By David N. Leff

Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

If you look out the window, you may notice a utility pole topped by a sizeable, cylindrical transformer. From it emanate a variety of insulated wires, transmitting electric power, telephone traffic and TV cable programs.

Under the microscope, nerve cells inside your brain display a superficially similar pattern. Neuronal cell bodies send and receive their cerebral signals via an emanation of slender, radiating axons, also insulated. Those axonal sheaths consist of layered membranes of lipoprotein called myelin.

In people with multiple sclerosis (MS), axons leading outward from the cerebral cortex suffer missing or degraded patches of myelin, which - like damaged insulation - diminish or distort the signals generated in the brain's mission control center, and executed via its spinal cord by motor neurons.

That demyelinating damage is believed partly the work of an ubiquitous protein called calpain, sent into action at the behest of an autoimmune response that see the axons' myelin basic protein as foe, not friend, of the central nervous system.

The above neat, plausible scheme is as much conceptual as factual, which is why clinicians can treat the symptoms of MS but not its root cause. Among the many long-time investigators of the demyelination phenomenon is research and clinical neuroscientist Donald Shields, at the Medical University of South Carolina, in Charleston.

He is first author of a report in the current Proceedings of the National Academy of Sciences (PNAS), dated Sept. 28, 1999. Its title: "A putative mechanism of demyelination in multiple sclerosis by a proteolytic enzyme, calpain." That name is short for "calcium-activated neutral proteinase." It's not the sole designated hitter of myelin. Inside the myelin sheath itself," Shields told BioWorld Today, "many different myelin proteins are degraded, and calpain doesn't just wipe them all out. Rather, it cleaves them at certain points. But that cleavage is enough to render the axons inactive to fulfill their duties.

"The expression and activity of this enzyme is increased at the site of axonal injury in MS," he continued. "The significance of this fact is that calpain degrades all major myelin proteins. And that destabilizes the myelin sheath, thus leading to multiple sclerosis or nerve-conduction deficits. There are many proteases inside the myelin sheath," Shields noted, "and calpain is only one of the many. Its activity is not exclusive to myelin; it's found in every cell in the body.

"The enzyme's normal function there," he said, "is subject to debate. One of the best conjectures I've seen so far is that it's involved in normal cytoskeleton protein breakdown, or turnover of cells. For instance, "if a macrophage [an immune-system scavenger cell] wants to move from place to place by forming a foot - a filopodium - or change its cell membrane shape, the cytoskeleton proteins right underneath it need to be degraded, so it can perform that outpouching. Calpain is believed to degrade those proteins, so it can do that. Calpain doesn't just obliterate them. Rather, it cleaves them at certain points."

In their PNAS paper, Shields and his co-authors described studies of axons autopsied from the brain cells of MS patients, and compared them with patients who died with Alzheimer's disease (AD) and Parkinson's disease (PD). They obtained these human samples from the National Neurological Research Specimen Bank in Los Angeles.

"When these MS patients undergo death, typically from other causes," Shields recounted, "they have MS on top of those other causes. We got frozen tissue blocks, maybe an inch by an inch, of the specific MS plaques, and also white matter [myelin-sheathed axons] from PD and AD patients to compare with normal controls."

Analysis revealed that calpain levels were 90.1 percent higher in the MS plaques, but were not increased in AD or PD patients' white matter.

"Now that we've done these human models," Shields observed, "we think it worthy of further research, using specific inhibitors that only inhibit calpain. If we can knock it out, we can see what percentage of myelin protein degradation is occurring due to this enzyme, as opposed to the other proteases." So far in this direction, he said, "We can't use the natural inhibitor, so we're having to use those synthesized by companies, see if they can pass the blood-brain barrier into the central nervous system, and then go to work."

Companies actively pursuing calpain inhibitors include BASF AG of Ludwigshafen, Germany; Fujita Health University, in Japan; Cephalon Inc., West Chester, Pa.; Rhone-Poulenc Rorer Inc., Collegeville, Pa., and Cortex Pharmaceuticals Inc., of Irvine, Calif. - which is credited with first synthesizing those proteinase inhibitors. (See BioWorld Today, Nov. 5, 1993, p. 1.)

Biotech Companies Present Trial Data On Their Therapeutic Products To International Conferences

On Sept. 29th, the University of Vienna's Burkhard Jansen informed the Cold Spring Harbor Conference on Programmed Cell Death of nearly completed Phase I/IIa stage-4 melanoma studies, testing G3189, the lead anti-cancer compound developed by Genta Inc., of Lexington, Mass. Two patients with late-stage metastatic disease, Jensen reported, "experienced major regression . . . and survival beyond one year." A third achieved "near-complete remission."

In Boston on Oct. 5th, attendees at an international symposium on "Advances in Anticoagulant, Antithrombotic and Thrombolytic Drugs" heard La Jolla Pharmaceutical's executive vice president of research, Matthew Linnik, present mouse studies of the firm's anti-thrombotic drug, Toleragen. He reported that "treatment reduced the relative production of pro-thrombotic antibodies. . . . in this antiphospholipid syndrome, which afflicts more than 500,000 patients in the U.S. and Europe."

In Montreal on Oct. 5th, McGill University biochemist Gordon Shore reported to the 8th International Conference on Differentiation Therapy "discovery of GX011, a small-molecule inhibitor of Bcl-2, an intracellular suppressor of apoptosis." Shore is founder and chief scientific officer of Gemin X Biotechnologies Inc., which like McGill is based in Montreal. "In preclinical studies," he told the conference, the compound "selectively destroyed cancer cells."