Scientists find new botulinum toxin, withhold genetic details

Scientists have discovered the first new type of botulinum toxin in 40 years, and in a highly unusual move, they are keeping the toxin's genetic sequence data secret for now so that no one can make it in a lab before an effective antitoxin can be developed.

Until now, Clostridium botulinum was known to produce seven types of toxins, all of which cause paralysis by blocking neurotransmitters in humans and animals. The last one was discovered in 1970.

The researchers discovered the new toxin, called botulinum neurotoxin type H, or BoNT/H, as a result of a case of infant botulism. They reported the discovery in two articles published this week in the Journal of Infectious Diseases (JID). Antitoxins are available for the seven other botulinum toxin types, but not for the new one.

The authors, most of whom are with the California Department of Public Health (CDPH), themselves proposed to omit the genetic data and consulted with a number of federal government agencies about the handling of their findings, said David C. Hooper, MD, deputy editor of JID and an infectious diseases physician at Massachusetts General Hospital and Harvard Medical School.

"We as editors had a lot of internal discussion as well and decided the information was important enough to proceed with publication, after scientific review, with withholding of the sequence data," he told CIDRAP News. "And it wouldn't be withheld forever," because the plan is to publish the data after an antitoxin is developed.

The authors believed that the genetic sequence information "poses an immediate and unusually serious risk to society," wrote David A. Relman, MD, of Stanford University and the Veterans Affairs Palo Alto Health Care System in California, in an accompanying editorial. He said the authors "decided to exercise voluntary prepublication control and to withhold this specific information."

Relman is a professor medicine and of microbiology and immunology and a member of the US National Science Advisory Board for Biosecurity (NSABB).

The handling of the toxin discovery recalls the heated controversy that erupted in late 2011 and early 2012 when two teams of authors announced plans to publish details about lab-modified H5N1 avian influenza strains that showed airborne transmissibility in ferrets. The studies were supported by the US National Institutes of Health.

In those cases the NSABB initially recommended against publication of the full methodologic details, out of concern that full disclosure could lead to an intentional or unintentional release of dangerous viruses. The recommendation triggered prolonged and intense debate in scientific and public health circles.

The board eventually endorsed publication after the authors briefed the group and made some clarifications in their manuscripts. The papers were published in May and June of 2012.

JID's general policy is to require authors to submit gene nucleotide sequences to the International Nucleotide Sequence Databases and include the accession numbers in their manuscript, notes an editorial by Hooper and Editor Martin S. Hirsch, MD. But in this case they made an exception.

The authors had "detailed consultations" with numerous government agencies, including the National Institute of Allergy and Infectious Diseases, the Centers for Disease Control and Prevention (CDC), the Department of Homeland Security, and the FBI, the editorial says. The upshot was that they "received approval to publish both manuscripts, while withholding the key gene sequences until appropriate countermeasures were developed."

Stephen S. Arnon, MD, of the CDPH, a coauthor of the two reports, commented briefly today on the background of the decision to withhold the genetic data.

"CDPH recognized the potential bio-threat implications of a new botulinum toxin and engaged with appropriate federal agencies in discussions about how to publish information about the new type," he said.

When asked if the issue triggered much debate, Arnon said, "There was agreement that it would be possible to publish this information to achieve the scientific and public health benefits of making this information known. The information published is important for the diagnosis, treatment, and control of botulism."

The researchers published two reports in JID. One, by Jason R. Barash and Arnon, describes how they discovered the new toxin; the other, by Barash, Arnon, and three others, describes the genome sequencing of the toxin. Two of the authors are with Los Alamos National Laboratory.

Mouse experiments crucial

The researchers, according to the first report, identified the new toxin after determining that a toxin from a patient sample of C botulinum could not be neutralized by any of the seven antitoxins available from the CDC, which cover types A through G. They learned this by dosing mice with combinations of the C botulinum strain, called IBCA10-7060, and each of the antitoxins.

They also determined that the IBCA10-7060 produces toxin type B as well as type H and that type B was present in larger quantities.

In further work, the team used rabbits to develop an antitoxin against IBCA10-7060. They found that it protected mice from the strain, but its potency was fairly low, compared with that of the existing CDC antitoxins.

"The recognition of novel BoNT/H after an interval of almost half a century serves as a reminder that additional novel botulinum toxin types likely await discovery and that for this purpose, the mouse bioassay remains indispensable," the report concludes.

Precedents hard to find

Hooper and Relman said they're not aware of previous cases in which life sciences researchers voluntarily withheld findings because of security concerns, although there were similar cases in the cryptography realm in the 1980s.

"I don't know of particular other instances, and this is clearly an exception to our usual practice," said Hooper. "I think these are instances we're striving to think very carefully about and to proceed on a case-by-case basis, to balance the free flow of scientific information with security needs."

Relman told CIDRAP News, "In the world of the life sciences, I am not aware of a definite [previous] example; however, I imagine that it has happened not infrequently, as researchers stumble upon information that poses an unusual risk, eg, a mutant strain created in the laboratory that has unexpected properties of heightened virulence, transmissibility, or drug resistance."

As for whether the current case sets an important example for future research publication dilemmas, Hooper said, "I think each instance really needs to be decided very carefully on a case-by-case basis, so I don't see this as necessarily setting some strong precedent. It's important that there be careful discussions on how to balance science and security issues."

Hooper said he doesn't see any negative effects of the secrecy, aside from the delayed release of the genetic information itself. An effort to develop a suitable antitoxin is under way, "but exactly when it'll be available, once can't say with date certain," he added.

A 'valuable test case'

Relman expressed hope that the botulinum toxin discovery "will become a valuable test case where unusually risky information prompts serious discussion about the benefits and risks of limited communication, and the mechanisms by which this can be undertaken, in order to buy time for risk mitigation, eg., development of new countermeasures."

In his editorial and in comments to CIDRAP News, Relman spoke of scientific information that falls in a "gray area," in that immediate full dissemination may pose security risks, but formal classification as secret might be inappropriate because it could hinder research on needed countermeasures.

In the case of the H5N1 transmissibility studies, he wrote, "the absence of a mechanism, other than classification, for limited distribution of the information confounded policy makers. The need for such a mechanism now deserves renewed serious deliberation and wider discussion, because we are inadequately served by just two options, that is, unrestricted dissemination and classification."

He said the toxin discovery is a good example of the kind of data that fall in the gray area. The strategy the authors used "has merit and deserves careful consideration, but some major caveats should be noted," he wrote in the editorial.

One problem is that the strategy offers only temporary benefits, since data will inevitably be disseminated, Relman wrote. Another is that the strategy endangers research in general if decisions to withhold data "are made casually, arbitrarily, or frequently."

"I hope that this discovery forces policy-makers, scientists, and other members of the general society to confront the reality of increasingly frequent and consequential risks that arise from work in the life sciences, and develop more robust strategies for risk mitigation," Relman added in comments to CIDRAP News.

"I am quite worried that the challenges and complexities of developing such strategies has caused many scientists, science policy-makers and others in government to turn away, and either proclaim that the risks are not real, or that we have no such mechanisms for limited communication and therefore that we should stop working on this," he said.

Barash JR, Arnon SH. A novel strain of Clostridium botulinum that produces type B and type H botulinum toxins. J Infect Dis 2013; online publication Oct 7 [Abstract]

Dover N, Barash JR, Hill KK, et al. Molecular characterization of a novel botulinum neurotoxin type H gene. J Infect Dis 2013; online publication Oct 7 [Abstract]

Relman DA. "Inconvenient truths" in the pursuit of scientific knowledge and public health. (Editorial) J Infect Dis 2013; online publication Oct 7 [Excerpt]

Hooper DC, Hirsch MS. Novel Clostridium botulinum toxin and dual use research of concern issues. (Editorial) J Infect Dis 2013; online publication Oct 7 [Excerpt]

Popoff MR. Botulinum neurotoxins: more and more diverse and fascinating toxic proteins. (Editorial) J Infect Dis 2013; online publication Oct 7 [Excerpt]

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