TR: What are the most important trends in research linking genes to human illness?VMcK: There are three. First, focus has shifted from looking at the cause of a disorder-the precise genetic defect-to the mechanism by which the disease is produced. As Francesco Ramirez, professor of molecular biology at Mt. Sinai School of Medicine in New York, has explained, now that we increasingly know the why-which genes cause certain diseases-we must find out the how-how the genetic defects lead to particular problems.
TR: Why is it important to look at the mechanism by which the gene acts rather than just focusing on how to insert a correct copy of a gene?
VMcK: Despite all the hype about gene-replacement therapy, researchers are beginning to realize that it isn’t going to happen soon enough for many medical conditions. Scientists have had a difficult time designing the vectors-the DNA couriers-that carry replacement genes to where they need to go, and producing genes that both persist and function at a high enough level.
If you know the steps that connect an abnormal gene to a disorder, by contrast, then you can often intervene along the way with appropriate drugs and essentially cure the condition.
TR: Why are researchers only now starting to look at the path between genes and disease?
VMcK: Some researchers have always focused on that, but interest is growing because of the rapidly advancing state of the human genome project, which participants hope will be completed by 2005. The public may have the impression that when the genome is completely sequenced-when we have determined the makeup of all of our DNA-we’ll know the whole story. But that point will really just mark the end of the beginning. Think of the work entailed in determining the function of the 80,000 or so genes in that structure-research that will suggest how altered genes lead to diseases.
TR: How do scientists figure out how genes work?
VMcK: One of the main methods investigators are exploiting is knock-out technology. In this technique, scientists remove a gene from, say, a very early mouse embryo and then see what happens to the animal as it grows. If, say, the mouse develops a disease, the indication is that the gene is related to the condition. The technology is rather crude, however. For instance, if the gene is essential to its early development, the mouse may not make it to birth.
A newer, more delicate technique is known as knock-in technology. Researchers can exchange a gene in an embryonic mouse with a corresponding gene from another species, such as a human. Doing so enables investigators to create particular mutations-one can, for example, put in the mutated hemoglobin gene that causes sickle-cell anemia. Then they can use the transgenic mice to figure out appropriate therapy for people. Investigators are now testing new drug treatments for sickle-cell anemia in such mice-a big advance since in the past humans were the only species that could be studied; no other animals naturally get the disease.
TR: What are the two other critical trends in medical genetics?
VMcK: The second area of great excitement is the burgeoning research on complex diseases-disorders involving more than one gene. Until recently we have largely studied single-gene disorders. Most of those are pretty rare, although there are plenty of them and for the people suffering from them they are very important. Diseases such as hypertension, cancer, asthma, and major mental illnesses involve a combination of genes, and that’s what researchers are starting to try to understand.
TR: How do multiple genes cause a single
VMcK: Each of these genes tends to be polymorphic-it occurs in a number of forms-so that throughout a population of individuals the gene produces a varying amount of a certain protein such as an enzyme. If only one of the genes produces a somewhat low amount of protein, that may not affect an individual significantly. But if, say, three such genes do, the combination might make an individual susceptible to diabetes, cancer, or high-blood pressure. If environmental factors kick in-say, someone predisposed to heart disease doesn’t exercise or eat properly-the person will end up with the disorder.
TR: Given that more than one gene has to be polymorphic to produce such conditions, I would think they’d be more uncommon than single-gene disorders. Why isn’t that true?
VMcK: Think about a disease marked by too small a production of several enzymes. Let’s say that 20 percent of a population has the form of gene a that produces little of enzyme a, and 20 percent of that group has the form of gene b that produces little of enzyme b, and 20 percent of that group has a third gene that produces little of a corresponding enzyme. Multiply these percentages together and the result is 0.8 percent of the population-making the resulting disorder not terribly rare.
Single-gene disorders, on the other hand, tend to be so disastrous that the individual often dies before he or she can reproduce and pass the abnormal gene to a new generation. Single-gene disorders often arise through new mutations, which are rare events.