A thin commentary on a fat receptor

Looking back on an exciting scientific enterprise can be a very nostalgic experience for any scientist, and this is particularly true for us in the case of cloning the leptin receptor. We had been very interested in tapping into the molecular mechanisms that regulate body weight. The molecular biology of body weight regulation was still largely a black box in the early 1990s when compared to other fields in which we had worked, such as immunology. This was largely due to the fact that body weight regulation is a "whole organism" phenomenon that is difficult to break down into convenient in vitro systems. Therefore, the identification of "factors" and their corresponding genes was quite challenging. Fortunately, revolutions in genomics technologies were looming and, therefore, we were optimistic about gaining a molecular foothold in this area. It was clear to many of us at the time that cloning the genes that corresponded to the mouse ob and db loci would provide such a key entry point. Mice mutant for the ob and db loci (which have a dramatic obesity syndrome) had been studied for decades. Obtaining a molecular understanding of the severe consequences on whole body weight regulation seen in these mutant mice would be a pivotal advance in the field. The first breakthrough came from the work of Jeff Friedman and colleagues when they used a positional cloning approach to clone the ob locus and define its gene product, leptin. This made it very likely that the receptor for leptin would correspond to the genetically defined db locus. There was immediate and very justified excitement about the identification of the leptin protein. However, it soon became clear from ongoing work in a number of laboratories (including our work at Millennium) that most obese humans are not deficient in leptin and actually produce it at higher levels. This implied that a better understanding of mammalian body weight regulation and, hence, human obesity, would come from the cloning of the leptin receptor and an understanding of signaling events downstream of this receptor. Needless to say, we were not the only ones to recognize the implications of this. In fact, nearly every pharmaceutical company, large biotechnology company, and many academic labs began a pursuit of the leptin receptor. Given the intense interest and clarity of the goal, we then found ourselves in a race. It may not be politically correct to refer to an exciting scientific endeavor as a race, but in this case we think it is justifiable. However, this in no way should detract from the sensibility of such an intense scientific effort, because it is the entire group of scientists participating in this endeavor that directly or indirectly moves the field forward by assuring eventual success.