The National Institutes of Health wants to make the process of finding new drugs faster and better. The effort will help all 27 of its research institutes and centers. So, the nation’s medical research agency awarded Tudor Oprea, MD, PhD, a 2-year $4.9 million grant to develop a tool scientists can use to link information about drugs, diseases and genes. The effort is so large that the NIH divided it into different parts. Dr. Oprea, at the University of New Mexico Cancer Center, will oversee the entire project. Larry Sklar, PhD, will develop the Administrative Core for the IDG-KMC and Anton Simeonov, PhD, will develop the User Interface Portal. Dr. Oprea says, “The 27 [NIH] institutes support this initiative because they recognize that everyone needs to work on new drug targets. If this is the bottleneck, how do we prioritize it?”
Dr. Oprea’s new project, called the “Illuminating the Druggable Genome Knowledge Management Center,” or IDG-KMC, will improve the way scientists manage and share what they know. The IDG-KMC will link known facts about drug molecules, the genes and cellular pathways they influence and the diseases on which they have been tested. And part of the work requires connecting genes to the proteins they produce in a cell. Genes provide the blueprints for many, many different kinds of proteins and each protein has a unique shape and function. Dr. Oprea explains, “We’re trying to map diseases to small molecules to [protein] targets. And making those associations is not trivial.” Initially, Dr. Oprea and the IDG-KMC team will focus on four large families of proteins.
Organizing this large set of information will make the links between drugs, diseases and genes better. But Dr. Oprea and his team will go farther: they will develop tools to suggest genes for drug targeting that researchers might otherwise overlook. To explain, Dr. Oprea uses the joke of looking for a key under the lamppost. “The key might be in the dark,” he says, “but we tend to look under the lamppost because that’s where the light is. With the IDG-KMC, we want to illuminate the genome and prioritize proteins for more studies.”
The effort to build such an advanced database and keep it current will require painstaking work. Dr. Oprea and his team will need to collect and verify each piece of information. They will work with Danish scientists Søren Brunak, PhD, and Lars Juhl Jensen, PhD, who have developed award-winning technologies for searching through large amounts of text. Called “text mining,” Drs. Brunak and Jensen have used these automated searches to discover connections between genes and their effects on the cell. Dr. Oprea’s team will search papers in published journals, and where possible, they will use the automated tools to find how drugs, diseases and genes relate to each other.
The IDG-KMC team will work with English scientist John Overington, PhD, whose team will search patents. They will also work with Stephan Schürer, PhD, in Miami who creates dictionaries to help computers distinguish between several meanings in English text. But the team will still need to handle information that automated searches can’t. “You want the computer to take sentences and parse them in an automated way so that the computer can ‘reason’ if given a structured syntax,” Dr. Oprea says. “We’re not there yet.”
Dr. Oprea’s team will also use additional sources of information. Private or pilot studies, for example, can verify other pieces of information even though the scientists conducting these studies may not yet be able to publish their data. And the team plans use tissue samples and full-genome sequencing from people who have given their permission to use their information in scientific work. Clinical trials, too, may offer insight. “Why do some drugs work better than others?” asks Dr. Oprea. “In target profiling, they look identical. And yet, some of them work and some of them don’t. That’s why we still conduct clinical trials,” he says. Dr. Oprea’s team will work with teams led by Avi Ma'ayan, PhD, and Joel Dudley, PhD, at Mount Sinai Medical School. Their teams have developed unique tools to extract knowledge from large volumes of genomic data.
Dr. Oprea’s team has already developed many of the tools the IDG-KMC will require. “At UNM, we’ve developed the technologies to map small molecule chemicals to diseases,” Dr. Oprea says. More than 8,000 diseases have been indexed. Physicians can treat only about 2,000 of these diseases with drugs. “Even accounting for surgery and other [medical] specialties, this number still implies that more than half of the known diseases have no cure. So we’re still a long way to go.”
When complete, the pilot phase of the IDG-KMC will offer scientists a public, prioritized list of drug targets in the genome. It will also provide a Web site, or “portal,” to connect drugs, diseases and genes. Scientists can expand the information as they discover new data and can create new ways to search and organize that information. “So if pharmaceutical companies, private sector or academics want to take our prioritized lists and work on them, they will do that,” says Dr. Oprea. “It will be open.”
About Tudor Oprea, MD, PhD
Tudor Oprea, MD, PhD, is a Professor and Chief of the Division of Translational Informatics in the Department of Internal Medicine at the University of New Mexico School of Medicine. He completed his medical and doctoral degrees at the University of Medicine and Pharmacy in Timisoara, Romania. Dr. Oprea completed post-doctoral training at the Center for Molecular Design, Washington University, with Garland Marshall and then at Los Alamos National Laboratory in Theoretical Biology, with Angel García. Dr. Oprea’s in silico evaluations at UNM Cancer Center have resulted in two compounds, raltgravir and ketorolac, now in clinical evaluation; three granted US patents; and several funded proposals, including an R01 grant from the National Cancer Institute.
About Larry Sklar, PhD
Larry Sklar, PhD, is a University of New Mexico in the Department of Pathology at the UNM School of Medicine. He is the Associate Director for Molecular Discovery and holds the The Maralyn S. Budke and Robert E. Anderson Endowed Chair in Cancer Drug Discovery at the UNM Cancer Center. Trained in Chemistry and Biotechnology at Stanford University and a Helen Hay Whitney Postdoctoral Fellow, Dr. Sklar is one of UNM and the nation’s most productive scientists and inventors. Through his leadership of the UNM Center for Molecular Discovery, one of nine NIH-funded Drug Screening and Discovery Centers in the U.S., Dr. Sklar and his team have identified many new therapeutic small molecules and cancer drugs through re-purposing. They are now testing these agents in pre-clinical models and clinical trials. Dr. Sklar’s research has led to 22 U.S. Patents and three biotechnology companies, one based in New Mexico.
Anton Simeonov, PhD, is the Acting Deputy Scientific Director of the National Center for Advancing Translational Sciences at National Institutes of Health.
Søren Brunak, PhD, is Research Director of the Novo Nordisk Foundation Center for Protein Research and a Professor in the Disease Systems Biology Program at the University of Copenhagen, Denmark.
Lars Juhl Jensen, PhD, is a Professor at the Novo Nordisk Foundation Center for Protein Research and in the Cellular Network Biology Program at the University of Copenhagen, Denmark.
John Overington, PhD is Team Leader at the European Bioinformatics Institute, part of the European Molecular Biology Laboratory in Hinxton, United Kingdom.
Stephan Schürer, PhD, is an Associate Professor in the Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami.
Avi Ma'ayan, PhD, is an Associate Professor in the Department of Pharmacology and Systems Therapeutics at the Experimental Therapeutics Institute and is Director of the Information Management Unit at the Systems Biology Center New York.
Joel Dudley, PhD, is an Assistant Professor of Genetics and Genomic Sciences and an Assistant Professor of Population Health Science and Policy at Mount Sinai School of Medicine.
About the Grant
The National Cancer Institute of the National Institutes of Health supported the research reported in this publication under Award Number 1U54CA189205-01-9, Principal Investigator: Oprea, Tudor. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
To learn more about the IDG initiative, including other funded research, please visit: http://commonfund.nih.gov/idg/overview.
About the UNM Cancer Center
The UNM Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in the state. One of just 68 premier NCI-Designated Cancer Centers nationwide, the UNM Cancer Center is recognized for its scientific excellence, contributions to cancer research, the delivery of high quality, state of the art cancer diagnosis and treatment to all New Mexicans, and its community outreach programs statewide. Annual federal and private funding of over $77 million supports the UNM Cancer Center’s research programs. The UNM Cancer Center treats more than 60 percent of the adults and virtually all of the children in New Mexico affected by cancer, from every county in the state. It is home to New Mexico’s largest team of board-certified oncology physicians and research scientists, representing every cancer specialty and hailing from prestigious institutions such as M.D. Anderson Cancer Center, Johns Hopkins University, and the Mayo Clinic. Through its partnership with Memorial Medical Center in Las Cruces, the UNM Cancer Center brings world-class cancer care to the southern part of the state; its collaborative clinical programs in Santa Fe and Farmington serve northern New Mexico and it is developing new collaborative programs in Alamogordo and in Roswell/Carlsbad. The UNM Cancer Center also supports several community outreach programs to make cancer screening, diagnosis and treatment available to every New Mexican. Learn more at www.cancer.unm.edu.
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