Mechanistically, how do medicines work? In general terms, most drugs act by either stimulating something (these are called agonists) or blocking something (these are called antagonists). These effects are generally directed against specific molecules, even if the exact target remains unidentified. Within these broad definitions, however, lies a great diversity of approaches that drug makers have taken to treat diseases. Let me share some examples:
Drugs can directly stimulate (e.g. morphine) or block (HIV protease inhibitors) enzymes. They can bind to and sequester molecules (TNF blockers for rheumatoid arthritis). Drugs can replace missing molecules (insulin, hemophilia) and alter the rate of movement of molecules into or out of cells (anti-arrhythmics like sodium channel blockers). Some drugs stimulate the immune system (Provenge, Yervoy), change the pH balance in the body (sodium bicarbonate for acidosis), or interfere with the assembly or function of intracellular structures (anti-cancer drugs like taxanes). Drugs can stimulate the release of stored molecules (epinephrine), or interfere with DNA synthesis (sulfa antibiotics). Drugs can perturb cell membranes (anesthetics), and effect the modification of proteins, thereby altering their function (histone deacetylase inhibitors). In gene therapy, the drug is often a replacement gene; anti-sense drugs block the formation of proteins by binding up specific mRNAs.
The above examples demonstrate the variety of approaches drug makers have taken in coming up with new medicines. Their goal: design in characteristics that enable the drugs to achieve the desired effects, while at the same time designing out their ability to bind to and effect secondary molecules. These secondary interactions (and sometimes primary ones as well) often lead to side effects that can be sufficiently serious to prevent a drug from ever being used in the marketplace. This particular aspect of designing small molecules is daunting. X-ray crystallography and other techniques often enable scientists to generate 3D images of the protein that wish to target. This information is extremely valuable in tailoring the design of a drug that is meant to bind to and modulate the function of this particular protein. Ideally, the drug only attaches itself to this one (or in some cases, a few closely related) target(s). Often, the primary challenge isn’t finding a chemical that can bind to the chosen protein, it’s identifying one that doesn’t bind well to the other 21,000 or so proteins that it might also interact with. Imagine trying to design a mask that will precisely fit your face, but won’t fit well on the faces of thousands of other individuals. This inherent difficulty has fueled the rise of biologics (protein-based drugs), where such discriminatory specificity is much easier to achieve because the appropriate molecules have already been selected for by the powerful forces of evolution.
For a number of medical conditions, the exact molecular defect that is responsible for the disease is now well understood. In a best-case scenario, the genetic defect that causes chronic myelogenous leukemia was identified and led to the development of an amazingly effective drug with a very high cure rate. Knowing exactly what causes a disease is useful, but this information doesn’t always translate into curative medicines. The mutated protein that causes cystic fibrosis was discovered after years of intensive research in 1989. In the two decades since this discovery was made, however, no one has developed a reliable method for replacing, correcting, or bypassing the single defective gene that encodes this key protein (although a recent trial looks somewhat promising for one specific subset of patients).
A recent study suggested that mutations in genes that are essential to survival are the cause of many rare diseases, whereas alterations in non-essential genes are the primary drivers of more common illnesses, such as heart disease. Many health problems, however, result not from a single defective gene, but from numerous mutations throughout the genome. It is estimated that
