Getting it right

Somewhere around 30 years ago, a young scientist sent a grant application to the National Insitutes of Health. The scientist worked at an obscure research center in Smithville, Texas — an institution as far as imaginable from being elite. The grant proposal dealt with a series of antibodies made by the applicant to T cells of the immune system. The pattern of reactivity of the antibodies was weird, giving evidence that different T cells had surprisingly variable patterns of reactivity to the panel of antibodies. Irrespective of the weirdness of the science, the young age of the applicant, and the obscure nature of the institution to which the applicant was affiliated, a member of the review group recognized that the science might hold great promise.

The applicant was James Allison. His antibodies were recognizing the T-cell receptor – which, of course, varies from T cell to T cell in order to establish specificity for that arm of the immune-response pathway. The reviewer was Marian Koshland. The grant was funded. Koshland was so impressed with the application that she and her colleagues recruited Allison from Texas to the University of California, Berkeley. There, Allison studied the pathways controlling T-cell activation, helping him to co-discover that a T-cell protein called CTLA4 normally dampens the immune response pathway. While at UC Berkeley, Allison also began his quest to discover therapeutic antibodies that might relieve the inhibitory activity of CTLA4 and thereby stimulate the immune-response pathway.

Fast-forward, and we see that Allison’s science has led to one of the biggest breakthroughs in cancer treatment ever: the development of therapeutic antibodies that assist the immune systems of patients in clearing away tumor cells. Allison was the 2015 winner of the Lasker–DeBakey Clinical Medical Research Award. What a wonderful story!

What nuggets of information can we learn from this story? First and foremost — to me — is the fact that Allison’s work dealt exclusively with basic science. He wanted no more than to understand the weird observation that different antibodies could distinguish variation on the surfaces of different T cells. He did not set out to find treatments for cancer; he was simply studying fundamental biology. Second, Allison’s initial discovery of merit came while he was working at an obscure research institution. One does not have to be in the imperial halls of science to make discoveries of consequence. Third, the grant-review system was successful in sorting the wheat from the chaff in its evaluation of Allison’s first grant application. Who knows, if not for Koshland’s eagle eye for scientific merit, melanoma patients might not be benefiting from Allison’s antibody to CTLA4.

Many members of the American Society for Biochemistry and Molecular Biology are basic scientists. We study in our small nooks and crannies at the outskirts of the huge biomedical industrial research complex. The complex is often loud in its promises to deliver breakthrough therapies to the most vexing of human diseases. Some of the most profound of advances can often be traced to cottage industry scientists working — when they hit it big — in obscurity.

How, I ask, can we communicate the need to preserve a culture that fosters individuality? How do we say to the people of power that the very best way forward has no plan or blueprint at all — other than the support of creative scientists willing to risk their careers on problems of unknown value? Without knowing what will make the biggest difference, how do we choose which projects to support? My wish is that more reviewers of grant applications would, as Koshland did, put more value in unique ideas and approaches than trendiness and predictability.

Steven McKnight Steven McKnight is president of the American Society for Biochemistry and Molecular Biology and chairman of the biochemistry department at the University of Texas-Southwestern Medical Center at Dallas.