Leptin And Obesity: So people have noted that I won two really wonderful awards. One from Hong Kong and one from Japan, in short order. I tell them that “At least I’m hot in Asia. Here, not so much.” The reason I say that is not long ago I wrote an editorial for Newsweek and it put forth the point of view that I hold true, which is that body weight is to a very large extent biologically regulated and that stigmatizing the obese probably can’t be defended, at least based on the science as we understand it.
So I wrote this editorial and for about a week or two it was one of the hottest uploads, hottest downloads from the Newsweek site and was the most commented upon article. Almost all the comments were negative. My favorites were one in which the writer kept referring to me as Dr. McQuack, and in another of the notes, a writer called Smokescreen made the comment that “I doubt anyone will ever nickname Dr. Friedman skinny.” And then one of the my defenders on the site wrote “I doubt anyone ever called Smokescreen smart.” So it turns out they were 78 pages in Microsoft Word of comments to date and a Yahoo! chatroom.
And what I found most amusing was that I was pilloried from both sides. I was pilloried by people who believe the obese should be responsible and now shared some of their vitriol for the obese with me, but also from obese people who felt that I was victimizing them when they don’t want to be victimized, understandably. Everyone has a personal set of experiences with eating and food, and more than half the population has also an experience with dieting and what they believed to be their own efforts to manage their own weight. And so because of that, everyone has such a rich set of personal and anecdotal experiences, that they immediately filter anything I might say through their own personal experiences or the people around them. And so for that reason, it is quite a bit different trying to explain our science to people than it is perhaps for other scientists.
Leptin And Obesity
On the other hand, it is a topic about which people are interested. I think to a large extent they’re interested mainly insofar as they could tell me why I’m wrong. In 1951, a genetically obese mouse was identified at the Jackson Laboratory in Maine. They breed millions of mice a year and because all the mice are maintained by brother/sister matings, you often see recessive mutations popping up. They have very skilled animal handlers there and so whenever a new phenotype, they call them a deviant, arises they put these animals out on the shelf and ask investigators if they’d like to work on them. This obese animal weighs three times more and has five times as much fat as compared to a normal animal. All as a result of a single defective gene. People have been interested for decades in what the nature of that gene product might be and no one was ever able to deduce what it was.
There was, however, prior evidence that the defective gene might encode a novel hormone that regulates weight. And so we set out to clone the mutant gene with the hope, or expectation, that it would encode a novel hormone In the 1980s, a new technology developed that made it possible to identify defective genes not based on any a priori knowledge of the function of that gene, but rather simply by knowledge of its detailed position on a genetic map. And that’s the basic approach now known as positional cloning that we employed to identify it. I’d befriended several years before we found the gene a famous scientist who studies the hypothalamus named Roger Guillemin. And Roger won the Nobel Prize some number of years ago for studying hypothalamic releasing factors and I gave a talk about our own ongoing efforts to find this obesity gene, as the ob gene was often referred to and after hearing my talk, Roger wrote me a letter and said they liked my talk very much but that he didn’t think i should refer to it is an obesity gene because the normal gene keeps you thin. It’s only in its absence that you become fat and suggested that I start referring to it as a thin gene. He then went on to say that “thin gene” didn’t sound very good and so he proposes an alternative that I call it a lepto gene, from the Greek root lepton (λεπτός), meaning thin. And so when we found the gene and had occasion to name it, that’d stuck with me and so that’s where the name leptin came from.
So we identified the gene for mice, but quickly identified the homologous gene from human. The main reason I was interested in doing that was just to confirm that we had the reading frame correct. But it was also gratifying to know that the human gene was as similar to the mouse gene as we now know it to be. Most of our work through the years – almost all of our work – is focused on animal experimentation. However, after the identification of leptin, several of the groups embarked on trying to find patients with leptin mutations. And one group in particular that led by Steve O’Rally in Cambridge so identified leptin-deficient children. Such cases are relatively rare, but the absence of leptin in human also causes massive obesity and leptin treatment of these children or adults has just dramatic effects. In one case, a patient described going to get their leptin injections for the first time [as] riding two seats on an airplane and going home in one seat. I never thought leptin as a therapeutic would be a magic bullet of sorts that would treat everyone and partly, part of the reason for that, is that we have done animal experiments early on that predicted almost completely what’s subsequently been seen in human.
And so I think there was an expectation on my part that it would prove to be a useful means for treating some patients with obesity and some patients with other conditions and that’s turned out to be true. I think part of the reason, however, other people might have expected otherwise had to do with how dramatic the pictures were. When you take this unbelievably obese mouse and make him skinny… And we were incredibly excited about that result because of the science it foretold. And the fact that it proved all of our work, proved that all of our work had been correct. For the rest of the public, though, however, the power of that image created an expectation that leptin would work that well in all settings and that hasn’t turned out to be the case. So I think that while perhaps leptin suffered from excessive expectations you know more broadly when it was first identified,
I think it’s gone overall as well or better than I could have hoped and we’ve learned a lot more. Now when we say the system that leptin regulates is complex, in a sense what we’re saying is behavior is complex because leptin is not the only thing that drives feeding behavior. On the other hand the ability now to study a behavior in response to a single stimulus, like getting leptin, gives us an opportunity in the future perhaps to really dissect in greater detail and with a greater level of understanding how we decide whether or not to go foraging. One of the things that resonated with me about the Keio Prize is their stated wish to develop ways by which science can improve the greater good and that resonated for me a little bit because I’ve become aware of the last year or so of a variety the early figures from Rockefeller’s history, one of whom, Samuel Meltzer, in 1914, on the eve of World War I, formed the society for experimental biology and medicine as a means to bring scientists from all countries together and try to prevent what turned out to be catastrophic war.
And so there is a tradition here, and I suppose through this prize to try to use the fraternity of scientists as a hedge against the forces that divide people. I thought it was a nice sentiment. I mean, the truth is that you do science – at least I do science – and it’s mainly for those moments where you know you see something in a way you didn’t see before or learn something new. You have that experience all the time in science. I would say certainly the discovery of leptin was quantitatively greater than that which I’ve experienced in other instances, but if I ever stop experiencing that sense of excitement about new results or new knowledge, I’d probably start thinking about doing something else. I haven’t gotten to that point yet.