NIH awards $10.4 million to Scripps Research Institute and Scripps Florida

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NIH awards $10.4 million to Scripps Research Institute and Scripps

Florida

22 Jun 2005 Medical News Today

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 screening center at The Scripps Research Institute and Scripps

Florida 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, and 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 A. Lerner, M.D. " 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. "

" 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, " says

Scripps Research Professor Hugh Rosen, M.D., Ph.D., who is the

principal investigator on the grant.

" Congratulations to The Scripps Research Institute, Scripps Florida,

Dr. Lerner, Dr. Hugh Rosen, and the entire Scripps team for

receiving this most significant grant from the National Institutes of

Health, " said Florida Governor Jeb Bush, who was instrumental in the

creation of Scripps Florida. " 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 G. Schultz, Ph.D., the

Scripps Family Chair in Chemistry at Scripps Research. " 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

scientists at Scripps Florida's temporary facilities in Jupiter,

including phine Harada, Ph.D.

Nick Tsinoremas, Ph.D., 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

, Ph.D., 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, 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, Ph.D., 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

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.

About The Scripps Research Institute

The Scripps Research Institute, headquartered in La Jolla,

California, in 14 buildings on 100 acres overlooking the Pacific

Ocean, is one of the world's largest independent, non-profit

biomedical research organizations. It stands at the forefront of

basic biomedical science that seeks to comprehend the most

fundamental processes of life. Scripps Research is internationally

recognized for its research into immunology, molecular and cellular

biology, chemistry, neurosciences, autoimmune, cardiovascular, and

infectious diseases, and synthetic vaccine development. Established

in its current configuration in 1961, it employs approximately 3,000

scientists, postdoctoral fellows, scientific and other technicians,

doctoral degree graduate students, and administrative and technical

support personnel.

Scripps Florida, a 364,000 square-foot, state-of-the-art biomedical

research facility, will be built in the near future in Palm Beach

County. The facility will focus on basic biomedical science, drug

discovery, and technology development. Palm Beach County and the

State of Florida have provided start-up economic packages for

development, building, staffing, and equipping the campus. Scripps

Florida now operates with approximately 100 scientists, technicians,

and administrative staff at 40,000 square-foot lab facilities on the

Florida Atlantic University campus in Jupiter.

Scripps Research Institute

http://www.scripps.edu