This month we talk with Michael Conneally, Ph.D., Director, Medical and Molecular Genetics, Indiana University. Dr. Conneally has been working in the field of genetics for more than 30 years and brings a keen scientific mind and a compassionate spirit to this burgeoning field.
FCA: Dr. Conneally, tell us a little about yourself.
Dr. Conneally: I am a Distinguished Professor of Medical and Molecular Genetics and Neurology at Indiana University School of Medicine. I came to Indiana 33 years ago to work on mapping genes, having a special interest in Huntington's disease (HD). Huntington's disease is a hereditary progressive neurological disorder which usually begins in mid-adult life. It is an autosomal dominant disorder, meaning that it affects both males and females equally (or does not sex differentiate) and that children of affected individuals each have a 50% risk of also inheriting the gene and developing the disease. Along with my colleagues I helped to start a Huntington's disease clinic in 1967. I believe that we were the first in the country to have a clinic specifically for families with Huntington's disease.
My main area of expertise is mapping genes. A graduate student of mine, Dr. Margaret Pericak-Vance, now at Duke University, was also interested in gene mapping and wrote her thesis on trying to map the gene for Huntington's disease. In our efforts to map the HD gene we collected families from all over the country. However, we were not successful because we now know that the markers available at that time were not in the Huntington's region of the genome, and so we were not able to map the HD gene.
In 1979, I became the director of the National Huntington's Disease Research Roster for Patients and Families. This roster is funded by the National Institutes of Health and currently contains over 2,000 families consisting of nearly 130,000 individuals. At about the same time, I became very involved in mapping the Huntington's disease gene and started a collaborative effort with Dr. James Gusella at Harvard. Dr. Gusella did the laboratory typing of the DNA samples and we did the linkage analysis on a mainframe computer.
Because we were the first to see the results off of the computer, we were the first to know that the HD gene actually mapped to chromosome 4. This finding was published in 1983. I continued to work on fine mapping the HD gene and along with a group known as the Huntington Disease Collaborative Research Group found the gene that causes HD in 1993.
FCA: Could you briefly discuss the Human Genome Project? This must be of great interest to you.
Dr. Conneally: The purpose of the Human Genome Project is to determine the complete sequence of the total human genome. As you may know, the language of life is a four-letter code which happens to be called A, T, G & C. These four letters stand for Adenine, Thymine, Guanine and Cytosine. These letters in combinations of two form what are called base pairs and these base pairs form strands of DNA. In combinations of three, for example CAG, these base pairs code for very specific amino acids, which are the building blocks of proteins.
There are three billion base pairs in the human genome, meaning that every cell in your body has six billion letters. Each of us inherits half of our base pair from our mother, or three thousand million and the other half, or three thousand million, from our fathers. The aim of the human genome project is to sequence these base pairs, to determine what the language of life is. By the way, these letters would fill about three sets of encyclopedias - I don't mean three volumes - I mean three whole sets of Brittanica.
Sequencing these base pairs in order to "read the language of life" is very important to people who are trying to map genes. This sequencing has led to the discovery of genetic markers, thousands of them, all over the genome which point to the whereabouts of genes that cause disease. The result of this work is the location of genetic markers and eventually the disease gene itself, as in the example of the location of the Huntington's disease marker in 1983 and the location of the gene itself in 1993. As you can imagine, this is an extremely important project. The work is mainly done in the United States, although other countries -- especially France, Japan, Britain and Canada -- are also working on the human genome project.
A large portion of the human genome project focuses on sequencing what are called model organisms, mainly, fruit flies, yeast, and mice. There are regions in these organisms which are similar in man, so that a lot of genes in man are being located first by looking in the mouse. In fact, the mouse's genome will be determined before man's. The goal of the Human Genome Project was to map the entire genome by the year 2005; however, the project may actually be completed by the year 2003.
FCA: Once that's done, what do you see as the promise of genetic research?
Dr. Conneally: The ultimate idea of genetic research is to cure the disease. First you must find the gene. It took us a long time to find the Huntington's gene, and were it not that Dr. Gusella was so fortunate, it would have taken longer. He used what are called probes, and by sheer chance one of them he chose was right next door to the Huntington's gene. The chance of that occurring in 1983 was about one in a thousand because there were only a handful of probes available. Today there are thousands of probes that have been identified so that if we started today to localize the Huntington's gene, we could map it in two months, easily. This is one of the legacies of the Human Genome Project, the discovery of thousands of markers throughout the genome.
The second step is to clone the gene in order to discover its normal function. Most of the human genome, in fact over 90 percent of it, is "junk DNA," not genes, and this "junk DNA" is included when you map a gene in the region that you're trying to explore. We now have more and more of what we call candidate genes whose sequence and function are known. We can now look at genes in specific regions and identify those genes that are out of the ordinary. We can also figure out how the disease gene functions so that ultimately a cure can be found for the disease. Theoretically, we may find a rational drug treatment to help alleviate the disease. For example, in diabetes you simply give insulin. This is a crude example, since of course we know that the treatment or cure for most genetic diseases will not be so simple; however, we may be able to discover the abnormal function of the gene and find a way to alter its function.
In a late onset disorder one idea would be to postpone the onset of the illness indefinitely. If we could postpone the onset of Huntington's disease until an individual is 80 years old, we have in essence "cured" the disease since one's life expectancy is not much more than this to begin with.
And finally, we have genetic engineering. We may someday be able to replace the Huntington's gene in the cell -- say in neuronal cells in the brain -- with the normal gene. This is what is known as genetic engineering. Replacement of a defective gene with a normal gene is the ultimate aim in many genetic diseases; however, this technique is way down the road for most genetic diseases.
FCA: What are some of the social implications and challenges facing individuals?
Dr. Conneally: There are, of course, a lot of social implications. For example, recently I was introduced to 3-month old twin boys whose biological father has the gene for Huntington's disease and yet they have no risk of developing the disease themselves. Knowing that the children of individuals who carry the HD gene each have a 50% chance of also carrying the HD gene, how can these boys not have any risk of having inherited the gene? In this case, the parents had in-vitro pre-implantation diagnosis. This technique is the same that is used in typical in-vitro fertilization but the eggs are grown until the 8-cell stage outside the womb. Then, one of these 8 cells is taken out of each of the embryos and tested for the gene. Those embryos that do not have the Huntington's gene are then implanted. There are lots of questions about this procedure from an ethical standpoint. It is also very expensive. So one aspect of this situation is the societal views of selective choice of embryos and another is the enormous cost of such a procedure.
Then we have, of course, the ethical issues of insurability and health care for individuals who are carrying a disease gene. Presymptomatic testing is now available for a variety of human genetic diseases. This means that for those individuals who are at risk of developing a hereditary disorder, a test is available which will tell them if they carry the disease gene or not. Individuals who choose to undergo this testing can find out whether or not they are going to develop a particular disease years in advance of the onset of their symptoms. A major concern we have is that discrimination will occur for individuals who carry genes for severe late-onset disorders. We all carry bad genes, and we're very fortunate that most of them are recessive. We carry somewhere between three and five bad genes on the average, but they're recessive and it's only when two of them get together - that is, our spouse would also have to carry the same bad gene -- and both of us would have to transmit these recessive genes to our child in order for him to develop the recessive disease. None of us is perfect from a genetic point of view, and it is unfortunate that discrimination occurs against those whose genetic endowment has led them to develop a disease like Huntington's.
Interview Date: October 1997
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