MIT professor’s book digs into the eclectic, textually linked reading choices of people in medieval London.
After more than 10 years of intensive effort, a collaboration of scientists including a team of eight MIT biologists has found the gene responsible for Huntington's disease.
As a direct result of the discovery, which was reported in the March 26 issue of the journal Cell, scientists will now be able to develop a more accurate and less expensive diagnostic test for the disease than is currently available.
A cure for Huntington's, which usually strikes in midlife and is characterized by jerky movements, spasms, and eventual dementia, is not yet in hand, and could take years to develop. "But today we've taken a step forward to that end," said Professor David E. Housman of the Department of Biology, who led the MIT team, at a press conference on the discovery last Tuesday at Massachusetts General Hospital. The gene was actually found at MGH, one of the six primary institutions that collaborated in the work.
About 30,000 Americans suffer from Huntington's disease. In addition, another 150,000 are at risk: each child of a parent with Huntington's has a 50 percent chance of inheriting the illness.
The MIT team, based at the Center for Cancer Research, played a key role in the Huntington's work by developing one of the genetic tools that led to the discovery.
Further, it turns out that the nature of the genetic defect responsible for the disease is strikingly similar to the defect responsible for myotonic dystrophy, the adult form of muscular dystrophy. Last year Professor Housman led another group of MIT biologists that helped find the gene for that disease.
As a result, "all the work we've done in the lab since discovering the myotonic dystrophy gene turns out to be very relevant to Huntington's disease," Professor Housman told MIT Tech Talk.
A DEADLY DEFECThe gene responsible for the havoc wrought by Huntington's was found at the tip of the short arm of chromosome 4. While all of us carry this gene, people with Huntington's disease have a version that's defective. Specifically, the defective gene contains one region that repeats too often-the molecular equivalent of a stutter.
Genes are composed of nucleotide building blocks-abbreviated as A, T, G, and C-that are grouped in threes. The defective Huntington's disease gene contains a CAG triplet that repeats a minimum of 42 times. In comparison, the CAG triplet of the normal gene repeats only 11 to 34 times.
The defective CAG repeat was found in all 75 Huntington's disease families studied.
The scientists also found a possible correlation between the number of repeats in the defective gene, and the age of onset of the disease. Specifically, it appears that the higher the number of repeats the earlier victims will show symptoms. The youngest person known to show symptoms of Huntington's disease was two years old; that person had 86 repeats of the CAG triplet, the largest number observed so far.
Although this correlation points to the possibility of a test that could tell people diagnosed with Huntington's when they might begin to suffer from it, Professor Housman and others stressed that the correlation first "needs to be confirmed." Further, Russell Snell of the University of Wales noted that "other genes could also affect the age of onset." (The University of Wales is another of the institutions that collaborated in the work.)
In another twist, the scientists discovered that the defective Huntington's gene is unstable: when the gene is passed to children, the number of repeats can change. Most often the number of repeats appears to increase, though sometimes a child can inherit a smaller number of repeats than his or her parent.
SIMILARITIES TO MYOTONIC DYSTROPHYAt an MIT press conference, Professor Housman noted that the repeating nucleotide sequence of the defective Huntington's gene "is very familiar to my lab."
It turns out that the defective gene responsible for myotonic dystrophy has a similar "stutter," though the number of repeats involved is larger. Clinical symptoms of Huntington's disease appear when more than 42 triplets are repeated, while clinical symptoms for myotonic dystrophy appear when more than about 60 triplets are repeated.
Nevertheless, the basic nature of the mutation is similar. "Since discovering the underlying basis of myotonic dystrophy we have focused on trying to understand how [this genetic defect] leads to clinical pathology," Professor Housman said.
"The discovery of a similar basis for Huntington's disease has increased the intensity of our efforts [to this end]. We hope that through these efforts a strategy for combating the devastating effects of both of these genetic disorders can be found."
UNIQUE TECHNIQUEOne of MIT's most important contributions to the discovery of the Huntington's gene is a new genetic tool developed in the labs of Professor Housman and Professor Phillip A. Sharp, head of the Department of Biology.
A gene on a chromosome is naturally divided into several pieces separated by large stretches of DNA known as introns that have nothing to do with the expression of the gene. The MIT tool, known as exon amplification, allows scientists to cull out the pieces of the gene itself from the introns. According to Professor Housman, "such scanning dramatically reduces the amount of work required to search for a [particular] gene."
Alan J. Buckler, a postdoctoral fellow in Professor Housman's lab who played a central role in developing the technique, said "The stimulus to develop exon amplification came from Huntington's disease. The ability to work closely with Dr. Sharp and his group made it possible to develop the technique quickly and efficiently."
The technique was critical to finding the Huntington's disease gene, and is representative of a variety of new technologies developed during the search "that are now taken for granted in other gene searches around the world," Professor Housman said.
IT'S BEEN AN ODYSSEYIn 1983 MIT PhD graduate James Gusella, who did his doctoral work with Professor Housman and was then working at Massachusetts General Hospital, narrowed the search for the Huntington's gene to chromosome 4.
That breakthrough led to the formation in 1984 of The Huntington's Disease Collaborative Research Group, six primary institutions that banded together to find the exact location of the deadly gene.
The collaborative was supported and catalyzed by the Hereditary Disease Foundation and its president, Nancy Wexler, and scientific director, Alan Tobin. Dr. Wexler's mother died of Huntington's disease. (She will not say whether she has been tested for the disease.)
The institutions that make up the collaborative are MIT, the University of Michigan, the Imperial Cancer Research Fund, the University of Wales, the University of California at Irvine, and Massachusetts General Hospital.
Over the years scientists in the collaborative met regularly and shared everything from data to ideas. "The collaborative is a different way of doing science that I think worked wonderfully. We kept each other up to date with exactly what we had," said Lynn Doucette-Stamm, a leader of the Huntington's disease group in Professor Housman's lab, at the MIT press conference. (Dr. Doucette-Stamm was a postdoctoral associate at the Center for Cancer Research; she recently left for a position at Collaborative Research, Inc.)
That sharing and persistence paid off with the discovery of the gene by scientists in Dr. Gusella's lab at MGH. "Many of us never thought we'd make it to this day. It's been a tremendous odyssey to get here," Dr. Wexler said.
To underscore the cooperative effort that went into the discovery, Professor Housman noted that the resulting paper in Cell "has one author [The Huntington's Disease Collaborative Research Group] and 58 names."
WHAT NOW?The discovery of the Huntington's gene has actually raised more questions than it's answered. For example, Professor Housman said, "Why does the gene only affect brain cells? What can we do to stop it? Why is there onset at a certain age?"
However, with the gene in hand the scientists should now be able to put it into animal models to learn more about the disease. "Mice models should be coming along soon," Professor Housman said.
"We don't stop here," Professor Housman concluded, "we move forward and continue to try to unravel this mystery."
In addition to Drs. Housman, Buckler, and Doucette-Stamm, the following scientists were part of the MIT team involved in the discovery: Deanna M. Church, a research affiliate at the Center for Cancer Research; Michael C. O'Donovan, a postdoctoral fellow at the CCR; Laura E. Riba-Ramirez, a technical assistant at the CCR; Manish A. Shah, a graduate student in the Harvard-MIT Division of Health Sciences and Technology; and Vincent P. Stanton, a postdoctoral associate at the CCR.
Further, Professors Richard C. Mulligan and H. Robert Horvitz, both of biology, were advisors to the Hereditary Disease Foundation and the Huntington's Disease Collaborative Research Group.
A version of this article appeared in the March 31, 1993 issue of MIT Tech Talk (Volume 37, Number 27).