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by Celia Hooper

The most recent meeting of the Advisory Council to the Director (ACD) of NIH, June 4, featured a discussion best described as "whither NIH research in an era of increased funding?"

Although no one knows how fast the NIH budget will grow, NIH director Harold Varmus thought it would be useful to consider how additional funds could best be used.

One group of 30 leading biomedical investigators assembled informally on a crisp, sunny Sunday morning in mid-February to address the question at the Watergate apartment of Bruce Alberts, head of the National Academy of Sciences. The folks came–on their own dime–from as far away as California, and were invited by Alberts and Eric Lander, director of the Whitehead/MIT Center for Genome Research in Cambridge, Mass., because they were deemed to be individuals who could see the big picture and not just argue for their own particular institution or discipline. Alberts’ furniture was moved aside to make room for chairs for everyone.

Site-Specific Targeting

The brainstorming session, led by Lander, also an ACD member, focused on four broad areas and then filled in specifics. The broad areas included which particular research topics were ripe for added support, what funding mechanisms should be used to provide the support, training issues, and what additional infrastructure was needed to support the growth of research.


Lander summarized the conclusions of the crowded crew for the ACD. Particular research areas that would and should be growing included genomic infrastructure, cell circuitry and molecular medicine, the development of disease models, cancer research, neuroscience, world health, bioengineering, and genetic engineering, including stem cell research. For genomic infrastructure, he said, a key fact of life will be that the scale of incoming information will zoom as the numbers of genes sequenced rise by orders of magnitude. NIH could expect in the not-too-distant future to see an entire mammal genome sequenced each year.

As the newly sequenced genes emerge, they will yield up for study vast numbers of proteins for which scientists will want to identify functions. This desire will mean a second, postgenomic, echo boom in research determining the complete molecular circuitry of the cell. Lander said that this research should be tightly coupled to molecular medicine, supported with lots of what NIGMS Director Marvin Cassman called "glue" grants to provide money just to bring different types of scientists together on projects. Essential to determining circuitry, as well as making the link to disease, will be animal models. Lander said the group also predicted that cancer research would be one of the areas capitalizing on the strides in molecular medicine, as would neuroscience, which is now driven by both neurogenetic discoveries and powerful new imaging breakthroughs.

Some of the increased funding should be directed to Third World diseases, Lander said, because these have been neglected in the past, and understanding the diseases could benefit all countries. Bioengineering similarly has been neglected because many NIH study sections simply didn’t see "building tools" as an appealing way to spend money. Research on stem cells and genetic engineering techniques is another booming area that could benefit from additional funds.

In an interview, Alberts recalled that as the morning wore on, various participants in the Sunday gathering would get up to make sandwiches for themselves from the deli offerings he had laid out. Sunlight danced on the Potomac River, visible from Alberts’ apartment, but the gatherers were not distracted from their task. A key point emerging from the discussion of funding mechanisms, Alberts said, was a surprising negative: that money should not just be poured into funding more RO1 grants. "We need to do something more creative," he said.

Tending to Talent

Lander told the ACD that as the Sunday gathering addressed mechanisms for supporting science, they suggested funding should be used to "keep bright people in the system." This might require some long-range rethinking of optimal numbers and sizes of grants, perhaps leading to loosening up the currently narrow range of grant sizes. At present, Lander said, grants cluster tightly around an average size of $160,000, with support for 1.7 full-time scientists. In remarks tinged with shades of the existing NIH intramural program, Lander said that focusing instead on providing long-term support of a particular scientist would make it easier for him or her to switch fields as interests changed and would smooth out funding peaks and troughs that can squeeze productivity or even create "cliffs" that spell the end of scientists’ careers.

In the broad area of training, the Sunday session cited training medical researchers as a priority for increased funding. Participants also felt that the level of support provided by NIH biomedical training grants should be reexamined: It does not appear to compare favorably with other fields, and more attention should be devoted to attracting minority scientists to biomedical research.

Building up infrastructure to support growth in biomedical research would also be important, Lander said. The Sunday assembly concluded that large, shared instrumentation was "grossly undercapitalized." Major shared facilities should be considered in the areas of combinatorial drug screening, advanced light sources for molecular structure, brain imaging, and computing. With respect to light sources, Lander said new X-ray synchrotron beam lines are needed for crystallography, with appropriate staffing and technical assistance to allow researchers at the proposed center to solve one molecular structure per day. Additionally, funds should be applied to the renovation or reconstruction of transgenic mouse facilities and perhaps a single, nationally shared clinical-trials facility.

Fair Sharing

Alberts said one of the things he found most surprising was the willingness of the mavens assembled in his apartment to accept the concept of creating shared core facilities, which inevitably would require some central, top-down planning. Alberts observed that this goes strongly against the common grain: Scientists have typically expressed a preference for the bottom-up, investigator-initiated approach of the RO1 and against top-down mandates such as the War on Cancer.

Lander’s discussion of shared facilities drew strong reactions from ACD members. Marc Kirschner, chairman of the Cell Biology Department at Harvard Medical School in Boston urged that the integrative approach–bringing together teams of scientists–should be a fundamental theme. Two areas, physiology and pharmacology, appear destined to undergo profound changes in the immediate future, thanks to the creation of transgenic mice and the vast numbers of genes that are now being sequenced, Kirschner said. Proportional to the increase in sequenced genes, he predicted, would be a huge number of chemical reagents that scientists would want to create and study through high-throughput screening. This would place demands on bioinformatics comparable to those emerging from gene discovery and would also necessitate the development of powerful chemistry research tools, protein-profiling systems, and mass-spectrometry approaches. These would require teams of scientists, including chemists, engineers, and computer scientists, as well as molecular biologists, pharmacologists, and clinical investigators who could then apply discoveries to the detection, treatment, and prevention of specific diseases.

Kirschner’s vision of such integrative science facilities sounded familiar to ACD member Philip Needleman, senior vice president of the Monsanto Company in St. Louis. Needleman estimated that if, to date, there had been 500 proteins identified as possible targets for therapeutic intervention, then in the years ahead there could be 100,000. In industry, he said, discovery of a juicy therapeutic target would result in a company tasking dozens of pharmacologists, chemists, and molecular biologists to the project. This sort of approach would not likely be possible for academia, he observed, and if the government were to head in this direction, it should work on diseases companies wouldn’t pursue due to inherent lack of profit potential.

All-Stars Approach

ACD member Shirley Tilghman, professor of molecular biology at Princeton (N.J.) University, suggested that academic scientists might not be attracted to the large-team-approach in tackling scientific problems because this was fundamentally contrary to the culture of universities, which rewards the individual for independent achievements. "We aren’t training people for this," Tilghman stated. She then asserted that government-supported centers established in the past were not good models for group efforts because some of the research conducted there was not of the highest quality.

ACD member Susan Horwitz, a professor at Albert Einstein College of Medicine, added that often the potential members of integrated research teams–MDs and PhDs–spoke "different languages," and finding time to fit in cross-training would be very difficult because thesis projects are becoming increasingly complex.

As the ACD discussion moved on to other areas and toward the morning coffee break, there seemed to be a sense that Alberts’ Sunday soundings had painted an exciting big picture, but that was actually the easy part. Resolving problems like changing the culture of science and creating integrated teams of cooperative scientists to pursue the vision would take more than 30 bright minds and one Sunday.

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