"Mighty mice" might
knock out muscle-wasting disease
A line of genetically engineered mice, two to three times larger than normal mice and sporting Arnold Schwarzenegger-like muscles, may lead scientists to new treatments for diseases that cause muscle wasting. The muscular mice, weighing 20 to 30 percent more than normal mice, were created after a research team led by Se-Jin Lee, an assistant professor of molecular biology and genetics at the School of Medicine, identified a gene called growth/differentiation factor 8, or GDF 8. The gene limits muscle growth.
Lee's team found gene GDF 8 while searching for new members of the transforming growth factor-beta gene family, a group of genes that includes proteins that stimulate bone growth. Once the gene was identified, researchers wanted to know how the lack of the gene would affect growth. To find out, Ann Lawler, assistant professor of gynecology and obstetrics at the School of Medicine, microscopically deleted, or "knocked out," the GDF 8 from the genetic code of mouse embryonic stem cells during the single cell stage. This left the developing animals without GDF 8.
Lee's team, who have created hundreds of mighty mice since the first generation was born in April of 1996, knew that GDF 8 was a "negative regulator," that it limited skeletal muscle growth. However, they did not expect the unusual muscle growth that resulted from erasing GDF 8.
"The first thing we noticed was that the knockout mice had unusually large shoulders and hips," said Alexandra McPherron, a doctoral student and the first author of the paper reporting the findings in the May 1 issue of the journal Nature. "Except for the muscles, the mice appear to be normal and healthy."
Lee pointed out that the organs in the mighty mice, and their smooth muscle tissue, are normal. Too, the fibers of the skeletal muscle are constructed normally, they are just bigger in the test mice. McPherron added that the super mice were "sluggish" and didn't move around quite as much as the normal mice. The muscular mice reproduce mighty mice that, like their parents, are otherwise normal.
"It's not that we made a bigger mouse," McPherron said. "All of the other organs are normal size. We just made a normal mouse that has twice as much skeletal muscle."
With the knowledge that the lack of the GDF 8 gene in mice promotes super muscle growth, researchers are optimistic that drugs might be produced to inhibit the expression of GDF 8 in humans, thereby creating an opportunity for rebuilding muscles wasted by diseases like muscular dystrophy, some cancers or AIDS.
Lee emphasized that all their studies have been done in mice and they don't know if the gene plays the same role in humans. He added that it is not now technologically possible, nor is it ethically feasible, to knock out the GDF 8 gene in humans. Equally unclear is the effect of interfering with, or blocking, the function of GDF 8 in other animals.
Currently, the team is producing a generation of mighty mice with a second genetic alteration, one that predisposes them to muscle degeneration. At issue in these experiments is whether the greater muscle mass produced by inhibiting GDF 8 will counter or repair muscle wasting. Even if wasting can be arrested by increased muscle mass, medical applications in humans are a long way off, said Lee.
If they find that GDF 8 has the same function in humans as in mice, Lee called the path to human medical applications "straightforward," toward finding drug inhibitors that might produce increased muscle mass like that caused by knocking out GDF 8.
Potential applications in agriculture, without the ethical issues in human applications, are closer on the horizon, however. "We've also found GDF 8 in cows and chickens," Lee said. "So we might be able to interfere with it to create livestock with more meat and relatively less fat."
While they have cloned the GDF 8 gene in many animals, Lee said they don't know whether it functions the same in all animals. Also, researchers don't know whether inhibiting the expression of the gene in adult animals--that is without knocking it out in the embryo stage--will promote the same kind of megamuscle growth in adults similar to the result realized after removing it in embryos. The potential to use GDF 8 to reduce disease-related muscle wasting rests on that yet-to-be-studied issue. According to Lee, research aimed at answering that question, and many more, is just beginning.
Audits Office reports fraud case conviction
Debora Jones, formerly of Student Services Activities at Homewood, was prosecuted by the State's Attorney's Office and found guilty of misappropriating $6,000. Jones' conviction was the result of an internal investigation performed by the university's Office of Audits and Management Services.
Jones initiated the fraud by opening a charge account in the name of the university and charging personal items to the account. She attempted to cover up the fraud by using various accounting techniques since she was responsible for reconciling statements and many of her purchases were similar in nature to purchases made by the department.
However, a staff member observed expensive personal purchases being delivered to Jones at the office and alerted a supervisor who requested an audit.
As in all fraud cases, when Jones' fraud was revealed she was terminated for cause and prosecuted. She received judgment before verdict consisting of three years' probation and a requirement she repay the misappropriated funds. Failure to do so will result in jail time.
The university has a firm policy of prosecuting fraud in every case, and is usually successful in obtaining favorable judgment. Managers or others who suspect fraud in their unit should contact either the Office of Audits and Management Services, the Office of the General Counsel or the Office of the Controller.
Hopkins has "whistle blower rules" in effect that allow all such referrals to remain anonymous, although if individuals suspect fraud "they should be very specific in their allegations," according to a senior member of the Office of Audits and Management Services team.
The Office of Audits and Management Services, located at 2216 North Charles St. in Baltimore, can be reached by calling 410-516-6391.
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