The eureka story

Abstract

In his 11 April Letter “Immunotherapy: It takes a village” (p. [149][1]), D. Pardoll recognized some of the scientists and research that led to the discovery highlighted as Science 's 2013 Breakthrough of the Year: cancer immunotherapy. Online commenters pointed out additional factors worthy of recognition. An excerpt from those comments is below. Read the full comments at . A selection of your thoughts: The Letter by D. Pardoll pays tribute to the basic science and its primary contributors behind breakthroughs in cancer immunotherapy. A major aspect of the breakthrough is the approach of blocking co-inhibitory receptors…. Pardoll's Letter leaves one asking, when was the “eureka” moment when immunologists understood that peripheral tolerance was not simply a consequence of AgR signals, the previous paradigm, but instead due to such co-inhibitory signals? …Nicholas R. StC. Sinclair did experiments that led him to publish in 1971 the model that B cells are made tolerant not by AgR engagement but instead co-engagement of AgR with a hypothesized receptor for the Fc portion of IgG on the B cell. The B cell FcR receptor was later discovered by others and was shown in tremendous cellular and molecular detail to be a co-inhibitory receptor…. [B]etween 1990 and 1993, Sinclair proposed that these co-inhibitory receptors underlie negative feedback regulation of T cells and not just B cells, a conceptualization driven by his quite radical view at the time that the AgR transmits positive rather than negative signals; hence the need for other signals to shut down lymphocytes. One wonders how such breakthroughs in understanding could have received so little attention. It raises broader questions of what we value in basic science. If we are to do our best to justify funding of basic science, we must ensure that the stories of such eureka moments illuminating a general principle in biology are told. [1]: http://www.sciencemag.org/content/344/6180/149.1.full