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Vol. LVIII, No. 17
August 25, 2006

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Molecular Libraries: Creating a Unique Research Tool
Roadmap 'Pathways' Boldly Go Where No Others Have

On the front page...

What if you glanced around at your workload and figured that — even if you toiled away at a superhuman pace — you'd still need 10,000 years to get the job done? Essentially that's what's facing Dr. Christopher Austin and his colleagues at the NIH Chemical Genomics Center (NCGC). And rather than shrink from seemingly insurmountable odds, Austin and dozens of scientists like him are rallying around their gargantuan objective: To learn what happens to all the proteins in the human body when they are exposed — individually — to all the known chemicals in the universe.


For record-keeping purposes, that's testing each of about 500,000 proteins against each so-called small molecule; the number of known small molecules is like, 10 megazillion or something (expressed actually as 10 to the 50th power). If you're trying to do the math, it's probably easier to just keep adding zeroes. Austin, however, will tell you that it's exactly projects like his that the NIH Roadmap (which gave birth to NCGC) was devised to do — provide resources for researchers "to boldly go where no one has gone before."

One of hundreds of 1,536-well microtiter plates that NCGC uses for all of its screening  
"NCGC is an icebreaker of sorts," director Austin explains. "We knew going in that it was pretty audacious, that NIH had not traditionally been in this area."

Essentially, the chemical genomics center is using small molecules to understand the human genome, biology and cell function. The ultimate goal is to provide research tools that any institution — academic organizations, non-profits and pharmaceutical companies — can use to develop medicines and other therapies for disease. Already the project has made tremendous strides.

"The Molecular Libraries and Imaging initiative has accomplished its anticipated mission to bring the power of small-molecule high-throughput screening (HTS) into the larger biomedical research community," says Dr. Linda Brady, director of NIMH's Division of Neuroscience and Basic Behavioral Science, and — along with Austin — a principal designer of the Molecular Libraries Screening Centers Network. The network falls under New Pathways to Discovery, one of the Roadmap's three core areas.

The room-size Kalypsys screening system used by NCGC features industrial refrigeration and storage units.  
"[MLI] has empowered the research community to use small-molecule compounds in their research," Brady explains, "whether as tools to modulate genes and pathways, as imaging probes in basic or clinical applications, or as starting points for the development of new therapeutics for human disease. It is anticipated that these screening projects will facilitate the development of new tools and new drugs by providing early-stage chemical compounds that will enable researchers in the
Drs. Chris Austin (r) and Jim Inglese pose inside the system, with a Staubli “anthropomorphic” robot arm that does the work of screening.  
public and private sectors to validate new drug targets, which could then move into the drug-development pipeline. This is particularly true for rare diseases, which may not be attractive for development by the private sector."

Brady says one roadblock before the initiative was limited access by the public sector to small-molecule tools. "Small molecules have proven to be extremely important to researchers in exploring function at the molecular, cellular and in vivo level," she points out. "Such molecules have also been proven to be valuable for treating diseases; most medicines marketed today are from this class. A key challenge is to identify small molecules effective at modulating a given biological process or disease state. Currently, researchers must systematically screen [via HTS] tens or hundreds of thousands of small molecules to find a successful match between a chemical and its target. The capacity for HTS has been built within the pharmaceutical and biotechnology sectors for the purposes of drug development over the last 10 years, but similar resources did not exist in the public sector."

Enter NCGC. One of 10 high-throughput centers in the network — and the only NIH intramural facility — NCGC "doesn't exist anywhere else in the world on this scale," notes Austin. In the last 12 months, the center has run through 30 assays, generated more than 10 million results and entered the data into PubChem (the new database of small molecule structures and activities created at NLM as another part of the Molecular Libraries Initiative). NCGC collaborates with scientists at labs inside and outside NIH who bring assays to the center for screening and probe development.

"We are very interested in hearing from researchers who would like to work with us," says Austin, "and I encourage them to contact me if they have a project they feel would benefit from a chemical biology approach."

A close-up of the robot arm’s gripper, which picks up and moves the 1,536-well plates from one station to the other within the screening system. A barcode reader on the gripper identifies the plate it’s handling.

What distinguishes NCGC from outside centers is the risk-taking capability. Big pharmaceutical companies have similar set-ups, but their testing agendas are also narrowly tailored to hunt for potentially profitable drugs. It's NIH's ability to pursue and document basic knowledge about protein- chemical interactions that makes NCGC — and the network — so valuable. That's also what energizes the researchers working on it.

Research Associate Adam Yasgar works on a multimodal imager used for reading a wide variety of protein and cellular assay formats.  
"When we started the network," Austin explains, "we knew that it would require all the NIH mechanisms working together to succeed. This is a highly unusual initiative in that it has had intramural and extramural components from the beginning, taking advantage of the strengths of each. NCGC and the extramural centers complement each other."

Administratively located within NHGRI, he continues, "our interests are more general than the other centers. Our mission is certainly to produce chemical probes of genes, pathways and cell functions relevant to health and disease. But the long-term vision is to put these individual results together to annotate the genome using small molecules and establish general principles by which small molecules interact with their targets. To do this at the current pace with current technologies would take 10,000 years — a lot longer than any of us want to wait.

"This is similar to the situation at the start of the Human Genome Project, when technologies available were not sufficient to meet the ambitious goals of the project when it started. So we are very focused on developing new paradigms to make the entire process of probe discovery more efficient. The first of these, which we call 'quantitative high-throughput screening,' is described in a paper published in PNAS (see sidebar). [However], the reason the Molecular Libraries Initiative as a whole, and the screening centers network, have worked is because they've been highly collaborative and cooperative." Expertise from 21 NIH institutes contributed to development of NCGC.

Roadmap's MLI Initiative Marks Milestones

Some accomplishments of the Molecular Libraries and Imaging initiative since the Roadmap was announced in 2002 include:
  • Established large-scale molecular libraries, screening and informatics infrastructures for public sector. The components were integrated and became operational at the end of 2005.

  • Offered public-sector medical researchers access to automated screening technology, diverse compound libraries and information on biological activities of small molecules. To date, 74 assays received from the research community are being implemented by the 10 screening centers; 65,842 compounds with unique structures have been distributed to the screening centers for testing.

  • Made biomolecular screening data and assay protocols available to the public. As of August 2006, 962,380 substances have been tested in 49 biological and biochemical assays by MLSCN centers; 3,936 bioactive compounds have been identified; screening data together with assay protocols have been deposited into PubChem.

  • Developed novel chemical probe as a research tool. Bioactive compounds identified through screening are being evaluated by the centers; some of these have since been developed into chemical probes.

  • Identified bioactive compounds for drug discovery projects for rare disease. NCGC has completed a screening assay for a drug target for Gaucher disease. 48,125 compounds were tested and three distinct chemical series were found to have inhibitory activity. The project has high potential to produce a drug candidate for treatment of this rare disease.

  • NCGC announced July 24 the development of a new paradigm for profiling every compound in chemical libraries. Traditional high-throughput screening measures the biological activity of chemical compounds at just one concentration. The new approach, however, called quantitative high-throughput screening, or qHTS, tests the biological activity of chemical compounds at seven or more concentration levels spanning four orders of magnitude. The multi-concentration screen produces a pharmacological characterization of all the compounds that is far more complete and reliable than traditional methods. A paper published online in the Proceedings of the National Academy of Sciences describes the new method.
The infrastructure necessary to conduct the work is "highly automated, roboticized and, I'm afraid, expensive," Austin points out. Since June 2004, when NCGC began, he has gone from having 1 staffer, no projects and no lab to 27 staff members, 56 projects and (by October, if construction promises are kept) 15,000 square feet of lab space. Of the more than two dozen scientists working at NCGC, all but three were recruited from pharmaceutical or biotech firms, where these technologies were developed and are in routine use.

Housed in a huge multi-building complex adjacent to Shady Grove Hospital in Rockville, NCGC boasts top-of-the-line robots and computer equipment able to sample and assess more than a thousand compounds in a single maneuver.

Imagine a human lab tech individually pipetting tiny amounts ("a millionth of a milliliter!" Austin clarifies) of hundreds of thousands of small molecules into multiwell trays with meticulous precision. The project would literally take forever.

In NCGC's basement, a room-size triple-armed robot goes to work, complete with several sample-storing fridges, automated incubators and computers to control its movements. It goes through hundreds of thousands of small-molecule compounds in a matter of hours. Still, with all available equipment humming along efficiently, Austin estimates the center can complete only about 50 assays tested against the 100,000 small molecules in the compound collection per year. That's why the Roadmap also funds nine centers outside NIH — every facility that can perform a different aspect of the work allows scientists to chip away at that 10,000-year mark.

"It's like doing a jigsaw puzzle with 500,000 pieces — and most of the pieces don't have any pattern or picture on them to give you a clue about what goes with what," Austin said, pointing out NCGC features during a recent tour. He and his deputy, Dr. James Inglese, both left similar projects at private biotech/big pharma companies. Their enthusiasm for this work is palpable. Sure, putting together something of this magnitude is a monumental undertaking. But the Roadmap provides unique benefits — time, resources and freedom to explore.

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