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"I was surprised by the findings, but have always thought that
these stem cells are amazing and that they represent a great
potential strategy," says Kerr who reported his findings in
November 2000 at the annual Society for Neuroscience meeting in
New Orleans. 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
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Doctors who need doctors About 16 percent of Americans do not regularly see a doctor. But according to a survey of Johns Hopkins School of Medicine alumni, many physicians themselves have an even worse track record. More than a quarter of the physicians surveyed--some 28 percent--did not see a doctor regularly, and 7 percent said they treated themselves. Pediatricians were most likely and pathologists least likely to have a regular source of care. Researchers used data collected through the Johns Hopkins Precursors Study, a long-term ongoing health survey of 1,337 physicians who trained at Hopkins School of Medicine between 1948 and 1964. The investigators asked the physicians in 1991 whether they used a regular health provider, then compared those results to the preventive health measures (such as colon cancer screening or having a flu shot) the doctors underwent six years later. Survey results appeared in the November 27 Archives of Internal Medicine. 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.
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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