Biological Chemistry: Study Finds Regulated Transcription of Novel RNAs Neuroscience: Old-line Antibiotic Saves Neurons After Spinal Cord Trauma Cell Biology: Structure Turns Iron Entry into Cells on Its Head Political Action Students Get Face to Face with Mass. Voters Letter to the Editor   Monkey Protein Blocks Infection by HIV Iron Maidens May Be at Higher Risk for Diabetes Protein Interferes with RNAi   The HMS Faculty Council Academy Honors 75 New Members MD-PhD Program Celebrates 30 Years Finalists Named for Teaching Award, Votes Invited Honors and Advances   Patient-Doctor Gets Dinged on Wards   House Fire Exposes Gaps in Care   Front Page

NEUROSCIENCE Old-line Antibiotic Saves Neurons After Spinal Cord Trauma The most severe spinal cord injuries extract their full toll in an instant, cutting off all communication between the brain and body below the wound. Lesser or partial injuries steal function through a more gradual process. As the first wave of neurons is destroyed, a torrent of molecules--ions, free radicals, toxic chemicals, inflammatory signals--is released that over the next hours, days, and even weeks, spreads to nearby cells, killing them outright or forcing them to commit suicide. Meanwhile, in an attempt to shore up failing neurons and to contain the spreading damage, astrocytes and glial cells proliferate. In some cases, they get so big that their spiny processes overlap and thicken, creating a cordon of scar tissue that can keep recovering nerve cells from reaching out and establishing new connections. Double dose. Partial spinal cord injury sets off a wave of destruction. Mitochondria swell, releasing cytochrome c into the cytoplasm, triggering cell death (top). Astrocytes and glial cells proliferate, growing so big that their spiny processes overlap and thicken, creating a cordon of scar tissue (bottom). Minocyline appears to block both of these responses. (Image by Jeff Cleary) To avert the self-destructive tide and the accompanying loss of function, patients were routinely given methylprednisolone, which has anti-inflammatory and other powers, within the first eight hours after injury. But the drug, once considered the gold standard of spinal cord therapy, lost its currency after a 2001 study found that treated patients displayed no more recovery of function than untreated ones and often suffered detrimental side effects. "The whole field has been crying out for a new treatment," said Yang Teng, HMS assistant professor of surgery in the department of neurosurgery at Children's and Brigham and Women's hospitals. Over the past few years, researchers have been exploring the possibility that minocycline--an old-line antibiotic that has recently gained new life as a neuroprotective agent in a variety of neurodegenerative diseases--might be used to avert this devastating course of events. Though initial experiments have been promising, the rush to develop minocycline-based therapies has led to a kind of shot-in-the-dark approach. Researchers have not been sure what molecule minocycline is targeting, which has made it difficult to design a safe and maximally effective therapy. Squelching the Death Message In the March 2 Proceedings of the National Academy of Sciences, Teng, Robert Friedlander, Howard Choi, and their colleagues report that minocycline works by preventing the mitochondria from releasing the well-known cell death messenger cytochrome c. By tracking how soon after injury cytochrome c is released, and at what rate, the researchers figured out when and in what dose minocycline would be most effective. Rats with spinal cord injuries affecting their lower limbs that were given the regimen recovered significantly greater use and control of their hindlimbs than untreated spinal cord-injured animals, and with minimal side effects. Upon closer examination, their spinal cords displayed fewer signs of secondary cell death--they retained more motor neurons and white matter. They also exhibited less scarring, suggesting that minocycline, which is known to exert anti-inflammatory effects, helps quell the activity of astrocytes and glial cells as well as preventing apoptosis. "One hour is a tough window to work with, but it is possible. One of our goals will be to see if we can delay treatment beyond the one-hour window to two hours or more." --Robert Friedlander One big obstacle to the development of new drugs to arrest the secondary destruction associated with spinal cord injuries has been the speed with which that damage occurs. "We have been focusing on glutamate release, free radicals, ion imbalances, the apoptotic pathway, and inflammation," said Teng, who is director of spinal cord injury research at VA Boston Healthcare System. "They happen very quickly. You have to block them almost immediately." What makes cytochrome c release such a good target, and what makes blocking it with minocycline such a potentially viable therapy, is its relative tardiness--release into the cytoplasm peaks four to eight hours after injury. Teng, Choi, an HMS clinical fellow in Teng's lab, and their colleagues found that they were able to arrest secondary injury in the rats by giving them their first full dose of minocycline an hour after injury, followed by half doses every 12 hours for five days. "The one-hour theory is clinically important because if somebody goes to the field--say a paramedic gets the patient--you can start an IV and give them minocycline," said Friedlander, HMS associate professor of surgery in the Department of Neurosurgery at BWH. "One hour is a tough window to work with, but it is possible. One of our goals will be to see if we can delay treatment beyond the one-hour window to two hours or more." An Antideath Antibiotic Friedlander is used to pushing the envelope. Having shown that minocycline limits neuronal damage in amyotrophic lateral sclerosis (ALS), Huntington's disease, and brain trauma by inhibiting cytochrome c release, he approached Teng with the idea that it might do the same in spinal cord injuries. "Our minocycline results are exciting in that they develop a novel post-trauma strategy in the form of a safe FDA-approved drug that could serve as a prototype for future therapies," said Yang Teng, second from left. He is shown with, from left, Federico Desilets, Howard Choi, and Robert Friedlander. (Photo by Leah Gourley) Though these injuries were known to trigger a spreading wave of apoptosis, researchers had only a sketchy account of how this played out at the molecular level. And though most believed that it took a huge toll on patients' abilities, nobody knew how much functional loss was due specifically to apoptosis as compared to other secondary processes. The minocycline findings provide tantalizing clues to these questions. The discovery that blocking cytochrome c prevents cell death suggests that cytochrome c release plays an important role in the molecular scenario. And the discovery that inhibiting apoptosis allowed rats to retain significantly more hindlimb function than untreated rats four weeks after treatment suggests that programmed cell death may take an important toll on patients--and that it can be avoided. Minocycline is currently in phase 3 clinical trials for ALS. Trials have begun or are being planned with Huntington's, Parkinson's, and multiple sclerosis patients. The drug has been used safely for years as an antibiotic, but even if it is effective in spinal cord patients, it would be part of a multipronged strategy. "It would be a cocktail approach," said Friedlander. "We would have minocycline or a drug like it, perhaps a better one in the future, that blocks cytochrome c release from the mitochondria. There are also calcium, free radicals, and a whole bunch of other factors that play a role in the mediation of the injury that you can attack." --Misia Landau