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."
"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."
|One of hundreds of 1,536-well microtiter
plates that NCGC uses for all of its screening
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.
"[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
|The room-size Kalypsys screening system
used by NCGC features industrial refrigeration and storage
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."
|Drs. Chris Austin (r) and Jim Inglese pose
inside the system, with a Staubli “anthropomorphic” robot
arm that does the work of screening.
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
||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.
"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."
|Research Associate Adam Yasgar works on
a multimodal imager used for reading a wide variety of protein
and cellular assay formats.
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.
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.
Roadmap's MLI Initiative Marks Milestones
Some accomplishments of the Molecular Libraries and
Imaging initiative since the Roadmap was announced in 2002
- 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
- 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.
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
"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.