|
||||||||
|
RESEARCH BRIEFS
Common Antibiotic May Slow Huntington's DiseaseA garden-variety antibiotic may thwart the progression of Huntington's disease say researchers led by Robert Friedlander, assistant professor of surgery at Brigham and Women's Hospital. Daily doses of minocycline, a tetracycline derivative, prolonged the lives of mice with the equivalent of Huntington's by 14 percent. The study appears in July's Nature Medicine.
In mice with Huntington's disease, those treated with minocycline showed 43 percent lower levels of interleukin-1ß, which indicates caspase-1 activation, than saline-treated mice. The protective effect is not due to the drug's antimicrobial properties—in tests, tetracycline, which cannot pierce the blood–brain barrier, did nothing to slow the disease. Instead, the paper shows that minocycline, which can act on the brain, inhibits the expression of the genes for caspase-1 and caspase-3, members of a cabal of enzymes involved in programmed cell death. Caspases, which number more than a dozen, act in concert and in sequence to systematically dismantle unwanted cells. But this and other research has shown that caspase-1 and caspase-3 become "trigger-happy" in cells of those suffering from Huntington's: the enzyme assassins cleave huntingtin, a key protein for normal development. Minocycline also inhibits iNOS, an enzyme that produces nitric oxide and may play a role in the disease. Researchers found that in the cell death pathway, caspase-1 acts as a trigger, reaching peak levels when the mice are 7 weeks old. Spurred on by caspase-1, caspase-3 acts as an executioner, rising steadily after the mice reach 9 weeks. Inhibiting either caspase on its own had no effect, while inhibiting both delayed the advancement of the disease. "It's a cup with holes," Friedlander explains of the futility of focusing on a single caspase. He suggests future treatments will be a cocktail of complementary caspase-inhibiting drugs. Friedlander cautions that mice treated with minocycline were not cured and high levels of the drug were toxic. Still, with the right dose, the drug holds promise for patients. Clinical trials are being planned. Specialized Neurons Team Up to Spot Foreground, MotionSeveral times a second, our eyes make minute adjustments to take in the world around us. In an instant, we can calculate how far to step down to cross the street or whether to jump back to dodge a speeding car. How exactly do our brains perform these common and yet exquisitely complex tasks? A team of researchers led by HMS assistant professor of neurobiology Rick Born has provided the first experimental evidence supporting the theory that neuronal center–surround systems enable us to perceive movement and distinguish between objects and their backgrounds. Widely accepted theories, such as in Gestalt psychology, suggest our brains make sense of the visual world by comparing nearby sections of a scene to see whether they are alike or different. Two types of neurons, which are sensitive to movement in a particular direction, are thought to be involved in how we use motion to do this. The theory holds that neurons that are sensitive to discrepancies in local motion signal the motion of an object, while those that pick up wide-field motion in one direction register background motion. Born and colleagues Jennifer Groh, assistant professor of psychological and brain sciences at Dartmouth College; Ruilin Zhao, an HMS graduate student; and former Harvard undergraduate Stephen Lukasewycz confirmed this hypothesis in a paper in June's Neuron. In one part of the experiment, the researchers electrically stimulated in rhesus monkeys either kind of neuron—found in the middle temporal visual area (MT)—while the animals detected and followed a moving spot. In most cases, the monkeys followed the spot with their eyes when the local motion neurons were stimulated. But when the wide-field neurons were stimulated, their eyes moved in opposition to the "natural" direction of the neurons, just as they did when the researchers replaced the electrical stimulus with a background that actually moved. Born likens the effect to what we perceive when we peer at the moon on a cloudy, windy night. "It looks like the moon is moving, but the background is moving," he says, explaining why our eyes seem to fight the current of clouds. Potential Tumor Vaccine Targets More Plentiful Than BelievedThough many doctors strive to give patients individualized care, a group at HMS is working hard to do the opposite. These scientists are searching for ways to treat all patients the same. Researchers in the lab of John Gribben, HMS associate professor of medicine at the Dana–Farber Cancer Institute, used bioinformatics to look for antibody peptides from malignant B cells that might be recognized by CD8+ T cells. They wanted to find out if these peptides were unique to each individual, like fingerprints, or if any of them were common to many people. To their delight, they found almost two dozen peptides that T cells in two thirds of the study's 192 patients could "see." "That's a pleasant surprise because if you want to make a tumor vaccine, you're looking for a drug that can be applicable to more than one patient," says Gribben. Until now, these vaccines have had to be tailor-made for each patient. "That's very, very expensive," he says. Soon, cancer patients may be able to rely less heavily on chemotherapy and more on treatments that activate their own immune responses, such as vaccines and adoptive immunotherapy, in which T cells are removed, trained to attack tumor cells, and then returned to the body. To arrive at their results, the researchers borrowed a bioinformatics technique often used by AIDS researchers to sift through sequences of peptides for those that might provoke a reaction from T cells. After the computer identified the best candidates, the scientists synthesized and tested them. "We found a very good correlation between what was predicted and what we actually saw.... The whole approach is widely applicable and we've already applied it to other malignancies," says Gribben, referring to current studies on prostate and lung cancer. Screening can also help scientists "design" peptides that T cells will bind to. If a particular peptide sequence is not inciting any response in a T cell, scientists can switch its endpoints with those that do bind, creating a "heteroclitic" peptide. First authors on the paper, which appears in the June Nature Medicine, are HMS research fellow Andreas Trojan and HMS instructor in medicine Joachim Schultze, both at DFCI. Cholesterol Med Shown to Reduce Bone FracturesIf drugs could be worn, statins would be reversible raincoats—versatile and protective. For years, they have been used to lower cholesterol, but now a growing body of research suggests they sport a flip side—they may prevent bone fractures in the elderly. In the June 28 JAMA, HMS instructor in medicine Philip Wang and colleagues analyzed a database of New Jersey patients, all at least 65 years old. They compared the statin use of 1,222 patients who had undergone surgery for hip fractures, associated with osteoporosis, with 4,888 who had not. Patients who had used statins to lower their cholesterol anytime in the previous 180 days were 50 percent less likely to have suffered these fractures. Intriguingly, the effect was not observed for other cholesterol-lowering drugs. And the risk of fracture dropped both as statin use became more recent and as the duration of use increased. All of this suggests that as in animal studies, "statins may not only slow down bone resorption but may actually lay down new bone," says Wang. In the paper, authors Wang; Daniel Solomon, HMS instructor in medicine; Helen Mogun, a senior programmer; and Jerry Avorn, HMS associate professor of medicine, all at Brigham and Women's, offer a connection between cholesterol and bone metabolism: statins seem to inhibit mevalonate, a metabolite involved in the production of both cholesterol and two lipoids that help osteoclasts resorb bone. Despite the fact that the researchers controlled for many possible confounding variables, Wang urges more research on the link between statins and bone fractures. "This is too early to discuss this as a possible treatment for osteoporosis," he says. —All briefs by Maggie McKee |
