By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
You can't catch Alzheimer's disease from a virus, a bacterium or another person with the malady. The same goes for Parkinson's, Huntington's, amyotrophic lateral sclerosis (ALS) and retinal degeneration. These neurodegenerative diseases are not contagious, but largely inherited. With rare exceptions, they kick in during the advancing years of life. That's when neurons at specific sites in the brain begin to sicken and die.
"Historically, I guess for about 30 years," observed molecular and medical geneticist Geoff Clarke, at the University of Toronto, "there's been the assumption that cell death in neurodegenerative diseases is caused by a gradual accumulation of damage within the neurons. That seems to be based on the observation that - for inherited diseases anyway - the mutation is there from birth. And you don't see any dramatic cell death for a long period of time. So people will be in their 30s, 40s, 50s, 60s, before they start to show any clinical symptoms."
Clarke is first author of a paper in the July 13, 2000, issue of Nature, which puts forward a contrarian interpretation. Its title: "A one-hit model of cell death in inherited neuronal degenerations."
He and his co-authors measured degeneration of photoreceptors in the retinas of mice, and noticed that the rate of receptor cell loss appeared to be exponential. So they ran some statistical regressions to see if that was true, and it seemed to be.
Clarke explained: "Exponential decay measures the overall rate - the actual number of cells that are dying per unit time. So if you take a month early on in an individual's life, you'll have more cells dying then than you would in a month later on. That is, the actual rate slows down over time. And that's what we found."
The group also studied cerebellar degeneration in a mouse model of Parkinson's disease (PD), as well as brain scans from human patients with PD and Huntington's disease. "We were able to see the same sort of characteristic exponential decline over time in cell number or metabolic activity," Clarke recounted.
"The old idea of cumulative damage would predict that cell death would start slowly," he pointed out, "because there hasn't been a lot of time for damage to accumulate in that cell. But as more time passes, more damage can accumulate. So the rate of cell loss would accelerate. We just didn't see that happening in these diseases, so we came up with a 'one-hit' model that tries to explain why you see this exponential decay, suggesting random cell death in time.
"So some random chemical change occurs within the cell," Clarke elaborated, "and that event causes the neurons to exit their homeostatic steady state and commit to cell death. And that's generally the thrust of our paper."
The putative potential of this new hypothesis, he added, "is problematic for therapeutics. Because to save any neuron that has any of these diseases, and stop it from progressing, we'd have to revert all the damage that's occurring within the cell. So if there are 15 things that occur before a neuron dies, we'd have to fix all 15 to stop it from dying.
"What our 'one-hit' model suggests," Clarke concluded, "is that there's only one thing you have to fix. And now it's just a matter of finding out what that one thing is."
Dog Takes Over From Mouse In Gene Therapy Experiment To Correct Muscular Dystrophy
Golden retrievers make admirable pets and efficient work dogs. They also have another gig: This canine breed is susceptible to Duchenne muscular dystrophy (DMD), the genetic disease that cripples one in 3,000 live male newborns. The mutation that causes DMD is deletion of exon 7 from the gene that encodes dystrophin, the protein missing in DMD patients. Affected mice also have this mutation, but gene therapy experiments in this mdx model have been hampered in part because the gene is too large for efficient transfer into a small rodent.
Now a 6-week-old golden retriever puppy, born with DMD, is the subject of a gene-transfer experiment at the University of Missouri College of Veterinary Medicine in Columbia. It's reported in Nature Biotechnology for June 2000, under the title: "In vivo targeted repair of a point mutation in the canine dystrophin gene by a chimeric RNA/DNA oligonucleotide."
Direct skeletal-muscle injection of the vector into a leg muscle of the affected dog, a media statement by the journal observed, "incorporated the corrected sequence into the chromosome, resulting in restoration in production of the full-length dystrophin protein." This effect was sustained for 48 weeks, but, "While the results are impressive, the technique still has a long way to go before it reaches the efficiencies required for use as a human therapeutic."
New Inhibitor Of Brain-Made Spur To Appetite, Pigging Out, Enters Anti-Obesity Sweepstakes
Leptin, move over. Another made-in-the-brain appetite suppressant has surfaced. The new, natural anti-obesity compound broke the waves in Science dated June 30, 2000, under the title: "Reduced food intake and body weight in mice treated with fatty acid synthase [FAS] inhibitors." Biological chemists at the Johns Hopkins University of Medicine in Baltimore reported identifying "a link between anabolic [body-building] metabolism and appetite control."
Mice the co-authors injected with C75, a synthetic compound that blocked FAS, turned up their snouts at the food trough and dropped their chow intake 90 percent in the first 24 hours. Not only did C75 switch off the prophagic appetite signal in the brain's hypothalamus, it did so "in a leptin-independent manner."
Obese mice of the ob/ob line get that way because their overweight bodies fail to secrete leptin. When the Hopkins team dosed ob/ob animals with C75 for two weeks, they lost 10 grams. The paper concluded, "Thus, FAS may represent an important link in feeding regulation. . . . an attractive target for the design of therapeutic agents."
Obesity is a major public health problem in the world's industrial nations, and getting worse in prevalence and severity. It's a life-threatening risk factor for Type II diabetes, heart attack and stroke. The Science paper observes that "recent difficulties with several weight-loss therapies emphasize the need for different approaches "