May 15, 2010 (Vol. 30, No. 10)

NIH Chemical Genomics Center Utilizes a Broad and Diverse Range of Technologies

Following completion of the Human Genome Project (HGP) in 2004, the scientific community moved to apply this knowledge to gain a better understanding of human disease. Specifically, the analysis of small molecules offered a unique opportunity toward the development of therapeutics.

To investigate this new area of science, the NIH Chemical Genomics Center (NCGC) was established, effectively creating a disease-research extension of the HGP. From an organizational standpoint, the center is unique in its focus on shared knowledge. The vehicle for disseminating much of this information is PubChem. Through this database, the discoveries at the center serve as major resources.

Additionally, the NCGC, intramural NIH project scientists, and extramural investigators maintain a close collaboration through a molecular libraries probe production centers network (MLPCN). In addition to the direct deposition of data generated from MLPCN projects into the PubChem database, members of the network and their extramural collaborators often publish the findings resulting from small molecule screening and probe optimization as more in depth studies in scientific journals.

The MLPCN’s small molecule repository contains over 350,000 compounds that are used for small molecule screening across the network of centers. Resource allocation, flexibility in data handling, and timely turnaround for test results all facilitate the communicative efforts between the institutions operating in the network.

NCGC uses various technologies and methods for small molecule assay development, quantitative high-throughput screening (HTS), cheminformatics, and chemistry. Using these techniques, the NCGC aims to elucidate an efficient pathway to small molecule probe discovery, the applications of which can include therapeutic discovery.

The main activities of the center focus on screening molecular targets and cellular phenotypes, chemical optimization of verified chemotypes, and expanding technologies enabling chemical biology, including siRNA screening. While there are specific goals based on researching particular diseases and biological pathways, the programs that involve general signaling pathways, for example, apply broadly and allow for the expansion of high-throughout screening technologies across disease categories.

Outside of basic research, the center partakes in studies on cancer and infectious diseases of the developing world, including malaria, schistosomiasis, and trypanosomiasis. Through the center’s partnership with the NIEHS and EPA, an investigation of in vitro systems toxicology has also been under way.

The NCGC’s use of HTS, which permits both target-driven and phenotype-driven drug discovery, has enabled the examination of diverse biological responses of large numbers of chemical substances. The main function of the technology is to promote “rapid testing,” according to Doug Auld, Ph.D., group leader for genomic assay technologies, and James Inglese, Ph.D., deputy director of the NCGC.

Projects involve screening the compound library using high-quality assays, often designed with input from the NCGC, on robotically enabled platforms; the results of the screens are then analyzed using informatics procedures developed at NCGC. To maximize output for the variety of chemical compounds as dose-response relationships, practices such as the reduction of reagents through assay miniaturization and quality control  through reagent stability and assay variability testing have proved beneficial.

NCGC’s ability to perform concentration response-based screening or quantitative high-throughput screening is enabled by Kalypsys robotics. Here, Drs. James Inglese and Natasha Thorne examine three Staubli anthropomorphic arms and a 1,536-well plate gripper.

Industry Experience

Dr. Inglese, a former scientist at Merck and Pharmacopeia, uses his previous experience in the drug development industry to inform the process of HTS at the NCGC. “By understanding the system’s limits, be it an assay design or screening process, one can innovate beyond them.”

Since the primary mission of the NCGC is to apply the tools of small molecule screening and discovery to the development of chemical probe research tools, demand has grown for screening technology innovations, library storage, delivery systems, and data interpretation to maximize the center’s data production efficiency. Dr. Inglese emphasizes that the center has a clear need to understand the impact of assay technologies on the chemical biology under study.

“In the course of developing assays as proxy measures for complex biological processes we often introduce new complexities related to the assay technique that must be appreciated during the interpretation of the screening results.

“We find that considerations of both the basic enzymology and cellular biology underlying the basis of the technology are critical to interpretation of the data based on reporter gene assays.”

For instance, discoveries based on the use of bioluminescent reporters have prompted further research into the depths of chemical biology for studies based on these systems. Thus, the broad-based chemical studies that are conducted at the NCGC have proven applicable to molecules that lie outside specific categories of interest. 

The NCGC is also involved in training post-doctoral fellows in the use of the center’s technologies. Through the NCGC’s participation in the MLPCN, post-doctoral fellows can expand their previous education in basic research. The NCGC provides training on assay development technologies, screening and data analysis, and follow-up testing and chemical probe optimization. Post-doctoral fellows at the NCGC learn to collaborate with investigators in other academic, government, and private labs.

When matching post-doctoral fellows with project teams at the NCGC, Dr. Inglese says that they seek “scientists who wish to acquire the understanding and skills that will be useful in allowing them to become active in translational research, be that in the pharmaceutical industry, academia, or elsewhere.” He adds that the center is also looking for candidates who can work with an integrated, interdisciplinary team and demonstrate capabilities to master the highly technology-enabled processes in place at NCGC.

NIH post-doctoral fellows work with investigators to learn how to scale assays and acquire the means to interact with chemists to optimize compounds that have been discovered as potential drug candidates. According to Natasha Thorne, a current NIH post-doctoral fellow at NCGC, she has been offered the opportunity to work on projects that involve a broad spectrum of biological fields.

“Whereas my graduate student training largely involved independent research that delved deeply into a single, specific scientific question, my post-doctoral training at NCGC is multidisciplinary and involves establishing and maintaining collaborations with other scientists.”

Christopher Austin, M.D., director of the NCGC, is expanding the organization to include a focus on creating a pipeline of potential drugs for the treatment of rare diseases. In this regard, the NIH recently initiated a program to expand upon the work of NCGC and other screening centers’ work in the probe development pipeline.

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