Posted on 12/29/2001 12:12:57 AM PST by aculeus
US researchers are pursuing entirely the wrong picture of anthrax pathogenesis, claims a bioweapons expert from the former Soviet Union who now runs a biotech business from a Washington suburb.
Experimental results due next month will prove that cell wall components from bacillus anthracis induce the septic shock associated with anthrax infection, says Ken Alibek. He insists that anthrax toxin, traditionally seen as the prime culprit, is merely a bit player, important only in the early stages of infection.
Alibek, once known as Kanatjan Alibekov, defected to the US in 1992, and is reported to have given the US government startling accounts of the bioweapons program in Russia.
Although his model directly contradicts the popular hypothesis, he tells BioMedNet News that his experience as the Soviet Union's second-in-command for developing germ weapons has won him and his company, Hadron Advanced Biosystems, various government grants and contracts to study anthtrax.
The progression of anthrax infection coincides with a rapid increase in inflammatory cytokines such as TNF-alpha, IFN-gamma, IL-1B, IL-8, and IL-6. Current dogma holds that the anthrax toxin, made up of three proteins, induces this "cytokine storm" and causes death.
Researchers accept that the bacterium uses the anthrax toxin to enter macrophages via a recently discovered receptor, and to escape from them when the cells burst. Controversially, Alibek suggests that the toxin's role ends there.
At a critical concentration, he says, the bacteria begin to break down in the bloodstream, releasing cell wall components that induce the inflammation indicative of septic shock.
At later stages of anthrax infection, blood contains a "shockingly high" concentration of between one and two billion cells per milliliter of bacteria, says Alibek, but no lethal toxin.
In contrast, he adds, lethal toxin does not have any effect in macrophages, lymphocytes, neutrophils, and monocytes from human donors. "[We] did hundreds of experiments," Alibek said. "It was kind of a shock because it changed the entire idea of anthrax pathogenesis."
Alibek and his collaborators say they are preparing to publish those results in the Proceedings of the National Academy of Sciences; two of Alibek's collaborators are members of the academy.
But John Collier, a leading expert on the anthrax toxin, reports that the recent anthrax victims in the US had "a large amount of toxin in the blood."
Also, Collier tells BioMedNet News, experimental studies show that purified toxin mimics the effect seen in anthrax-infected animals and humans. Antibodies against the toxin can also protect against the disease, so while the toxin hypothesis is not proven, "I would say the evidence so far supports it," he said.
"I think [Alibek] has the right to express his opinion," said Collier, who is professor of microbiology and molecular genetics at Harvard Medical School. "He's going against the prevailing wisdom on this, so the weight is on his shoulders to prove otherwise."
Alibek first presented his controversial model at the US Health and Human Services a year ago, and again at US Army Medical Research Institute for Infectious Diseases early last summer, but no response was forthcoming, he says.
"For me, this was frustrating because this discovery was so important and nobody else paid attention," Alibek recalled. "There was no negative response, but no support either."
If the US government had paid more attention, Alibek tells BioMedNet News, "by October or November, we would have known much more of what needs to be done [about an anthrax infection]."
Alibek contends that part of the problem is that most anthrax research is being performed by molecular biologists with little understanding of disease pathogenesis. "It's very bad that there are no [infectious disease] experts in anthrax," he said. Instead, he says, US anthrax researchers are focused either on vaccines or on the anthrax toxin.
If cell wall components - and not the toxin - are the real culprits, antibiotics would not only be ineffective in later stages of the disease, as is observed, but would exacerbate infection, Alibek says.
He is instead developing filtration systems to remove cell wall debris and sepsis mediators from the bloodstream. He is testing miniaturized systems in mice, and plans to move on to monkeys.
Alibek is also collaborating with Howard Young at the US National Cancer Institute (NCI) to compare the effects of toxin and cell wall components on cytokine expression.
"What is shocking is that no one, not a single person, has [had] the courage to say let's do a comparison study," Alibek told BioMedNet News. "But [my team members and I] know we're right and we're going to prove it."
Results of the first round of experiments should be in by mid-January, says Young, who wants to "keep an open mind" about both hypotheses. "I don't think anyone has a clue" what the actual mechanism is, Young told BioMedNet News. "The absolute wrong thing to do is to take sides and rule out any hypothesis."
Collier says he too will withhold judgment until he sees the experimental results. But "I can't imagine that this quickie experiment is going to prove it all," he said.
Told of Alibek's claim that he has already run hundreds of experiments, Collier retorted: "Hundreds of experiments? Yeah, well, we'll see."
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