By David N. Leff

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

Ciguatera is not a household word in the medical profession, except between latitudes 35o North and 34o South. In certain tropical and subtropical regions of the Pacific Ocean, West Indies and Okinawa, this severe seafood poisoning lays fish-lovers low with gastrointestinal, neurological and cardiovascular disturbances, sometimes followed by paralysis, coma and ¿ rarely ¿ death.

¿Ciguatera,¿ observed Japanese organic chemist Hiroki Oguri, ¿is the most widespread human poisoning caused by the consumption of seafood.¿

Sporadic cases occur along the East Coast of the U.S. and Hawaii. The condition is probably underreported, because many sufferers dismiss their attacks as flu or seasickness. The marine food chain that erupts as Ciguatera begins with the dinoflagellate (Gambierdiscus toxicus), a microorganism that eats reef macroalgae, and produces the potent cigua neurotoxin. Herbivorous reef-dwelling fish dine on G. toxicus, and are in turn gobbled up by some 400 species of carnivorous fish. Among these piscine predators that reach the table of human fish-fanciers are amberjack, barracuda, grouper, moray eels, red snapper, sea bass, surgeon fish and Spanish mackerel.

Those contaminated fish look, smell and taste perfectly normal, and the ciguatoxin they harbor is not destroyed by cooking, drying, salting or freezing. Symptoms come on in minutes to hours after ingestion of these fishy delicacies. They range from diarrhea, vomiting and muscle pain to sensations of numbness, burning, tickling, tingling, sweating and itchiness. These toxic effects usually die down in a week or so, but some may hang in there for months or years.

There is no overall therapy for ciguatera, only palliation of specific symptoms. ¿The extremely low content of the causative neurotoxins in fish,¿ explained Oguri, ¿has hampered the isolation, detailed biological studies and preparation of anti-ciguatoxin antibodies for detecting these toxins. Until now,¿ he pointed out, ¿the complicated and large architecture of ciguatoxins has impeded chemists from completing their total synthesis.¿

He made the added cautionary point: ¿Because reef fish are increasingly exported to other areas, ciguatera may become a worldwide health problem. Currently, there are no rapid and reliable methods of detecting these toxins at fisheries.¿

A faculty member of Tohoku University in Sendai, Japan, Oguri is co-author of a paper in Friday¿s Science, dated Nov. 30, 2001. Its title: ¿Total synthesis of ciguatoxin CTX3C.¿

¿We wanted to analyze this toxic substance,¿ he told BioWorld Today in a telephone interview, ¿in order to prevent cigua poisoning, and disclose the toxin¿s physiological mode of action. Our research group began work on this project 11 years ago. We designed and developed a very efficient methodology,¿ he continued, ¿to synthesize this very large molecule, which is 3 nanometers long and has a molecular weight of around 1,100. It¿s a polycyclic macromolecular structure, consisting of 13 ladder-like, connected aromatic rings and 30 stereogenic centers.¿ (Its chemical formula is C35H65NO8.)

¿Our strategy,¿ Oguri recounted, ¿involved building up this large molecule, and dividing it into a left wing and a right wing. Then we managed the final coupling in the center portion in a very convergent double-decomposition way. It gave us a yield of 77 percent.¿

The team conducted in vivo toxicity studies in mice, comparing the natural product to synthetic compounds. Results revealed, Oguri concluded, ¿that our synthetic route is fortunately nontoxic until the final deprotection step.¿

Since submitting their article to Science last summer, Oguri noted, ¿we have designed antibodies to detect this CTX3C ciguatoxin, and are now focused on efforts toward developing antagonists against it. And we are working on a very nice probe to disclose the toxin¿s mode of action.¿

Mutations In New Gene Cause Rare Paraplegia Plus Other, Less-Rare Neurological Disorders

A toddler who begins to walk on tip-toes may be in the early stage of a rare, insidious disease called hereditary spastic paraplegia (HSP). From toe-walking, HSP typically goes on to subtle difficulty ambulating, and occasional stumbling. But as nerves within the spinal cord break down, it may progress to total weakening of the legs, and more severe disabilities. HSP strikes at any stage of life, from infancy to old age. Depending on the mode of inheritance, it can affect parents and some or all of their children.

The number of Americans with HSP is variously guesstimated at 10,000 to 20,000, but many more patients may well be misdiagnosed as familial cerebral palsy, primary lateral sclerosis, multiple sclerosis, even vitamin deficiencies. This ambiguity could be cleared up by a paper in the November 2001 issue of Nature Genetics titled: ¿Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia.¿ Its senior author is neurologist John Fink, at the University of Michigan, Ann Arbor. He heads one of the few HSP clinics in the world.

¿This is a major step forward in our understanding of HSP¿s causes,¿ Fink stated, ¿and has already allowed us to provide diagnostic testing to a few patients. We¿ve been looking for HSP genes since 1993, and we¿re happy to have found, at last, the first one for a childhood form of the disease.¿

Mutations in the SPG3A gene ¿ which resides on the short arm of chromosome 2 ¿ alter the newfound protein ¿atlastin,¿ which it encodes. This may account for as many as 25 percent of childhood HSP cases, Fink observed. Applying that knowledge to treatment, he added, ¿could be years away.¿ The mutations the co-authors found in their newly discovered gene were identified in multiple members of six families in the U.S. and Turkey, with many HSP-affected members. Specifically, the team focused on families that had the autosomal dominant inheritance pattern of the disease ¿ which can be passed down to a child by one carrier parent, even if the other is completely normal.

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