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Rheumatology Researchers Should Learn from their Lab Animals, Not Imitate Them
by Bruce N. Cronstein, MD
Recently, my laboratory manager came to my office to report on what was happening in the laboratory. She told me about the progress of a number of ongoing experiments and projects that were beginning or that we were just completing. This was a generally optimistic and upbeat meeting, but as she was about to leave, her body language began to shift. Her eyes were downcast and she looked like she was trying to run out of the room. I knew that the news would be bad. Then she told me—the mice that we had been breeding in anticipation of a critical experiment had had their first litter, but there was a problem. The mouse mother had eaten all of the pups, so we would have to start over and the experiment was on hold for another few months.
This disaster was a clear consequence of a decision we had made years before. We had bred our knockout mice onto a common strain of laboratory mice, C57Bl6 mice, so that the genetic background of these mice would be uniform. C57Bl6 mice are known to have a number of immunologic and other peculiarities, but for my lab the biggest problem with C57Bl6 mice is their behavior. These mice are notorious for eating their young.
In addition to animal husbandry issues, there are many obstacles to successful research. Coming up with an interesting and compelling hypothesis to test, designing experiments that fairly test the hypothesis, and executing the experiment are just the tip of the iceberg. The greatest barrier to successful research is, increasingly, funding.
The budget for the National Institutes of Health (NIH) has been flat for several years, reflecting the strains in the federal budget, and many foundations that support research have watched their resources shrink over the past few years so that the percentage of research proposals that are supported is declining. When the percentage of research proposals that gets funded falls (currently 11% of grant R01 proposals are funded by the National Institute of Arthritis, Musculoskeletal, and Skin Diseases) the funding decisions for specific grants become more and more arbitrary and capricious—a grant at the 11th percentile is probably no better than one at the 12th percentile, although both are likely much better than one rated at the 25th percentile.
Rheumatologists, as a group, tend to be detail oriented, critical thinkers with strong opinions, and these same characteristics make them extremely rigorous as grant reviewers.
Peer review has been both the greatest strength and the greatest difficulty in research funding. Review of proposals by a group of scientists with expertise in a specific research area generally results in a fairer distribution of scarce resources and ends up directing research funds to the area where the science is the best. This contrasts with other systems in which a small claque of investigators controls all of the funding (and all of the science); being a member of the club is more important than proposing the best science. So, it seems fair to balance the review groups that rate rheumatic disease research projects with researchers in the area.
The NIH goes to great lengths to assure that researchers in the rheumatic diseases are represented on the committees that review research proposals, although the main committee reviewing rheumatic disease research proposals also reviews research proposals in skin diseases, as the parent institute funds research in both the rheumatic and skin diseases. Herein lies the problem. Rheumatologists, like C57Bl6 mice, eat our young (researchers). Moreover, eating our young is only an appetizer for gobbling our peers.
Lessons from Lab Rodents
Rheumatologists, as a group, tend to be detail oriented, critical thinkers with strong opinions, and these same characteristics make them extremely rigorous as grant reviewers. But researchers in the area of rheumatic diseases tend to be more skeptical than many other groups that seem more supportive and inwardly focused. So, when rheumatologists review grants, they see the empty half of the glass. The clear consequence of this approach is that a grant proposal reviewed by a rheumatologist will end up at the 12th percentile but a grant proposal of identical merit reviewed by an investigator from a more supportive group will be judged to be in the 8th percentile. Both grants are rated as outstanding, but only one will be supported—and the people running the NIH say we have no choice, this is what our outside experts tell us to do.
Obviously, telling reviewers who are rheumatologists to automatically score rheumatology grant proposals more highly is inappropriate and should be discouraged. Nonetheless, adjusting our glasses so that they impart a somewhat more rosy tinge would help support research in the rheumatic diseases. Unlike our mice, rheumatologists can be taught not to eat their young or to gorge on the mutton of our senior investigators.
Dr. Cronstein is the Paul R. Esserman Professor of Medicine and director, Clinical and Translational Science Institute, New York University School of Medicine in New York.