Every September the Lasker Foundation announces the names of those scientists who will receive awards for their outstanding contribution to fighting disease, and over time these prestigious awards have gained a reputation as “America’s Nobels.” Many past awards have been awarded to scientists whose research depended on the use of animals, and this years awards illustrate once again just how important animal models are to both basic and applied medical research.
The 2008 Lasker-DeBakey Clinical Medical Research Award went to Dr. Akira Endo for his discovery of statins, a class of drugs that lower the levels of “bad” LDL cholesterol and help to prevent heart attacks and stroke. When Dr. Endo started his research it was already known that high levels of LDL cholesterol were associated with heart disease, but lowering these levels by dietary modification was difficult since most cholesterol in our bodies is made in our own liver. An enzyme called HMG-CoA reductase was found to play a key role in the manufacture of LDL cholesterol, so perhaps blocking it’s activity would help lower cholesterol levels.
Dr. Endo knew that fungi secrete chemicals to kill their competitors, antibiotics to you and me, and screened thousands of fungi for chemicals that could block HMG-CoA reductase activity in vitro. He identified a fungal product named compactin that could block HMG-CoA reductase activity and then demonstrated that it could inhibit cholesterol synthesis in mice and rats. Subsequent studies in dogs, rabbits and monkeys demonstrated that blocking HMG-CoA reductase activity and reducing cholesterol synthesis could lower circulating LDL cholesterol levels as had been proposed earlier, and human trials were initiated. Unfortunately just as the first human studies of compactin were being yielding very promising results long-term high dose studies in dogs indicated that the drug was more toxic than it had appeared in earlier studies, and further trials of compactin in humans were halted. However by this time scientists at Merck research Laboratories had identified a similar molecule named lovastatin which animal studies showed to be effective and without the toxicity of compactin. Following successful human trails lovastatin became the first statin to be approved by the FDA. Compactin didn’t go away entirely either, the FDA has recently approved a safer modified version of compactin known as pravastatin for lowering cholesterol. Dr Endo’s legacy is a whole new class of effective drugs for preventing and treating heart disease.
Basic research is an important part of the overall medical research effort, scientists trying to understand apparently esoteric biological processes often make discoveries that have profound implications for the future of medicine. This year’s Albert Lasker Basic Medical Research Award to Victor Ambros, David Baulcombe, Gary Ruvkun for their discovery of microRNA is an excellent example of how we can learn about our own biology by studying organisms with whom we appear at first to share little. Working with the nematode worm Caenorhabditis elegans and plants they discovered a new mechanism by which living organisms control gene activity. What they found was a novel type of gene that produces an short single-stranded RNA molecule that binds to and tags complementary messenger RNAmolecules, marking them for destruction. Since messenger RNA is required for a gene to produce the protein product that carries out the gene’s function, microRNA effectively reduces or blocks that gene’s activity.
So what does this have to do with medicine? Well the discovery of microRNA provided an explanation for what is happening in a process known as RNA interference (RNAi). RNAi was discovered in 1998 by Andrew Fire and Craig Mello, who found that introducing double stranded RNA sequences that matched the sequence of a gene into a cell could suppress the activity of that gene. This breakthrough won Andrew Fire and Craig Mello the Nobel Prize in 2006 but it was not until the discovery of microRNA that the mechanism by which RNAi works was understood. The work of Ambros, Baulcombe, Ruvken, Fire and Mello has opened up a very exciting new area of biomedical research as RNAi offers a novel way to regulate the function of genes that cause disease, and the first clinical trials are already underway.
Not bad for what the antivivisectionists call “junk science”!
Speaking of Research extends a hearty congratulations to Akira Endo, Victor Ambros, David Baulcombe, and Gary Ruvkun on their awards, their work shows how by studying different living organisms we can make the breakthroughs that lead to new treatments in the clinic.