The interviewer’s embarrassment was rising by the moment. Despite having inserted fresh batteries and tested the tape recorder before the interview, she couldn’t get the machine to work. Almost instantly Victor McKusick, at 75 the acknowledged founder of modern medical genetics, which focuses on the relationship between genes and human disease, dived below his desk. As the time he had carved from his packed schedule ticked away, he started crawling through a maze of computer cords to try connecting the recorder to an electric outlet.

McKusick’s approach to the problem suggested his modus operandi: get involved. Indeed, he has thrown himself into four overlapping careers, beginning in cardiology, moving on to medical genetics, serving as physician-in-chief at Johns Hopkins Hospital, and finally helping to organize the international human genome project. Today McKusick spends most of his working hours updating Mendelian Inheritance of Man, a voluminous bible for researchers and doctors concerned with human genetic disorders. McKusick started compiling the text-which catalogs all human genetic sequences linked to particular functions, such as the gene associated with muscular dystrophy-in the early 1960s. At this point the compendium, also accessible online, contains some 9,000 entries. The 11 printed editions serve, as McKusick notes in the hard copy’s 1994 edition, as an “archive of progress in human genetics in the last 30 years.” 

In the 1980s McKusick helped to bring about the Human Genome Project as a member of the National Academy of Sciences (NAS) committee that evaluated the proposed project to determine the makeup of our entire code of DNA. During this period he also was a founder and the first president of the Human Genome Organization (HUGO), an international group involved in coordinating the effort. Through 1995 he contributed to a federally sponsored group grappling with the ethical, legal, and social implications of human-genome research. And he indirectly contributed to the infamous O.J. Simpson trial by chairing the NAS committee that evaluated the use of DNA technology in forensic science.

These are just a few of the tasks McKusick has handled over the years (he still sees patients weekly). And he has seemingly done nothing with ennui. “I’ve always enjoyed what I’ve done and approached it with great zest,” he says; reporters who have seen him in action concur. In this spirit McKusick writes about human genetics in a chapter of Emery and Rimoin’s Principles and Practice of Medical Genetics: the field “holds particular fascination because it involves the most fundamental and pervasive aspects of our own species.” He continues, “To have combined with this intellectual and anthropocentric fascination the opportunity to contribute to human welfare and to be of service to families and individuals through medical genetics and clinical genetics is a privilege.” Technology Review senior editor Laura van Dam recently sat down with a functioning tape recorder to ask McKusick where medical genetics is going today.

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
disease?

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.

TR: How do scientists uncover all the genes involved in complex diseases, let alone determine the role of each gene?

VMcK: Investigators still have to find each gene one at a time, using the same process they employ for a single-gene disorder. But mathematicians and computer scientists have now devised methods for determining whether additional genes beyond those already identified are likely to be related to a complex-gene disorder. For example, Neil Risch, a distinguished biostatistician and professor of genetics at Stanford University, has proposed several approaches.

One entails working with genetic “markers”-known bits of DNA whose location on the genome has already been found. Risch has extended a long-understood notion: that if the same marker is found in many affected individuals, researchers can deduce that a gene that plays a role in the disease lies near the marker. Risch has determined that the frequency with which pairs of siblings with the same complex-gene disease have the same marker indicates how much of a role the nearby gene plays in the disease. The statistical findings tell investigators whether they have to search for other genes elsewhere. The technique is a little mind-boggling to someone who’s not a biostatistician but it works.

As you can see, medical genetics relies on contributions from many fields, and it especially benefits from people who combine disciplines, for instance, those who keep one foot in computer science and the other foot in biology.

TR: And the third trend?

VMcK: The exciting effort to compare the genomes, or entire genetic complexes, of different species. Right now researchers are determining the genetic makeup of the genomes of the mouse, the fruit fly, a very simple roundworm called Caenorhabditis elegans, and a variety of bacteria. Several bacteria have already been completely sequenced, as has the yeast, a relatively advanced organism in that each yeast cell has a true nucleus. Because computer databases now contain genome information of various species, including the functions of identified genes, scientists can compare a particular human DNA sequence with similar sequences of other creatures. Researchers do this when they think they have found, for instance, a human DNA sequence with the characteristics of a gene, but don’t have the foggiest idea about its nature. Using the databases, they can see if the human sequence closely resembles, say, a yeast gene with a known function.

TR: Why would our genes function like those in yeast cells?

VMcK: Humans obviously need many more genes than yeast-probably at least 12 times as many-but the fundamental program for cells is the same in both species. Consider, for example, what happens in a form of colon cancer known as hereditary nonpolyposis colon cancer (HNPCC). Investigators have figured out that this disease occurs because of defects in a class of genes called mismatch-repair genes. Those genes normally survey the genome and repair bits of DNA upon finding so-called mismatches between the two sides of the coiling DNA ladder. But a mutation in the mismatch-repair genes themselves can cause that check-and-balance system to go awry. When the resulting unrepaired mismatch is in a gene that normally suppresses tumors, such as of the colon, the result is the development of a cancerous tumor. For quite some time researchers knew only that mismatch-repair genes existed in bacteria and yeast. Then Bert Vogelstein, a professor of oncology at Johns Hopkins University School of Medicine, used a database to check a genetic sequence he had isolated from people with HNPCC against sequences of other species. He found that the sequence he had isolated was a mismatch-repair gene, and went on to show that mutations in this and related genes could lead to HNPCC.

TR: Given all these new directions, geneticists would seem to have their hands full for quite some time.

VMcK: Oh, but there’s more. Once the human genome project nears completion, we will have to face the fact that we do not know the distribution of various forms of genes around the world. That’s important for determining what diseases, both infectious and degenerative, particular populations are prone to. Experts have therefore been discussing the idea of a human genome diversity project, which would look at gene variability.

Some human-rights groups have reacted to the idea with alarm, because early advocates emphasized the notion of sampling the DNA of small, isolated populations in the Amazon and other out-of-the-way parts of the world before the groups disappear. Advocates for these groups worried that the populations would be exploited or stigmatized by the studies.

But the scientists promoting the human genome diversity project have started to recognize that they should instead focus on the rest of us. After all, the main pay dirt won’t be found by studying small populations but by understanding the larger groups around the globe. That information can help researchers to determine future health prospects of large populations-groups with millions of members.

TR: Don’t researchers already have a sense of how different diseases, such as stomach cancer, vary across the globe?

VMcK: To some extent, yes. For instance, we have a good deal of information based on studies from blood. But to get to the roots of disorders we need to examine the genes. After all, the variation of genes is related to the frequency of complex traits. Different populations can have different variations of those polymorphic genes I mentioned before-the ones that can have multiple forms-with the result being varying frequencies of specific complex disorders.

Of course, as I suggested before, environmental conditions also play a role in disease distribution. Diabetes is a good example. One of its two main forms, which usually occurs in people once they are adult, is often related to obesity. Increasingly sedentary populations are more apt to experience this kind of diabetes.

TR: As suggested by some groups’ concerns about the human genome diversity project, much of the work to tease apart the human genome is raising significant ethical issues. What systems does society need to develop to address the dilemmas?

VMcK: This may sound simple, but airing ethical concerns, such as about the possible misuse of genetic information in connection with insurance and employment, is half the battle. Then, in part, groups such as-get ready for a mouthful-the Joint National Institutes of Health/Department of Energy Committee to Evaluate the Ethical, Legal, and Social Implications of the Human Genome Project (it’s commonly called ELSI) can study the issues and make recommendations to the federal agencies funding genome research.