Vol 5. Issue 20 / June 20, 2005
NIH Awards $10.4 Million to Scripps Research in La Jolla and Palm Beach County
By Jason Socrates Bardi
A group of researchers at the La Jolla, California, and Palm Beach County, Florida, campuses of The Scripps Research Institute has been awarded a $10.4 million dollar grant from the National Institutes of Health (NIH) to establish The Scripps Research Institute Molecular Screening Center. This is a pilot program to discover small-molecule tools for translating basic biomedical discoveries more quickly into medically relevant applications.
The Scripps Research screening center, together with nine screening centers from the public and private sectors, will comprise the Molecular Libraries Screening Centers Network (MLSCN), a part of the NIH's strategic funding plan, the Roadmap Initiative. The funds will be administered jointly by the National Institute of Mental Health (NIMH) and the National Human Genome Research Institute (NHGRI) on behalf of NIH. The work, which is scheduled to last three years, begins this month.
These centers will conduct high throughput screens against various biological targets to uncover "proof-of-concept" molecules useful in studying human health and in developing new treatments for human diseases.
"This sort of work has traditionally been done by pharmaceutical companies, never before in the public/non-profit sector," says Scripps Research President Richard A. Lerner. "With this grant, the NIH has recognized the unique capabilities of our established researchers in La Jolla with our newest investigators and equipment in Palm Beach County."
Scripps Research Professor Hugh Rosen, who is the principal investigator on the grant, says, "Our goal is to provide tools for the broad scientific community so that we can accelerate the pace of the application of chemical biology to the understanding of physiology and pathophysiology."
Florida Governor Jeb Bush, who was instrumental in the creation of Scripps Florida, congratulated the entire Scripps Research team, adding: "Today's announcement is a testament to the dynamic synergy that exists between The Scripps Research Institute/Scripps Florida and our national objectives to cure disease and improve human health. I am proud of Scripps Florida, its scientists, and the Florida support organizations that will participate in the implementation work associated with this grant. This kind of cross-pollination between The Scripps Research Institute and its East Coast campus, Scripps Florida, is an example of the synergies we envisioned when we first approached Scripps, and is only a precursor of what lies ahead."
The Grant: Part of the NIH Roadmap Initiative
The NIH Roadmap Initiative (see: http://nihroadmap.nih.gov) is a series of separate initiatives, many of which cross the traditional boundaries between the NIH's 27 institutes and centers. One of these initiatives is the "Molecular Libraries and Imaging" initiative, which aims to provide university investigators and other publicly funded researchers with high-throughput screening resources and small-molecule tools for exploring human proteins and other molecules involved in human health and disease.
One such resource is called the Molecular Libraries Small Molecule Repository, a public collection of hundreds of thousands of chemically diverse small organic compounds. This repository consists of the active ingredients of drugs approved by the U.S. Food and Drug Administration (FDA), a targeted set of bioactive compounds, natural products, and other compounds. These molecules are "probe-like" in terms of their size, structure, and other properties, and scientists expect that many of them will interact in some way with the various human proteins and other molecules involved in different diseases. The only question is how—which probe-like compound will interact with which human "target" involved in which disease? Once these "targets" are identified, scientists armed with this knowledge can take the next step and work on finding ways to control or otherwise correct them.
By placing these molecules in the Small Molecule Repository, the NIH is granting biomedical researchers access to them. Gaining access to the compounds will allow public sector scientists to explore these questions, and the Molecular Libraries Screening Center Network grant is intended to speed the process along.
The MLSCN will act as a national resource capable of providing relatively high-throughput screening approaches for taking a significant number of targets, testing them against hundreds of thousands of compounds from the Small Molecule Repository, and coming up with new chemical probes to study the normal and abnormal physiology of cells, organs, model systems, and/or organisms.
"With this sort of approach, we can learn things we would not necessarily have stumbled across given what we currently know," says Rosen, who cites the high-throughput screening research established in La Jolla in the last few years by Scripps Research Professor Peter G. Schultz, who also holds the title of Scripps Family Chair in Chemistry. "Our competitiveness rested on the critical infrastructure put in place by [Professor] Schultz."
The Search for Proof-of-Concept Molecules
In the world of basic biomedical science, a great disparity exists between the information that's available and the information that's useful.
There is almost no end to the available information that basic biomedical science has uncovered. We know of hundreds of diseases that afflict humankind, thousands of distinct phenotypes and physiologies that characterize human health and disease, tens of thousands of genes that are in the human genome, an even larger number of protein variants and other products made by these genes, an impossible to estimate number of interactions that these various biological molecules make in the body, and an almost infinite universe of "probe-like" small chemical compounds that might possibly modulate these interactions.
But what would be most useful to know for any one disease is which particular human molecules are interacting and which exact type of small chemical compounds could modulate these interactions.
The primary goal of the Molecular Libraries Screening Center Network is to help close these gaps for diverse "targets" involved in health and disease.
Ultimately, the Scripps Research scientists will be tasked with screening at least 100,000 compounds per year against 20 or more different targets to develop probes that Rosen refers to as proof-of-concept molecules. These proof-of-concept molecules will be compounds that modulate these targets in ways that allow other scientists to test biological hypotheses and define the key properties of the target and its related physiology or disease.
To take an abstract example, a target might be a membrane-spanning protein that is believed to be involved in inflammation. A proof-of-concept molecule would be one that activates the protein and produces an inflammatory effect—or conversely, one that blocks the protein and protects from inflammation.
The target need not be a defined molecule, but might be a cellular process or complex pathway such as the complicated process of synthesis and secretion of insulin in the body. A proof-of-concept molecule in this sense would be one that induces insulin production, and such a molecule would be helpful in establishing which particular human proteins are involved in the process.
These proof-of-concept molecules may also open promising avenues for drug development in academic laboratories or in the biotech or pharmaceutical sectors because some of them may show some degree of efficacy against a particular target. These could serve as "lead compounds," or starting points for designing what would eventually become a new drug.
Research Across the Nation: From La Jolla to Palm Beach County
This grant is the first to fund a variety of activities across the two campuses of Scripps Research. Assay development will take place in La Jolla, and the high-throughput screening will be conducted by Scripps Florida scientists, including Josephine Harada, at temporary facilities in Jupiter.
Nick Tsinoremas, senior director of Bioinformatics at Scripps Florida, will oversee the establishment of a data management infrastructure for managing and analyzing the flood of data that comes from those screens. He will also develop the interfaces for users and for scientific instruments so that data can be automatically analyzed and uploaded once acquired. The data will have to be standardized and pass quality control to ensure it is accurate and relevant.
After the data is acquired, scientists in La Jolla and Palm Beach County will perform high-level data analysis. If a compound interacts with a particular molecular target, they will investigate the interactions of the compound and whether these interactions could be adjusted to optimize the compound's drug-like characteristics—its potency, solubility, stability, the degree to which it is absorbed by the body, and whether or not it is degraded into dangerous metabolites in the body.
These are all issues that fall generally within the purview of Pat Griffin, professor in the Department of Drug Discovery and head of Drug Metabolism and Pharmacokinetics at Scripps Florida. By looking at which compounds are the most promising, Griffin and his colleagues will be able to take them a step further by modifying the compounds to optimize some of their chemical features.
Key to this effort will be a chemistry group in La Jolla led by Assistant Professor Sheng Ding, who is a graduate of Scripps Research's Kellogg School of Science and Technology. Ding and the other chemists in La Jolla will take the information generated by Griffin and others and perform medicinal chemistry on individual compounds—making improved versions, including some that may serve as high-quality leads for drug design. Ding and his group will also be helping to develop some of the screens that the Molecular Libraries Screening Center Network will utilize as well as some of the chemical probes that will be used in these screens.
Finally, all the chemical structures and biological data generated by the network screening centers will be deposited into a government-owned database called PubChem, which is a component of the NIH Molecular Libraries and Imaging Roadmap Initiative and maintained by the National Library of Medicine.