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Chemical Genomics

NIH conference focuses on emerging area of using chemistry to tackle biological problems

March 29, 2004 | A version of this story appeared in Volume 82, Issue 13

NHGRI Deputy Director Alan E. Guttmacher (from left), Lander, Schwab, and Austin exchange ideas at the conclusion of the two-day meeting.
NHGRI Deputy Director Alan E. Guttmacher (from left), Lander, Schwab, and Austin exchange ideas at the conclusion of the two-day meeting.

After years of operating independently of each other, chemistry and biology are once again coming together to address challenging biological systems. The emerging field--known as chemical genomics--holds the promise of preventing, diagnosing, and even curing a wide range of diseases.

To illustrate the diverse opportunities and challenges of this emerging area, the National Institutes of Health hosted a meeting on March 15 and 16 called "Chemistry & Biology: Partners in Decoding the Genome." Cosponsored by NIH's National Institute of General Medical Sciences (NIGMS) and National Human Genome Research Institute (NHGRI), the meeting attracted more than 300 chemists, biologists, and other scientists to hear presentations on a range of topics including organic synthesis, information management, and drug discovery.

"The breadth of the science in the symposium was a great illustration of the many useful ways that chemistry and small molecules can contribute to advances in biomedical science," said John M. Schwab, program director in the Division of Pharmacology, Physiology & Biological Chemistry at NIGMS and coorganizer of the meeting. The work presented at this meeting shows that there are "great opportunities for academic scientists who are willing to break out of the historical patterns of doing science," he pointed out.

"I felt like I was at a scientific all-star game, where every person getting up to bat is a 0.400 hitter and hits a home run," said fellow meeting coorganizer Christopher P. Austin, senior adviser to the director for translational research at NHGRI. "We have seen these 'the whole is greater than the sum of the parts' insights in genomics many times, and I think this meeting demonstrated to us that we can look forward to these kinds of paradigm-shifting insights from chemical genomics as well," he said.

Although the meeting was not part of the NIH Roadmap for Medical Research--which was launched last year to transform the way NIH does research (C&EN, Oct. 6, 2003, page 10)--the theme of the meeting was tied to the road map's Molecular Library initiative, NIGMS Director Jeremy M. Berg explained. The goal of this initiative, which falls under the broad area of new pathways to discovery, is to encourage the application of chemistry to important biological problems.

NIH Director Elias A. Zerhouni was on hand to underscore the importance of chemical research to the success of this initiative. The mission, he noted, is not drug discovery, but rather "an attempt at providing tools that will allow us to interrogate biological systems in a quantitative way."

"The meeting served to showcase chemistry to the NIH community, and it will help focus our thinking about the new road map or other NIH initiatives," Berg told C&EN. He also pointed out that meetings like this one help uncover which biological problems can be solved in a straightforward way and which ones will require more time and scientific advances to crack.

To that end, Zerhouni kicked off the meeting by sharing an important historical note about the interaction of chemistry and biology. According to Zerhouni, it was the American Chemical Society in 1930 that pushed NIH to transform itself from a hygienic laboratory with an epidemiology focus into an agency that included basic science--in particular chemistry.

Since that time, the connection between the two sciences has faded. "Now is the time to converge chemistry and biology again and have the two fields ignite each other in a way, I think, that was not possible a few years ago," Zerhouni said.

But for this reconvergence to occur, chemists and biologists must learn to talk to each other. "It's a sociological experiment," explained Stuart L. Schreiber, Howard Hughes Medical Institute investigator and chemistry professor at Harvard University. He noted that in some cases chemists don't realize that small molecules designed in their labs are being screened as potential drug leads. Making chemists aware of these studies will help get them involved in biological research and lower the barriers to collaboration, he noted.

"Chemical genomics is fertile territory that remains relatively uncultivated, since most academic research is directed by a single faculty member, and the vast majority of faculty pursue their research in either chemistry or biology, rather than the interface area," NIGMS's Schwab told C&EN. "Although academic chemists and biologists use one another's skills from time to time, our speakers showed the tremendous benefits that can come from a more synergistic, interdisciplinary approach."

For example, Kevan M. Shokat, professor of chemistry at the University of California, Berkeley, and professor of cellular and molecular pharmacology at UC San Francisco, discussed how his lab was developing new chemical tools to fill in the gaps after genetic and biochemical tools have been applied.

"Now is the time to converge chemistry and biology again and have the two fields ignite each other."

USING THE FAMILY of protein kinases, Shokat has developed a method to engineer a protein of choice (in this case a specific kinase) in a way that does not affect its activity. The method involves engineering a binding pocket for a small-molecule inhibitor, which binds with a high degree of specificity. He used this approach to show how a targeted kinase can then be tracked to uncover its function.

Another example of research at the chemistry and biology interface was presented by David R. Liu, professor of chemistry and chemical biology at Harvard University. Following nature's lead, Liu has developed a new approach to controlling chemical reactivity based on effective molarity. He has also developed a new way to discover functional synthetic molecules using methods that are similar to biological evolution.

Liu uses DNA-templated organic synthesis to direct a wide range of chemical reactions. When complementary DNA oligomers linked to small-molecule groups undergo Watson-Crick base pairing, chemical reactions between the groups take place in a sequence-programmed manner. Liu showed data that templated reactions will often occur even if the reactive groups are separated by large distances on the template, enabling multistep DNA-templated synthesis. This approach was used to translate a library of DNA into a library of corresponding multistep synthetic small molecules. A single member of the DNA-templated library was selected in vitro for target protein affinity and identified by the sequence of the associated template after PCR amplification.

Computational methods are also playing an important role in chemical genomics. One example of how these methods can be used in drug discovery was presented by Dimitris K. Agrafiotis, senior research fellow and team leader of molecular design and informatics at Johnson & Johnson Pharmaceutical R&D.

Agrafiotis described his work at Johnson & Johnson to develop an integrated suite of chemi-informatics tools known as DirectedDiversity. The program has the power to generate more than 300 million compounds that are potential drugs in a virtual screening process that takes less than seven seconds and can be run on a laptop computer.

Although the meeting provided a number of examples of how chemistry can be used to unlock biological mysteries, the field of chemical genomics is only in its infancy. Eric Lander, director of the Eli & Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard, noted that the field stands at the same place genomics stood 20 years ago and pointed out that for chemical genomics to make strides, heavy investments must be made in it over the next decade.



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