By David N. Leff

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

A predatory sea-going snail called Conus secretes the deadliest toxin known to man - or fish or worm. This grenade-sized mollusk aims and fires a squirt of its venom at passing prey to stun it in its tracks. (See BioWorld Today, Nov. 15, 1995, p. 1.)

Last year, Conus scored three stunning triumphs, one clinical, two commercial:

Scientists at Neurex Corp., in Menlo Park, Calif., had parlayed the snail's toxin - a neuron-specific calcium channel blocker - into a non-narcotic analgesic for easing chronic pain. They named it zinconotide, and began testing it in two Phase III studies on patients with intractable cancer pain. It worked so well that they stopped the second trial in mid-course.

The company announced this success on March 31, 1998. Exactly one month later, Ireland-based Elan Corp. plc disclosed its plan to acquire Neurex for more than $700 million. (See BioWorld Today, April 30, 1998, p. 1.)

But pain-killers are only one jewel in the seemingly inexhaustible treasure chest of Conus multiple toxins. Later last year, Cognetix Inc., based in Salt Lake City, acquired Viatech Imaging LLC, of Ivoryton, Conn., to speed up the process of screening some 50,000 conopeptides for treating nervous system disorders, including epilepsy and Parkinson's disease. Cognetix, founded in 1993, focuses on mining the chemotherapeutic resources of the 500 or so Conus species. Each of these averages 100 active compounds, according to Tyler McCabe, the company's vice president of research and development. (See BioWorld Today, July 21, 1998, p. 1.)

Now it turns out that the prodigal mollusk may boast the world's fastest evolving genes. Harvard University biologists report as much in the current Proceedings of the National Academy of Sciences, (PNAS), dated June 8, 1999. Their paper bears the title: "Molecular genetics of ecological diversification: Duplication and rapid evolution of toxic genes of the venomous gastropod Conus." It compares the gene sequences of toxins from two distantly related snails, Conus abbreviatus and C. lividus, gathered from sites around Oahu, Hawaii

In the worm-eating C. abbreviatus species, they found that "the rate of conotoxin evolution is higher than that of most other known proteins." They calculated the average mutation rate for the toxin genes at five times that of any mammalian gene. This genomic versatility arms the snail with an arsenal of varying toxins specifically targeted at each of the various worms it hunts. But the co-authors extended their finding to the 500 Conus species, some of which chow down exclusively on fish, while the diet of C. lividus fancies a variety of worm species.

"Different conotoxins," the genetic analysis points out, "are maximally effective on different prey species," - and this feature is linked to their molecular evolution. The PNAS paper concludes: "Because conotoxins are intricately related to a species' ability to paralyze its prey, the rapid adaptive evolution of these loci suggests that conotoxins are under strong selection in response to changes in the availability of or accessibility to particular prey species over time or because of a type of 'arms race' between conotoxins and the cell channels and receptors of prey."

After 250 Million Years, Chemists Synthesize Ginkgo's Putatively Therapeutic Ingredient

An unrelated, and as yet unpublished, natural product is the Ginkgo biloba tree. This ornamental plant, also called the maidenhair tree, lines the sidewalks of many cities. However, only male trees need apply, because. the fleshy seed of B. biloba emits the obnoxious odor of butyric acid. (Paradoxically, that malodorous chemical goes into the manufacture of perfumes and food flavors.)

What the extract of ginkgo goes into these days is mainly the shelves of health food stores and TV commercials, touting the ability of such products as Ginkoba, among other patent medicines, to boost alertness and other mental functions.

"Ginkgo extract has been used to treat coughs, allergic inflammations, circulatory disorders and other conditions in Asian cultures such as India and China," observed Michael Crimmins, professor of chemistry at the University of North Carolina, in Chapel Hill. "Recent, still-early studies have shown it apparently does have some effect in delaying the onset of Alzheimer's disease."

The ginkgo tree has been cultivated in Chinese and Japanese temple gardens for millennia, but botanically it goes back some 250 million years to the Paleozoic geologic era. Charles Darwin called the tree a "living fossil." As such, it's a one-species-only plant.

Crimmins and his co-workers at the University announced on June 10 that, after 12 years, they have succeeded in completely synthesizing ginkgolide B, an active ingredient of the tree currently purveyed by health-food products. Scientists call ginkgolide B a platelet-activating factor antagonist. "It's the most active component of the extract," Crimmins observed, "in terms of helping treat asthma and other allergic responses."

The team began their synthesis from the bottom up. That is, they started with a molecule of 3-furaldehyde, a simple commercially off-the-shelf chemical. To it they added on other molecules until the construct matched the natural ginkgolide B precisely, as verified by spectroscopic analysis. "The advantage of making the molecule synthetically," Crimmins said, "is that now we can make similar molecules with slightly different structures. Some of these could be more active or absorbed better or be better tolerated in the body. Our next steps will be to improve the synthesis by making it shorter and more efficient if possible. We also will probably look at analogs or other forms of the molecule to test their activity in cell culture."

He expects a report on the novel synthesis to be published this fall, "probably in the Journal of the American Chemical Society."