While animal rights activists were busy fire bombing the cars of researchers in Great Britain in early September, the journal Science reported a stunning breakthrough in understanding myotonic dystrophy thanks to a savvy neurologist and genetically modified mouse.
    Myotonic dystrophy afflicts about 40,000 Americans — it is the most common form of muscular dystrophy. The disease causes progressive muscle weakness that often starts by causing stiffness in the hands and eventually makes it extremely difficult for victims to walk, swallow or breathe. Almost nothing is known about the disease. In 1992 researchers discovered the genetic defect on the chromosome that causes the disease, but so far that knowledge hasn’t gotten researchers very far.
    The obvious solution was to create an animal model for the disease, but until the new research, the numerous efforts to create mice afflicted with symptoms of myotonic dystrophy failed. Neurologist Charles Thornton managed to succeed, however, where others had failed, and his breakthrough pointed to an immediate puzzle that might help break research into the disease wide open.
    Like human beings with myotonic dystrophy, the genetically modified mice suffer from a degenerative stiffening of the muscles. Thornton’s research team added a genetic defect into mouse chromosomes that closely resembles the genetic defect in human chromosomes (in normal genes, a particular base sequence is repeated about 30 times, whereas in the genes of those who suffer from myotonic dystrophy, the base sequence is repeated literally hundreds of thousands of times).
    The results were fascinating — the muscle stiffness in the mice was caused by an accumulation of messenger RNA (mRNA) in the nuclei of the muscle cells of the mice.
    This, to my knowledge, is an unprecedented discovery. Messenger RNA is supposed to be little more than an instruction manual for building DNA. Think of RNA as a sort of robot builder — it collects the proteins it needs in the environment and then assembles them according to its instructions to create a DNA strand which it then sends off to do the job of building the body. Genetic diseases occur when the RNA has faulty instructions and thus builds faulty DNA.
    What Thornton’s team found, however, was that large numbers of mRNA were somehow accumulating in the nuclei of the muscle cells and causing damage to those cells in ways that will require a lot more research to understand. As Thornton put it,
Normally, messenger RNA transmits genetic information out of the nucleus and into the main part of the cell where its instructions are carried out. That’s its only job. In this case, it seems to stay in the nucleus, and it’s doing something entirely different that’s harmful. The messenger itself is actively making cells sick.
    This is the sort of basic science discovery that would be very difficult to arrive at relying solely on experiments with human beings — in fact decades of research on muscular dystrophy never even came close to suggesting the possibility that RNA of all things might be capable of damaging muscle tissue. As Thornton eloquently described the benefits of using mice in a press release,
Why all the fuss over mice? Well, it is possible to test dozens or even hundreds of potential treatments in mice in a short span of time. Without an animal model, it takes several years and some risks to test just one treatment in people. I’m hopeful that these mice will accelerate the discovery process.
    Thornton’s discovery opens up a whole line of previously unknown areas that have implications not only for myotonic dystrophy, but for diseases such as Huntington’s and Fragile-X syndrome which are caused by similar genetic defects.
Source:
New mouse marks latest stride in muscular dystrophy research. EureakAlert!, press release, September 6, 2000.