We often read that understanding the human genome promises the transformation of medicine, because finding the genes associated with major diseases provides potential new targets for therapy. So what are the obstacles in developing new drugs?
To understand this formidable challenge, let us consider the example of creating a new drug to treat Alzheimer’s disease. Scientists long knew that a protein called amyloid formed “plaques” in the brains of people with Alzheimer’s but not whether it was involved in causing the disease. Identifying abnormalities in genes regulating the synthesis of beta-amyloid in the brains of patients with an inherited form of Alzheimer’s helped remove the doubt in most scientists’ minds. But how can this help us develop a new treatment?
Studies with isolated cells in a culture showed that beta-amyloid can kill cultured nerve cells grown outside of the body. Together with the information from genetics research, this suggests that the progression of Alzheimer’s might be controlled (or, in early stages, reversed) by clearing amyloid from the brain or blocking its production.1 Different Many molecules appear in the test tube or even in animal models to function in ways that suggest that they could be drugs, but either they fail to have the right effect in humans or they cause unacceptable side effects. So the most challenging hurdle for drug development is testing a molecule in humans. strategies for doing this have been proposed, such as finding ways of “washing” beta-amyloid from the brain, using large molecules called antibodies that irreversibly bind to beta-amyloid. Such therapeutic antibodies could be either injected (passive immunization) or generated through vaccination. Just imagine a future in which children are given a quick jab to prevent mumps, measles, rubella, whooping cough—and Alzheimer’s disease. Another drug strategy would be to develop chemicals that inhibit the brain enzymes (large molecules made by cells in the body that perform particular chemical tasks) that are responsible for producing beta-amyloid in the brain.
Having established a biological strategy and rationale for the treatment of Alzheimer’s disease, the drug industry faces the next challenge: to engineer molecules that can perform the required tasks. This means engineering an antibody (or other binding molecule) that can potentially pull beta-amyloid out of deposits in the brain or designing a chemical that can block the actions of enzymes that produce beta-amyloid. The rapidly growing predictive power of computational biology makes designing such molecules increasingly scientific, but important elements of the process remain an art. Many, many antibodies must be produced and screened in order to discover the few that work well, or researchers must synthesize a variety of small molecules expected to bind to the enzyme target. Luck continues to play a role, and not all biologically validated targets can be further developed to become potential drugs.
The next hurdle is to show that a molecule can do what is intended in a test tube or in cells in a culture dish, such as selectively recognizing beta-amyloid or blocking the target enzyme without interfering with other enzymes that have important functions. And successful test tube experiments are not enough. Researchers must show that the potential drug can be administered safely to an animal and, ideally, that it can reduce beta-amyloid in an animal model of Alzheimer’s disease.
Many molecules appear in the test tube or even in animal models to function in ways that suggest that they could be drugs, but either they fail to have the right effect in humans or they cause unacceptable side effects. So the most challenging hurdle for drug development is testing a molecule in humans. The first question is whether a safe dose range can be determined, one that will allow high enough doses to have the action predicted in the earlier animal experiments. For instance, in our example of a hypothetical drug for Alzheimer’s, researchers would have to establish that the beta-amyloid antibody can be given at high enough doses to bind significant amounts of beta-amyloid while not triggering undesirable activation of the body’s immune responses. Or they would need to show that an enzyme-inhibiting small molecule does not damage the liver, which is responsible for deactivating many small molecules in the bloodstream. This kind of critical safety information is acquired in Phase I experimental trials, in which the drug is carefully administered to closely monitored healthy volunteers. Success in Phase I is not guaranteed; overall, 35 percent of candidate drugs fail here for one reason or another.