This morning, the Lasker Foundation announced its awards for biomedical research, prizes considered to be some of the most significant in the field. This year's prizes go to researchers who made significant strides in understanding the biology of obesity, and another who turned our knowledge of blood vessel development into a therapy for a degenerative eye disease. It's an interesting choice for the awards; the initial discoveries were indeed seminal, but they raised hopes for rapid medical progress that haven't quite panned out. The Lasker Award for Clinical Research is going to Napoleone Ferrara who works at the biotech company Genentech (now a part of Roche). Ferrara could easily receive awards for his role in the discovery of VEGF (Vascular Endothelial Growth Factor), a protein that signals to the cells that line blood vessel walls. In response, these cells begin to divide and migrate, enabling the formation of new blood vessels.
Ferrara recognized that this process played a key role in age-related macular degeneration, where blood vessels in the retina grow in an uncontrolled manner, ultimately leading to severe reductions in vision. Ferrara helped develop a treatment for this by generating an antibody that neutralized VEGF by preventing it from interacting with its receptors. By eliminating a key signal for blood vessel growth, the vision of many patients facing macular degeneration can be preserved.
Two aspects of this approach are pretty notable. The use of an antibody for targeted therapeutic work has been considered for decades prior to Ferrera's work, but very few treatments of this sort had ever reached the market. In recent years, a number of other similar treatments have arrived, many of them targeting cancer-promoting proteins. They're effective to a degree, but none of them have been outright cures, and most come with far more side effects than the specificity of antibodies might have led many to suspect.
In fact, VEGF antibodies were originally developed as a therapy for solid tumors, which require the growth of new blood vessels to keep the cancerous cells supplied with nutrients—Genentech sells one of these, and Ferrara played a central role in its creation. But, again, this approach hasn't quite been everything it was hoped it would be, as the treatment is only partially effective in combination with other therapies, and its high costs have caused a number of national and private healthcare providers to drop it as a treatment option. This may explain why the prize citation primarily focuses on the more clearly effective macular degeneration treatment.
Obesity and genetics
The Medical Research award went to Douglas Coleman and Jeffrey Friedman for their work, which led to the discovery of one of the first hormones linked to obesity, leptin. Coleman is based at the world's foremost mouse-breeding site, Jackson Labs, and benefitted from the fact that its staff is trained to identify unusual looking mice that sometimes arise spontaneously within the breeding stocks. Over the years, two different lines of mice were discovered that had an inherited form of obesity.
The award citation notes that Coleman demonstrated that one of the two genes involved was a circulating hormone through an amazing experiment: he linked the two circulatory systems of the mice together, and showed that one of them produced a soluble factor that could rescue the phenotype in the other, but remained obese itself. Friedman eventually isolated the gene for this factor, called ob for the obese phenotype; the protein that it produces has since been termed leptin.
Leptin is now known to be produced by fat cells, and signal to areas of the brain that influence food intake. Animals lacking either leptin or its receptors never experience satiation, and continue eating long after filling their dietary needs. A few humans with mutations in the leptin gene have since been identified; they are also obese.
Again, this was an area that seemed very promising. Other hormones that influence appetite were identified later, raising the hope that obesity might be controlled by a careful suppression of appetite that used the body's own natural mechanisms for doing so. But that hasn't quite worked out either; even using leptin to block the obesity of the people with mutant forms of it hasn't turned out to be easy. Ultimately, a better understanding of how the body decides when and how much to eat may help cut into the high obesity levels, but that still seems to be a few years off.
The Laskers act as recognition that, even though these discoveries may not have worked out as many people had hoped, they have fundamentally changed how we view two very significant problems (obesity and cancer) and, in one case, led to an effective treatment for an unrelated disease.
