Conversely, treatment of some disorders —for instance, hypercholesterolemia —might involve enhancing the transcription of selected genes. Hypercholesterolemia increases a person's risk for heart disease. Cholesterol accumulates to destructive levels in the blood when low-density lipoprotein (LDL), otherwise known as the bad cholesterol, is not removed efficiently. In theory, the disease could be corrected by turning up transcription of the gene for the LDL receptor in liver cells. This receptor helps to clear LDL from the blood. This idea may soon be testable, because studies by Michael S. Brown and Joseph L. Goldstein of the University of Texas Health Science Center at Dallas are teasing apart the specific molecular constituents of the apparatus that regulates transcription of the receptor gene.
Until recently, no one put much effort into screening small molecules, natural products or other compounds for their ability to modulate transcription. Even so, a number of drugs already on the market have been found by chance to work by altering the activity of transcription factors. One of these, RU 486 (the French "abortion" pill), represses the function of particular steroid receptors, a class of activators that direct embryonic development. Similarly, the immunosuppressants cyclosporine and FK506 suppress transcription of a gene whose protein product is needed by certain cells of the immune system. These drugs act indirectly, however. They activate an enzyme that impedes the functioning of a transcription factor for the gene.
As time goes by, the precise combination of transcription factors that regulate individual genes is sure to be identi fied. And drug developers will probably use this information to devise sophisticated compounds for fighting cancer, heart disease, immune disorders, viral infections, Alzheimer's disease and perhaps even the aging process. How well these agents will succeed is anybody's guess, but it is likely that therapies of the future will benefit in one way or another from basic research into transcription—research that began not out of a wish to design drugs but rather out of a simple desire to get to the heart of the molecular machinery that controls the activity of our genes.