Restoring lost movement
	Doctors who need doctors
	Gene fine-tunes chemotherapy
	Q&A

Restoring lost movement

Last summer, Hopkins neurologist Douglas Kerr mixed together a solution containing master cells known as stem cells, and injected it into the base of the spinal cord of 18 recently paralyzed mice. His hope: these primitive cells would migrate to sites of nerve damage and compensate for the neuron loss.

Four weeks later, Kerr saw no change in the mice. But by eight weeks, he was elated. "We first saw a flicker of movement [in some mice], then a second limb, then flexing of a hind limb," he says. Finally, several of the animals placed down a hind paw and bore weight on that limb. In all, 11 of the 18 mice had regained at least some degree of limb movement.

Kerr and his colleague, Hopkins neurologist Jeffrey Rothstein, say the results are promising step toward using the cells to restore movement in patients with paralyzing illnesses and injuries, such as amyotrophic lateral sclerosis (Lou Gehrig's disease).

The researchers caution, however, that clinical use of stem cells for motor neuron conditions is years away. Many unanswered questions remain, such as: What mechanism explains how the cells helped the mice regain movement? And, would stem cell injections have lasting effects or need to be repeated?

Until recently, researchers studying neural stem cells have focused on conditions such as Parkinson's disease or stroke, which affect a smaller, circumscribed group of neurons. Directing stem cells to more diffusely damaged regions of the nervous system was presumed to be a bigger challenge.

Kerr and Rothstein hypothesized that the cerebrospinal fluid, the nutrient soup that bathes the spinal cord, might be a means of delivering stem cells to damaged neurons. So working with stem cell biologists John D. Gearhart, at Hopkins, and Evan Snyder, at Harvard University, they created injections containing neural stem cells from mice. They injected the cells into mice infected with a virus that causes paralysis and may serve as a model of paralyzing conditions in people.

Did the stem cells get into the spinal cord? Kerr dissected the mice, which were sacrificed at the end of the experiment. "Absolutely, they made a beeline to it," he says. Thirty percent of the stem cells had migrated into the spinal cord of the infected mice, to a region called the ventral horn, which contains neurons that extend processes to the muscles controlling limb motion.

About one-third of the cells that made their way into the spinal cord appeared to have become some type of primitive neuron. "But they are clearly not motor neurons," says Rothstein. So how did they help the mice regain movement? The cells may have differentiated into supporting cells called astrocytes, which supply hormones and other vital factors to motor neurons, Rothstein suggests.

Curiously, the stem cells did not enter the spinal cord of healthy animals that served as controls. "There is some signal that has to do with motor neurons dying that serves as a trigger," posits Kerr. "It's fascinating to see."

The researchers, who received funding from Project ALS and the Muscular Dystrophy Association, next plan to expand their study and to test the effects of a variety of different types of neural stem cells. --Melissa Hendricks

Physicians who did not have a healthcare provider were more "fatalistic" about their health, says senior author Daniel Ford, an associate professor of medicine and of health policy and management, while people who see a doctor regularly appear more likely to avail themselves of preventive health procedures-- measures that can save lives, says Ford. --MH

Gene fine-tunes chemotherapy

A new genetic test may help predict which brain cancer patients will respond to a chemotherapy drug, allowing those who would not to avoid the difficult therapy.

"If you know who is not going to respond, you can then try radiotherapy or another chemotherapeutic drug. Why treat a patient with a drug we know is not going to be useful?" says Manel Esteller, a research fellow at the Hopkins Oncology Center and test co-developer.

Esteller and his colleagues used the test to screen patients with glioma, a particularly fast-growing and lethal form of brain cancer. Glioma patients are routinely treated with the drug carmustine and radiation. While most do not respond, chemotherapy does shrink tumors in a minority of patients; herein lies a clue to predicting its effectiveness.

Glioma patients with an altered MGMT gene were more likely to see their tumors shrink through chemotherapy. Image courtesy Esteller et. al., The New England Journal of Medicine, ©2000, Mass. Medical Soc., All Rights Reserved

The researchers found that patients who had an altered version of a gene called MGMT (altered through a naturally occurring biochemical process known as methylation) were more likely to have their tumor reduced in size by carmustine. Twelve of 19 patients with a methylated MGMT gene responded to chemotherapy, compared to only one of 28 patients with an unmethylated version. Further, patients with a methylated MGMT gene lived an average 13 months longer. The researchers reported their findings in the November 9, 2000, New England Journal of Medicine.

The researchers are now testing agents that will inhibit the MGMT gene, and thus increase carmustine's effectiveness. Esteller and Hopkins oncologist James Herman developed a screening test for the MGMT gene and its methylated version, and Virco Lab Inc., of Great Britain, licensed the technology and plans to commercialize it.

Esteller predicts it will one day be possible to tailor cancer therapy based on a tumor's genetic profile. --MH

Q&A

With a five-year $7.8 million grant from the NIH, Johns Hopkins Medicine recently established the Center for Complementary and Alternative Medicine (CAM), which will sponsor lab and clinical research on alternative forms of cancer treatment, and train physicians and medical students. Adrian Dobs (pictured at right) is a principal investigator at the center and professor of endocrinology.

Many critics would say Hopkins has held back on exploring CAM in the clinic and research lab. Why pursue it now?

Dobs: Initially there was some reluctance, thinking that none of these therapies actually worked, and that it was not consequential to patients' health care. But we've grown a lot in the past few years.We have learned that many of our patients were taking complementary and alternative medicines. The estimate is that approximately $12 billion is spent out of pocket for these kinds of therapies in the U.S. And there's very, very little data to say how effective and safe they are. We've also become more aware that some of these therapies may work, that they may have active drugs in them. On the other side, we think many are actually strong drugs that may indeed have side effects or be harmful. And then there are groups that may not be harmful but may not have any efficacy.

One of your initial projects involved looking at the health benefits of a group of Chinese herbs (called PC-SPES) on men with prostate cancer. Have studies suggested they may be helpful?

So far, it seems some have low doses of hormones in them--phyto estrogens, which are plant estrogens. There is preliminary data that suggests they may shrink tumors. In all of our grants, we're not just interested in outcome but in the mechanisms--how the intervention affects the disease state. If there really are high doses of estrogens in these compounds, there might be a complication. High doses of estrogens have been associated with blood clots. So we're very concerned with safety.

Do you currently prescribe any alternative therapies to your cancer patients?

I'm still very leery. There's such poor standardization of what's really in them, and they're very expensive, with little regulation. But I'm optimistic we're going to find things that are effective. That's because I think they're really drugs. Many drugs come from botanicals--like the heart drug digitalis, from foxglove.

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