoral fellows forleadership positions in tomorrow’sresearch laboratories. The Center isstaffed by researchers who are wellversed in the approaches used in thepharmaceutical industry. At the sametime, it draws from Yale’s leadership inbasic and applied biology, chemistry,and engineering departments andhelps to sustain a growing programof clinical research. This high-tech,multidisciplinary setting supports thecutting edge of biomedical educationas well as research. The Center conductsmore than eighty projects per year, eachinvolving students, and it sponsors asummer internship to provide undergraduates with a meaningful researchexperience. A series of “nanocourses”helps students and faculty navigatethe challenges of translating basicresearch results into candidates fordrug discovery.2For Yale, this early-stage research and development work is more essential than ever. A pharmaceutical company needs a solid foundation beforeit will commit a compound to the drug discovery pipeline: What is thestructure of the chemical compound, how does it interact with the cell,and what will it do in the body? Today, just a few hundred compoundsare well understood. There remains a vast knowledge gap that must befilled—what drug companies call “the valley of death”—that distinguishesour expanding knowledge of how the body works from our ability tointervene and correct known defects.Increasingly, the ability to bridge this divide is something that only thenation’s top academic institutions can accomplish. Large pharmaceuticalcompanies facing new economic constraints have dramatically curtailedtheir funding of major research and development e orts. Leading universities like Yale must build the capacity to conduct translational research ona new scale, or the pipeline of critical new medicines will begin to run dry.Yale biologist Craig Crews, director of the YCMD, has a deep understanding of this landscape. In July 2012, Crews completed the goal ofsuccessfully shepherding a compound from the lab bench into the clinic.His cancer drug, Carfilzomib (Kyprolis), was approved by the US Foodand Drug Administration to treat recurrent multiple myeloma, a blooddisorder, without the painful complications that often accompaniedearlier therapies.Building on this expertise, Crews now helps fellow researchers findtheir own paths to drug discovery, using high-throughput technologiesto characterize a novel chemical, learn how that chemical a ects cellularprocesses, and envision how it might be repurposed to cure disease inthe human body.

Only a select few compounds have the potential to impact disease ina way that is targeted, safe, and affordable, and fewer still will actuallysurvive the long and expensive path to becoming an approved drug.3

Leaders in DiscoveryAbove: Advanced molecular modeling graphics allow the detailed examination ofAdenosine monophosphate (AMP) interacting with a new target protein. Oppositepage, top: A researcher prepares copies of master assay plates using the TECAN liquidhandler. Opposite page, right: The molecular interaction of Streptavidin with its naturalligand Biotin serves as the basis of many biochemical techniques at the Center.4

Yale is widely known for its strength in the life sciences, spanningbasic biology, biomedical engineering, and medicine. In labs acrossthe University, scientists are now turning to the Yale Center forMolecular Discovery, illustrating the promise of high-throughputscreening technologies in solving urgent problems in areas from theenvironment to human health.Neuroscientist Stephen Strittmatter studies key genes and proteinsimplicated in devastating neurological conditions. With the supportof the YCMD, he is searching for drug candidates that can arrest theprogress of Alzheimer’s disease, and he hopes to understand the actionof compounds that prevent the regeneration of adult neurons—researchwith promise for victims of stroke or traumatic spinal cord injury.Diane Krause seeks to pinpoint the molecular mechanisms that regulatethe formation of blood cells. Her work at the YCMD, screening stemcells derived from bone marrow, is shedding light on the processes ofself-renewal and di erentiation—findings that may lead to improvedstrategies for bone marrow and stem cell transplantation as well asnovel therapies for treating leukemia and lymphoma.What new functions can be found for engineered RNA and DNA? Andcan the ancient functions of dormant nucleic acids be discovered andput to use? These are the big questions that inspire Ronald Breaker’sresearch. Of special interest are ribozymes and riboswitches—RNAmolecules that catalyze chemical reactions or that serve as chemicalsensors and gene control elements. With help from the YCMD, theBreaker lab is investigating the potential use of riboswitches in a newclass of antibiotics that circumvent bacteria’s ability to develop resistance.5

David F. Stern and Marcus Bosenberg investigate ways to combinethe actions of di erent chemotherapeutic drugs to provide a more safeand e ective means of combating cancer. Their research uses tumorsamples and treatment models taken directly from the Yale CancerCenter, advancing our knowledge of combination therapy while havingimmediate clinical impacts.Michael Kinch, managing director ofthe YCMD, leads a scientific team of teninvestigators spanning academia and thepharmaceutical industry. Their mission isto assist Yale faculty members who wantto use high-throughput screening toolsnot found in conventional academiclabs. These include extensive compoundlibraries, cutting-edge robotics, highresolution imaging, and state-of-the-artcomputational approaches that dramatically accelerate the discovery process.“We want to provide to the Yale facultythe advice and equipment they need tobegin the journey from discovery todevelopment of new drugs,” says Kinch.“This work can speed the translation ofbasic research and broaden the attractiveness of Yale as a partner of choicefor biopharmaceutical companies.”Kinch has a background well suited tohis leadership role. From 1996 to 2001,he was a tenured professor at PurdueUniversity, where he focused on cancerresearch. In 2001, he was recruited to leadthe departments of cancer biology andtranslational sciences at MedImmune, asuccessful biotechnology company. Helater served as chief scientific o cer atFunctional Genetics, which pioneerednew approaches for treating infection byHIV, influenza, Ebola, and other viruses.He came to Yale in 2010 to help advanceYale’s West Campus initiatives.6Susan Baserga is interested in the nucleolus—a structure within thecell’s nucleus composed of proteins and nucleic acids. A healthy cell hastwo or three of these structures, which act as essential ribosome producing machines. In contrast, a cancer cell may have too many nucleoli, orperhaps a single, oversized one. Baserga is using the tools of the YCMDto identify proteins that lead to these unhealthy nuclear formations, inhopes of finding a druggable target in the fight against melanoma andother cancers.Jo Handelsman takes a big-picture view of biology as a pioneer of metagenomics, an emerging discipline that looks at the diversity of genesfound in specimens across a whole ecosystem. Opening a window ona vast microbial world that was previously inaccessible, metagenomicshas both theoretical and practical applications, allowing Handelsmanto look for new antibiotics, for example, or to explore the genetic basisof antibiotic resistance.