Before the end of the year, scientists must decide whether todestroy the last remaining strains of the smallpox virus,variola. Over the centuries, this pathogen, species-specific toinfecting only humans, has taken more lives than any otherinfectious disease.

Eradicated from the human race by a World HealthOrganization (WHO) campaign of vaccination, smallpox slew itslast natural victim 16 years ago in Somalia. When WHOlaunched its worldwide anti-variola crusade in 1967, itconfronted 10 million active cases of the disease in 40countries.

Today the virus lives on, deep-frozen in liquid nitrogen, at onlytwo spots on earth, Moscow and Atlanta. And its days arenumbered even at these two virology laboratories, the RussianResearch Institute for Viral Preparations and the U.S. Center forDisease Control and Prevention (CDC).

In May 1990, Louis Sullivan, then U.S. secretary of Health andHuman Services, told the WHO assembly that it was possible tosequence variola's entire genome within three years, afterwhich all remaining stock of the virus should be destroyed.WHO's committee on orthopoxvirus infections ratified thisproposal and set Dec. 31, 1993 for variola's execution, providedthat sufficient sequence data had been gathered and no seriousscientific objections raised to terminating the virus.

The current issue of Nature reports that one of variola's mostvirulent strains has been completely sequenced. And twopapers in the Nov. 19 issue of Science carry appeals by eminentvirologists for and against destroying those last remainingstocks of the virus. As the "pro-kill" group noted, this wouldrepresent the first deliberate elimination of a biological speciesfrom this planet, but should be done anyway.

Among the groups favoring destruction are the American TypeCulture Collection and the American Society for Microbiology.

WHO's sentence of death hanging over the smallpox virus setCDC's Division of Viral and Rickettsial Diseases to worksequencing the condemned pathogen, CDC virologist RobertMassung told BioWorld. He is first author of the Nature papertitled "Potential virulence determinants in terminal regions ofvariola smallpox virus genome."

One of the 15 co-authors is J. Craig Venter of gene fragment-patenting fame, whose Institute for Genomic Research providedthe project with DNA sequencing facilities, Massung said.

Having sequenced all 186,102 base pairs of the highly virulentBangladesh variola strain, CDC's virologists compared its geneticsimilarities and divergences with vaccinia virus, the benignvehicle for smallpox vaccination. Of variola's 187 identifiedproteins possibly involved in pathogenicity, fully 150 arestrikingly homologous with vaccinia.

There are "at least 500 isolates of smallpox virus, all locked upin Moscow and Atlanta," Massung said. If the order fordestruction takes effect, the process would involve simplyautoclaving the 2-milliliter vials of virus at high temperatureand pressure for perhaps half an hour in the presence of aWHO panel of expert witnesses.

Massung said he hopes that the present reprieve lasts at leastseveral years so he can pursue his molecular-level studies ofwhat makes variola virulent and its close cousin, vaccinia,harmless. Such research, he suggested, could lead to newvaccines or pharmaceutical agents.

The smallpox virus genome is studded with gene sequencesthat presumably encode proteins similar to major molecularplayers of the human immune system. One is a full-blowntumor necrosis factor receptor; its vaccinia homologue istruncated and inoperable, the CDC group reported.

The Nature paper strongly favors preserving the residualstocks of variola on ice for continuing investigation. Itsprincipal author is Joseph Esposito, who chairs the CDC'spoxvirus section and heads the WHO collaborative committee.Curiously, another co-author is Brian Mahy, director of CDC'sViral and Rickettsial Diseases Division and first author of lastmonth's Science paper, "The Remaining Stocks of SmallpoxVirus Should Be Destroyed."

To Kill or Not to Kill?

In a rough analogy to post-Cold War wariness of nuclearweaponry, Mahy et al. argue that "recent political uncertaintyin various parts of the world, including the former SovietUnion, has re-emphasized the danger ... of any terrorist groupthat succeeded in gaining access to the virus."

Bernard Moss, chief of NIAID's Laboratory of Viral Diseases,argued against obliterating the virus. He is a co-author of thecompanion piece in Science, "Why the Smallpox Virus StocksShould not Be Destroyed." He and his collaborators refute the"terrorist weapon" rationale on the grounds that "far morereadily accessible and effective potential biological weaponsexist." Moreover, they point out, caches of the virus may stillcome to light from unexpected sources, such as the thawing of asmallpox victim preserved for centuries in permafrost.

The "save the variola" contingent declared that retaining thesmallpox virus stocks in Atlanta and Moscow, and studying indetail their molecular pathogenesis would be of enormousbenefit to humanity. Among proteins encoded by the poxvirus'genomic arsenal, they list:

-- cytokines and lymphokines resembling epidermal andtransforming growth factor;

-- receptors for IL-1b, INF-g and TNF;

-- proteins that regulate complement.

The combined effects of such proteins, they argued, "can't begauged merely by guessing at motifs in strange sequences."

Recalling that "the realization that poxvirus genomes encode allthese hitherto undreamt of proteins that function to counteracthost defense mechanisms is less than 10 years old," they askedrhetorically, "Should we now destroy this extraordinaryparadigm of host-virus interactions before we have discoveredwhich human defense mechanisms smallpox virus has evolvedto evade?"

They concluded, "Who is to say that (this knowledge) may notpoint the way to solving the problem of HIV pathogenesis?"

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.