Genomic Medicine – The Hope and the Hype

Ten years ago this month, President Clinton, along with Drs. Craig Venter and Francis Collins, announced the completion of the Human Genome Project – the complete DNA sequence of the human genome. As is typical of such announcements, there was much pomp and circumstance, as the President declared it a “day for the ages.”

Why the excitement? It was fully expected by participants in the struggle to sequence our genome that achieving this goal would rapidly lead to a new understanding of the genetics of common disease, and would yield new genomic treatments that would revolutionize the practice of medicine. In fact, Dr. Collins predicted that the genetic diagnosis of disease would be accomplished within 10 years, and treatments would begin to appear 5 years later.

This, sadly, has not happened.

So does that mean the Human Genome Project was a bust? Hardly. While medicine has not been revolutionized, basic biology has been. The complete sequence of the human genome has shed tremendous new light on a variety of ways that genes are regulated, especially by RNA, which would never have been understood without sequence information.

So why has the sequence of the human genome not revolutionized medicine? As discussed in an article from The New York Times, there are several reasons. One reason cited by The Times is that many of the sequence variations associated with common diseases are not found within genes. This raises the possibility that these sequence variations are a statistical fluke, not really associated with the disease at all… or by anything other than chance. More disconcerting, if your goal is to develop a new treatment, is that common diseases may be caused by a large number of very rare sequence variations, so that individuals with a particular disease may have very little in common with each other, and nothing amenable to a drug.

Is this result entirely a surprise? To any serious student of human genetics, the answer has to be, “Not really.”

The First Genetic Disease

After reading any article in the popular press about genomic medicine, one would get the impression that the genetics of human disease is a new field, and that before the human genome was sequenced, there was nothing known about how gene mutations cause disease. This, however, is not true. In a paper published in Science in 1949, Linus Pauling and his colleagues demonstrated that sickle cell anemia is caused by a mutant form of hemoglobin, the protein that carries oxygen in red blood cells. In 1956, Vernon Ingram and his colleagues proved that this mutation was at the 6th amino acid of the protein. This change was soon shown to be the result of a single DNA base pair change.

For more than 50 years now, physicians and scientists have understood Sickle Cell Disease in molecular detail. Nevertheless, we are still unable to explain how this molecular defect causes any of the symptoms of the disease, and we are unable to do anything about it. To this day, despite how long we have understood the molecular biology of the disease, treatment remains supportive (meaning prophylactic antibiotics, pain medicine, and transfusions) or aimed at changing the way the hemoglobin genes are controlled (using a medicine called hydroxyurea). There is no treatment available that is directly related to the genetic cause of the disease, the mutation at amino acid 6.

I think this should be a warning to those who think that the path from the molecular understanding of a disease to a treatment will be straightforward. The era of genomic medicine may be upon us, but it is probably going to be a very slow change, not an overnight revolution.

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