Basic Biology: The Complex Core of Drug Discovery
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reproductive problems as well. Mammary glands in female mice failed to develop normally, and estrus cycling times were more infrequent and irregular than normal. Male mice showed decreased testosterone levels, lowered sperm counts, and they mated less frequently than normal mice. Would there be the potential here to develop a drug that affected contraception or fertility in either sex?
Now we had a clear understanding of a protein, CSF-1, that had biological effects on several distinct cell types that were mediated by its interactions with the fms receptor. Well, the story got more complicated when a discovery was made by colleagues of mine at Immunex in 1998. Melanie Spriggs and coworkers were studying a gene contained in the Epstein-Barr virus that had been given the wonderfully descriptive name of BARF1. Their experiments demonstrated that the protein made by this gene also bound to CSF-1, even though it was not related to fms. This observation suggested that there was an evolutionary advantage for this virus to carry a gene whose protein product could bind CSF-1 made by human cells. Would there be some potential here for the development of a treatment for Epstein-Barr virus, which causes infectious mononucleosis and can also lead to the development of two different types of cancer?
At last, the full function of the fms gene was known. It bound CSF-1 (as did BARF1) and was involved with the formation of blood cells and helped to regulate bone density and tissues in the reproductive system. That was the story until 2008, when yet another research group of people at FivePrime Therapeutics, Schering-Plough and DigitAB showed that a second growth factor, IL-34, was also capable of binding to and activating the normal fms gene. This raised the question as to why there would be two different proteins that seemed to function through the same receptor. Interestingly, CSF-1 and IL-34 do not appear to have identical biological activities. Perhaps CSF-1 and IL-34 are produced by different cell types at different times in development to regulate distinct processes? Would there be potential here for the development of IL-34 as a treatment for blood, bone, or reproductive disorders, or for treating Epstein-Barr virus or other infections?
Well, that was the story until several months ago. Our understanding of the biology changed again when an international team of researchers was trying to determine the cause of a particularly rare type of dementia (that affects people in their 40’s and 50’s) with the unwieldy name of hereditary diffuse leukeoencephalopathy with spheroids (HDLS). The molecular biology tool kit was once again brought out, and the results were entirely unexpected. It turns out that this disease results from genetic mutations in fms that eliminate its enzymatic activity, leading to the loss of a particular type of brain cell and dementia. Researchers wondered: Would there be potential here for the development of either a new drug, or the transplantation of a particular type of cell as a treatment for HDLS or other brain disorders?
Looking back, an inquisitive veterinarian taking care of a sick cat launched a lengthy journey of discovery whose end has likely still not been reached. This investigative process has stretched out over four decades, involved countless research groups, produced thousands of science papers, and led to biological insights in oncology, hematology, bone formation, reproductive biology, virology, and brain development. The biology of this single gene turned out to be much more complicated than many would have predicted after it was initially discovered. This level of complexity is not rare; the closely related kit receptor regulates the levels of a different set of blood cells, affects pigmentation and fertility, and also plays a role in tumor formation.
At any one of a number of different time points fms might have been viewed as a viable drug target for a variety of distinct disorders. A key question is whether the entire biological “story” really needs to be known in order to successfully develop a drug. The answer is clearly no, since you can never be sure that you have a complete understanding of the biology of any potential drug target or molecule. Having said that, any drug that seeks to either inhibit or stimulate this receptor will likely affect a number of different tissues. This would certainly complicate its potential development path. I’ve long been a strong proponent of using research collaborations to acquire additional data that will facilitate making the most informed decision possible regarding the potential development of a drug. More data is always helpful, but there will always be a tension between accumulating additional information and pulling the trigger for a drug development program. At some point, drugmakers have to accept the biological unknowns they confront, and commit themselves to the significant time, expense, and risk that comes with mid-and-late stage drug development.
For those of you who have wondered why coming up with new medicines is so difficult, the answer should now be apparent. Biology is amazingly complex, and just when you think you have it all figured out, something new pops up to muddy the waters or point you in a new direction. Physicist Yaneer Bar-Yam summarized it nicely when he said “To understand the behavior of a complex system we must understand not only the behavior of the parts but how they act together to form the behavior of the whole.”