Inside the Mind of NIGMS—You Never Know Where the Next CRISPR Will Come From

The paper that previewed the CRISPR revolution? NIGMS Director says you never know where the next high impact discovery will come from.

The paper that planted the seed for the CRISPR revolution? NIGMS Director says you never know where the next high impact discovery will come from.

If there ever was a Golden Age in bioscience research, it was 1998-2003, or so say those who lived through it. This was the time of the fabled doubling in the NIH budget. It launched many a young investigator’s career and doubled (or tripled) the size of many a senior PI’s lab force. But even before the doubling era yielded to the shrinking horizons of more recent NIH budget history, something funny happened to the “portfolio” of the leading NIH institute supporting basic cell science research, the National Institute for General Medical Sciences (NIGMS). The overall scale of NIGMS spending went up from around $25 million in 1999 to around $78 million in 2003 (a tripling at least in non-inflation adjusted dollars) but the percentage of investigator-initiated grants went down from nearly 99% to 80%, largely because of “programmatic initiatives,” mandates or perceived mandates from outside NIH to target favored diseases. That balance of 80/20 of investigator-initiated vs. programmatic NIGMS grants has stayed roughly constant ever since but that is going to change, or so says NIGMS Director Jon Lorsch in a “Perspective” column just published in MBoC.

“With the budget doubling more than a decade behind us,” Lorsch declares, “It is time to return the institute’s focus to investigator-initiated research, to ensure that new scientific territory is opened for exploration by adventurous investigators.”

NIGMS is moving the balance back toward investigator-initiated proposals because Lorsch believes that is where real longtime impact comes from, or in “NIH-speak,” that is where federal funders get the greatest ROTI, that is, return on taxpayer investment. Lorsch cites the string of discoveries by curiosity driven investigators that led to the development of restriction enzymes as an example of “a truly transformative advance that propelled biomedical research in the 1970s into the age of molecular biology and launched the biotechnology industry.”

Such transformative technologies arise from a “complex web of knowledge,” says Lorsch. “It is impossible to know in advance where in this web the next big breakthroughs will arise or which strands of knowledge will be required to make them.” He points to CRISPR, the hottest technology in bioscience today, which started from an obscure reference in a 1987 Journal of Bacteriology paper on a gene sequence in E. coli. Writes Lorsch, “Describing the mysterious repeat sequences, the paper ends with the sentence, “So far no sequence homologous to these has been found elsewhere in prokaryotes, and the biological significance is not known.” Slowly, through years of careful characterization of the CRISPR pathway, our understanding of what this initial observation meant fueled the development of a novel technology that has dramatically improved our ability to replace genes in living cells, paving the way for advances in medicine and biotechnology.”

Throughout, Lorsch takes readers on a surprisingly candid tour of recent NIGMS decisions and still-to-be-solved problems on how to best invest federal dollars in basic medical science. He lays out NIGMS thinking on weighing up grants by the number of investigators vs. the number of projects or the maximum productive size of a lab vs. the number of its NIH grants. He even tiptoes into the issue of funding young junior investigators vs. older established PIs. NIGMS doesn’t have a solution to that one yet but Lorsch is hopeful, basing his hope on how alarmed so many stakeholders are, not only NIH institute directors but academics, science policy wonks, Congress, and especially the junior investigators themselves.

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