Perspectives from the National Institutes of Health

Marvin Cassman

Director, National Institute of General Medical Sciences

National Institutes of Health

The interplay between the biological sciences and solid state sciences is clearly manifest in the rapid acceleration of the number of crystal structures of proteins that are being determined. Over the course of 10 years, 1987-97, for example, the number of protein crystallographic structures that have been deposited in the Protein Data Base has increased from tens to thousands. This rapid increase in the number of structures has been made possible, in part, by the improvements in x-ray synchrotron sources. Over this period, the x-ray brightness has increased by orders of magnitude—from first-generation sources, like the Stanford Synchrotron Radiation Laboratory, to second-generation sources, like the National Synchrotron Light Source at the Brookhaven National Laboratory, to third-generation sources, like the Advanced Photon Source (APS) at the Argonne National Laboratory. At present, within a 90-minute experiment at the Advanced Photon Source, sufficient data can be collected to determine a structure. The rate-limiting step in a structural determination is the ability to produce a high-quality crystal. Although x-ray brightness is a key element in the massive increase in the number of crystal structures determined, the need and desire to know the spatial distribution of chemical entities as well as the realization that distribution underpins the functionality of the protein have also been of critical importance to this growth.

This coupling of the need from the biological community with the advances in the x-ray sources, constructed primarily for solid state science research using traditional funding sources like the Department of Energy (DOE) and the National Science Foundation (NSF), has provided a synergy that is virtually unparalleled. The excitement over such advances comes at a cost. It is very apparent that biologists are becoming increasingly heavy users at the synchrotron sources, which draw their operational costs from the physics and materials sciences at the DOE and the NSF.

This raises an important question as to how funding from the National Institutes of Health (NIH), the primary funding agency of biological research, can be introduced effectively and efficiently into the picture. The recent report of the Basic Energy Sciences Advisory Committee on Department of Energy Synchrotron Radiation Sources (the Birgeneau/Shen Report) clearly states the desirability of restricting the operation of the sources to only one funding agency. Using multiple funding agencies to operate a single source would lead, in the opinion of the report, to duplication of effort, unnecessary complication of operations, and inefficiency. Yet, the dilemma stands as to the partitioning between different agencies of funding for these sources, for supporting staff scientists, and for instrumentation.

A study that was recently released from the Office of Science and Technology Policy addresses this issue. The working group that produced the report consisted of representatives from the NIH, DOE, the NSF, and the National Institute of Standards and Technology. Some of the more important findings of this study are discussed below.

How can this rapid expansion in protein crystallography be supported? It is clear that existing facilities are being stretched to their limit in terms of the staff scientists. It is inconceivable that current staff levels can support increased demand. Consequently, enhancing the number of the staff and the number of staff capable of interfacing with the biological community is imperative. In particular, it should be possible for a biologist, totally unfamiliar with diffraction methods, to determine the crystal structure of a newly isolated protein without having to spend years in developing an effort in crystallography. Along with this, improved access procedures to existing sources need to be established. Procedures need to be set in place where nonspecialists can perform experiments at the sources and walk away with a crystal structure in a easy and straightforward manner.

Although many advances have been made in the sources, advances in experimentation require parallel advances in the supporting equipment. This includes advances in the detectors, the diffractometers, and the ancillary equipment. If the efficiency in detecting diffracted x-rays does not keep pace with the advances made to the source, then what has been gained? Similarly, if the limiting step in data accumulation rests with the



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