Research Notes

Brain Cells Transplant May Prove Useful as Stroke Treatment About 4 million Americans are survivors of a stroke, the leading cause of adult disability, according to the American Heart Association. Historically, stroke medicine has focused on prevention, immediate treatment, and years of rehabilitation. Now, University of Pittsburgh Medical Center (UPMC) researchers have initiated clinical trials that may ultimately lead to restoration of affected abilities even years after stroke occurrence (D. Kondziolka et al., "Transplantation of cultured human neuronal cells for patients with stroke," Neurology, 55:565-569, Aug. 22, 2000). Following transplantation of laboratory-grown neuronal cells into a stroke patient's brain earlier this year, Douglas Kondziolka, UPMC professor of neurological surgery and radiation oncology, and co-researchers recently completed a 12-patient trial using the same type of cells, LBS-Neurons, supplied by study sponsor Layton BioScience, Inc. of Atherton, Calif. The patients, whose strokes occurred six months to six years previously, had major movement disabilities such as arm or leg paralysis. This research effort, the first time that a treatment has been tried to reverse stroke deficits, is designed to evaluate whether it is feasible to put such cells into the brain and whether the process is safe. The patients received two-six million cells transplanted into sites within and around the stroke-damaged areas of the brain. Researchers report positron emission tomography (PET) scans showed a 15 percent improvement in metabolism in the area of the transplant in six of the patients, suggesting that the transplanted cells may be integrating with existing tissue and functioning. Six months after transplantation, none of the patients had experienced complications or other problems related to the transplant. Although encouraging, there is a significant amount of research still needed before a firm conclusion can be drawn about the effectiveness of the therapy. As Kondziolka says, "The information learned on safety and feasibility of neuronal transplantation for stroke has encouraged us to continue with additional studies that will tell us more about both safety and efficacy." Reports Sharon DeCesare, UPMC certified clinical research coordinator, "We are getting prepared to do another phase--a multicenter dose-escalating randomized trial with 30-40 patients." This trial, which will include the University of South Florida in Tampa and the University of California at Stanford, is to find out whether these transplants really do help patients recover lost abilities. --Kate Devine Targeting TB The discovery of an enzyme critical to the survival of Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), could open the door to a new TB therapy that's more effective than those currently available (J.D. McKinney et al., "Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase," Nature, 406:735-8, Aug. 17, 2000). Researchers from Washington University in St. Louis, collaborating with researchers from the Albert Einstein College of Medicine and Rockefeller University, found that an enzyme called isocitrate lyase (ICL) helps the bacterium acquire sustenance by degrading fatty acids. Investigators showed that unlike mice infected with normal M. tuberculosis, those infected with recombinant bacteria missing ICL were able to eventually eliminate the infection. The ICL metabolic pathway is a particularly attractive drug target because it is likely active even while the bacteria are lying dormant for months or years in the host. While all currently available TB drugs primarily target replicating organisms, an ICL-associated drug could, theoretically, target inactive bacteria. By doing so, it might shorten the necessary period of treatment and give drug-resistant strains less time to develop. Senior author David G. Russell, now the chairman of microbiology and immunology at the College of Veterinary Medicine at Cornell University, and his colleagues are now in the early stages of drug development in collaboration with Glaxo Wellcome as part of a philanthropic program called "Action TB." (TB drugs, because they are of greatest use in developing nations where the disease is prevalent, generally are not moneymakers). Thus far, scientists have been pleasantly surprised by the specificity of several candidate compounds, a concern because humans do have an enzyme similar to ICL called isocitrate dehydrogenase. "It looks very encouraging," says Russell. "Of course, there's a long way to go before one would actually get a product." --Eugene Russo Synapses Sound Off Like voices carried through telephone wires, the electrical signals at neurons' synapses must, to be "heard," move along the dendrites of neurons without losing strength. Neuroscientists have generally proposed two possible means of signal transmission: a "boosting" mechanism, in which synapses are amplified by voltage-gated channels, or "synaptic scaling," in which the strength of a synapse increases proportionally with its distance from the cell body or soma. According to a recent study, the latter is true: distant synapses are not amplified, but they operate at a high volume from the get-go to be heard (J.C. Magee, E.P. Cook, "Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons," Nature Neuroscience, 3:895-903, September 2000). To arrive at their conclusion, investigators had to measure signal strength--the amplitude of the excitatory postsynaptic potential (EPSP)--simultaneously at the sites of input and output, the dendrites and the soma respectively. The findings help elucidate the biological basis of behavior and memory; if synapse strength were fixed according to cellular location, it would be difficult to explain how synaptic inputs vary based on individual experience. Future research will investigate whether the model, tested in CA1 hippocampal neurons, holds for other neuronal types and for different regions of the same neuron. "We're pretty confident of our results, mainly because it's a very straightforward experiment," says lead author Jeffrey C. Magee, a neuroscientist at Louisiana State University Medical Center, but "how general of a phenomenon this is ... hasn't been worked out yet." Researchers will also attempt to characterize the actual synaptic mechanism responsible for synaptic scaling. --Eugene Russo Polio as Herald for Healing Gene therapy researchers may have a new tool in their disease-fighting arsenal. Preliminary research from University of Alabama researchers suggests proof-of-principle for recruiting the polio virus to deftly deliver foreign genes to hard-to-reach areas in the spinal cord and central nervous system (A.W. Bledsoe et al., "Cytokine production in motor neurons by poliovirus replicon vector gene delivery," Nature Biotechnology, 18:964-9, September 2000). Therapies would target damage caused by neurodegenerative disease, stroke, or spinal cord injuries. As part of experiments in mice, investigators "disarmed" the poliovirus by removing the genes that encode for capsids, the viral coat proteins that enable the virus to spread. To illustrate the resulting replicon's delivery capacity, they replaced those proteins with genes for two proteins: green fluorescent protein (GFP) and tumor necrosis factor (TNF). Researchers used GFP as an innocuous marker to demonstrate the extent to which they had reached neurons in the spinal cord, and to show that delivery could be done safely without unwanted viral effects. They used TNF, a cytokine known to have widespread effects on the spinal cord in several cell types, to show that they could actually deliver something to the intended target. "In the traditional sense, it's not gene therapy," explains senior author Casey D. Morrow, a professor of microbiology at the University of Alabama at Birmingham, adding that the idea is to use the virus's motor neuron affinity not to correct a gene defect, but to deliver a therapeutic agent. Other groups are trying to use attenuated polio to attack hard-to-treat gliomas rather than to deliver genes (E. Russo, "Putting Polio to Good Use," The Scientist, 14[13]:19, June 26, 2000). Continuing their work in mice, Morrow's group is now trying to transport genes such as nerve growth factors that have a known therapeutic benefit for spinal cord trauma. --Eugene Russo Biotech Decaf for Sleepless in St. Louis Coffee mavens might not be too fond of the palpitations, upset stomach, and sleepless nights that sometimes accompany a strong cup of jo, but if industrial-grade decaf is the only alternative, it's not worth the sacrifice. The process that removes caffeine also kills much of coffee's special something. But hope's a brewing--a Japanese-Scottish research team recently cloned a cDNA for caffeine synthase from tea leaves (M. Kato et al., Nature, 406:956-7, Aug. 31, 2000.) The enzyme catalyzes addition of two methyl groups to 7-methylxanthine, creating theobromine, then caffeine. Escherichia coli transformed with the tea gene dutifully made active enzyme. A morning cup of intestinal bacteria is not what the researchers had in mind, though. Instead, they want to transform Coffea arabica plants with an antisense version of the gene to turn off caffeine synthesis. If they succeed: voilà, 'natural' decaf. Transgenic coffee may not win over regulars at Jittery Joe's in Athens, Ga. Flavor is a complicated affair, and tinkering with secondary plant metabolism is not straightforward. Good caffeine-free brew might be welcome in St. Louis right now, though. On Aug. 30, transgene giant Monsanto announced a 35 million share initial public offering, or IPO, amounting to 14 percent of company stock (the rest is owned by New Jersey parent, Pharmacia.) With ag biotech in turmoil, execs may toss and turn worrying whether they'll meet their $20-$25-a-share expectations. --Barry A. Palevitz

Research Notes

Brain Cells Transplant May Prove Useful as Stroke Treatment

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