The hardest task in major league sports is hitting a baseball. Those who can successfully do this even three out of every ten times over the course of a career are likely to find themselves enshrined in Cooperstown at the Hall of Fame. Unfortunately, scientists who strive to discover new medicines can only fantasize about a 30 percent success rate for their efforts. Drug discovery is a remarkably complicated process, and the success rate for advancing any potential medicine through the first three stages of clinical trials alone is less than 10 percent. Even then, few potential drugs ever get to the clinical trial stage due to toxicity, poor absorption or distribution into tissues, or a host of other problems.
Why is drug discovery and the development of new medicines so difficult?
There are some 23,000 genes within the human genome that carry the instructions for making a wide spectrum of proteins, many of which interact with each other in an interwoven mesh of complicated networks. Trying to understand how all of these molecules work together to develop a human being is a future dream, but understanding the biological role of even a single protein recalls Churchill’s famous quote about “a riddle wrapped in a mystery inside an enigma”. Let me share a simplified summary of the biology of a single gene I used to work on named fms (rhymes with rims) to illustrate the arduous challenge that medical researchers face.
Back in 1971, a young veterinarian in Philadelphia was trying to figure out why a cat under her care had developed a sarcoma (a type of cancer). This biological question initiated more than 40 years of research studies, yielding novel and important insights in not just cancer but in at least five other fields of biology. Susan McDonough, the veterinarian, was able to isolate a virus from the cat’s tumor that, when injected into another cat, resulted in the formation of a new tumor. Eventually the virus, now known as a feline sarcoma virus, was found to contain a gene, designated v-fms, that conferred on the virus the ability to cause tumors. What was it about this gene that enabled it to cause malignant cancers to form? Would there be the potential here for the development of an anti-cancer treatment for cats, and maybe humans as well?
Years later, my late colleague Joe Woolford showed that the v-fms gene in the virus was actually a modified version of a fms gene that is normally present in all cat cells (and many other vertebrate species as well, including humans). Somehow the virus had “captured” and integrated part of this gene, a process that turned the virus from a relatively benign state to one that could transform a normal cell into a cancerous one. The protein encoded by the normal fms gene is a member of a family of tyrosine kinase receptors, which are expressed on the surface of different types of cells. These proteins normally function by activating various intracellular pathways in response to binding a specific signaling molecule, which at the time was unknown for fms. The identification of the molecule that bound to and activated the fms receptor was finally determined in 1985. It turned out to be a previously identified blood cell growth factor known as CSF-1. This protein had previously been shown to stimulate the growth and development of blood cells known as monocytes and macrophages, which are important components of the immune system. The scientific finding raised an important new question: Would there be potential here to develop a drug that stimulated the production of these cells as a way to fight infections?
The story didn’t end here. As it turns out, if you remove the gene that encodes either the fms or CSF-1 proteins from developing mice using molecular biology techniques (the popular “knock-out” approach), the animals that develop have not only a deficiency in certain blood cells, they also suffer from a rare bone disorder known as osteopetrosis. This manifests itself as bones that are abnormally thick and heavy, which also makes them relatively brittle. Results of the knock-out experiment suggested that CSF-1 binding to fms played a role in normal bone development. Osteopetrosis is not just seen in these bioengineered mice; it afflicts humans as well. Again, this result raised a provocative question: Would there be potential here for the development of one or more drugs that could either block the development of osteopetrosis, or conversely, stimulate bone production in people with osteoporosis, the much more common bone-breakdown disorder ?
The fms knock-out mice also showed clear evidence of
