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Controversy Over H5N1 Flu Continues

Just when it seemed like consensus existed on how to handle the hot potato of mammalian-transmissible H5N1 influenza, the public release on Friday afternoon of a letter sent April 12 from the respected influenza and public health researcher Dr. Michael Osterholm to a National Institutes of Health official collapsed the apparent consensus like a house of cards.

To recap: On March 29 and 30, the U.S. government’s National Science Advisory Board for Biosafety (NSABB), organized by the NIH’s Office of Science Policy, met to reconsider the NSABB’s original decision last December that said the paper written by Dr. Yoshihiro Kawaoka and another paper by Dr. Ron Fouchier on their respective efforts to produce and study H5N1 mutants transmissible by air from ferret to ferret should only be published without the methods sections, a way to prevent release of the details on how they developed these potentially dangerous mutant strains. The initial NSABB recommendation to allow publication of only the redacted papers failed to win support from a panel convened by the World Health Organization in February, creating a conflict between the NSABB (and hence the NIH) and the WHO. Claiming that new data first revealed to the WHO group led to the different outcome, Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases — the U.S. agency that sponsored the work of both Dr. Kawaoka and Dr. Fouchier — called on the NSABB to rethink its initial decision, which resulted in the NSABB reversing itself on March 30 and supporting full publication, in a unanimous vote for Dr. Kawaoka’s work, and in a 12-6 vote for Dr. Fouchier’s. So, by early April, the NSABB (and hence, pending official U.S. policy) and the WHO agreed that full H5N1 publication could proceed. Peace reigned across the land.

Dr. Michael Osterholm

Until 2 weeks later, when Dr. Osterholm an NSABB member, upset the tranquility by writing his bombshell letter to Dr. Amy Patterson, NIH’s associate director for Science Policy. In it, Dr. Osterholm took vigorous swipes at how the NIH set up the NSABB’s reconsideration session and detailed his grave concerns about public release of how the H5N1 work was done. Both “Science” and “Nature” received the letter on April 13, and according to a report in “Nature,” Dr. Osterholm said he was not the source for the leak.

“I believe the agenda and speakers for the March 29 and 30 NSABB meeting as determined by the Office of Biotechnology Activities [part of the NIH’s Office of Science Policy] staff and other U.S. government officials was designed to produce the outcome that occurred,” Dr. Osterholm charged in his letter. “It represented a very ‘one-sided’ picture of the risk-benefit of the dissemination of the information in these manuscripts. The agenda was not designed to promote a balanced reconsideration of the manuscripts.”

A major problem, he said, was that the “experts that addressed [the March NSABB session] have a real conflict of interest in that their laboratories are involved in this same type of work and the results of our deliberations directly affect them too.” The same problem occurred at the WHO meeting in February, he added.

Dr. Osterholm tempered his charge by saying he did not “suggest that there was a sinister motive by the U.S. government,” but still leveled a hefty blast, saying “I believe there was a bias toward finding a solution that was a lot less about robust science- and policy-based risk-benefit and more about how to get us out of this difficult situation.”

The upshot was that in the revised decision NSABB, U.S. policy makers, and researchers failed to “come to grips with the very difficult task of managing dual-use research of concern and the dissemination of potentially harmful information to those who might intentionally or unintentionally use that information in a harmful way.” His worry is — if not in this case — “will the Board ever find a bright line for redacting publication” of any future research that could potentially threaten public health?

Dr. Osterholm cited a major danger if details of this research became fully public: “A ferret-to-ferret experiment is expensive and technically demanding, and could only be done by a handful of labs in the world. Once the mutations are public, individuals … in many other labs could generate the mutants in a few weeks given several thousand dollars for gene synthesis,” using reverse genetics.

Finally, Dr. Osterholm questioned the public-health benefit from full release of the methods sections of the two H5N1 papers. “The most important aspect of the results in these two studies on surveillance and control has already been accomplished namely alerting the world to the possibility that H5N1 influenza virus surely can become a mammalian-transmitted virus and poses real pandemic potential.” Publication of more details from the research will not add to that alert, nor would it immediately help in the development or production of countermeasures against a potential H5N1 pandemic, he said.

Despite his concerns over full disclosure of the methods, Dr. Osterholm affirmed his overall support for this H5N1 research in a comment to “Nature” on Friday.  “I have been and continue to be a supporter of this kind of research,” he told the journal.

—Mitchel Zoler (on Twitter @mitchelzoler)

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WHO Trumps U.S. Plan for H5N1 Flu

The American plan for dealing with public release of details from the H5N1 influenza research funded by the U.S. government got trumped last Friday by the contrary conclusion of a committee assembled by the World Health Organization.

The WHO assembled a group of 22 researchers and policy makers from 10 countries in Geneva on Feb. 16-17 to discuss H5N1 airborne-transmissibility research, and the group came to three main conclusions, according to a statement they released and comments later in a press conference by Dr. Keiji Fukuda, the WHO’s assistant director general for Health Security and the Environment:

■ Research into H5N1 virus capable of airborne transmission from mammal to mammal is important and should continue.

■ Full public reporting of all details of the research done so far by Dr. Fouchier in Rotterdam and Dr. Kawaoka in Madison, Wis., should occur in the near future.

■ Until WHO crafts a process by which these full reports can be released publicly, they should remain under wraps along with continuation of the self-imposed moratorium on further research on the new H5N1 strains previously pledged by both Dr. Fouchier and Dr. Kawaoka.

WHO headquarters, Geneva/courtesy WHO ©WHO P. Virot

The WHO panel’s decision directly refutes the ruling first made public last December by the U.S. National Science Advisory Board for Biosecurity (NSABB) to redact the methods sections when the papers by Dr. Fouchier and Dr. Kawaoka are published. Science magazine has been holding the Fouchier manuscript, while Nature has the Kawaoka paper, and until late last week both journals intended to publish the redacted versions of their articles in March. Those plans are now on hold.

While the WHO’s Dr. Fukuda repeatedly stressed that consensus had been reached by the panel, news reports with comments from the two U.S. panelists, Dr. Anthony Fauci, director of  the National Institute of Allergy and Infectious Diseases, and Dr. Paul Keim, acting NSABB chairman, suggest something else: Their views got buried.

“I stand by the NSABB recommendations,” said Dr. Fauci, according to a report in Science. During the press conference, Dr. Fukuda admitted that “the representative from NIH pointed out that himself and others from the U.S. on record comply and understand and support the NSABB decision.”

Dr. Keim was blunter in his critique: “I was disappointed in this conclusion [by the WHO panel] as it was one that NSABB worked hard to achieve,” he told Science.

Dr. Bruce Alberts, editor-in-chief of Science, noted in a separate press conference last Friday that the issue had grown too global to be settled by a U.S.-centric group like the NSABB.

“In the long run, an international organization like WHO had to take charge of this… It may be the start of an international version of the NSABB,” Dr. Alberts said.

—Mitchel Zoler (on Twitter @mitchelzoler)

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H5N1: Keep That Genie in the Bottle

Throw out a hint of some meaty research and say “Don’t Ask! Don’t Tell!”  You might as well draw a map to the Christmas cache and tell the kids, “Don’t follow this trail!”

The U.S government seems to be engaging in the worst kind of this delusion by asking the journals Science and Natureto withhold the methodology sections of two important papers on H5N1 viral mutation.

Michele G. Sullivan/Elsevier Global Medical News

The papers, one by University of Wisconsin-Madison veterinary virologist Yoshi Kawakoa and one by Dr. Ron Fouchier of Erasmus Medical Center in Rotterdam, Netherlands, detail their work on avian flu H5N1 mutation. Each describes genetic engineering that created a new strain almost 100% lethal to ferrets — generally considered the best animals to model a human respiratory infections.

Presumably, Drs.  Kawakoa and Fouchier conducted their experiments with the goal of helping to protect mankind against the virus’ inevitable change. But the National Science Advisory Board for Biosecurity sees a dark side. The agency’s official plea to both journals suggests that publishing “the  methodological and other details … could enable replication of the experiments by those who would seek to do harm.”

Their concern is not unfounded: It goes without saying that an individual, or even  a country, could use this with evil intent.  A weaponized bird flu with a 90% or higher mortality rate would make the anthrax letters of  2001-2002 look like a scuffle in a kindergarten sandbox.

But is censoring going to keep this knowledge hidden?

Scientific discoveries almost always build upon prior knowledge in a long, nearly unbroken, chain of meticulous research. Researchers publish long strings of studies on the same topic, each one evolving just slightly from the last. Others with a passion for the same topic climb on board as well, so that eventually everyone benefits.

A clear representation of this? At least some of the research that so troubles our government has already been disseminated.

Colorized transmission electron micrograph of Avian influenza A H5N1 viruses (seen in gold). Courtesy the Centers for Disease Control and Prevention

Last year, Dr. Kawakoa described his lab’s creation of an H5N1 mutation almost universally lethal to ferrets.  The study describes his work with the two most virulent forms of H5N1, both isolated from humans and both with a human kill rate of up to 80%. Dr. Kawakoa and his colleagues manipulated the genes in both to create a novel virus that appeared even more lethal, killing all of the intranasally inoculated ferrets.

The paper not only identifies the genes — hemagglutinin (HA) and nonstructural protein (NS) — but the method of reverse engineering and  the modifications’ chromosomal positions. Its purpose was not to create a super-pandemic among humans, but to identify the genes and loci that most contribute to H5N1’s uniquely dangerous potential.

His new paper, according to the National Institute of Health’s  comment,  shows “that  the H5N1 virus has greater potential than previously believed to gain a dangerous capacity to be transmitted among mammals, including perhaps humans.”

Last September, Dr. Fouchier presented his now-to-be-edited work at the Fourth ESWI Influenza Conference. During an oral presentation, he described work that resulted in some potent H5N1 mutations. According to the conference daily, the researchers infected ferrets with the new H5N1, also formed by plasmid reverse engineering and also manipulating hemagglutinin.  The infected ferrets died, but didn’t transmit the virus.

The team then let the virus do its own thing,  just moving it repeatedly from a sick ferret’s nose to a healthy nose without tinkering – the way a virus would naturally mutate by adapting to each new host.  Dr. Fouchier found a new H5N1 with new mutations: It became an airborne form after 10 transmissions, suggesting that avian flu can mutate within one species, rather than requiring a “mixing bowl” animal, like a pig.

“This virus is airborne and as efficiently transmitted as the seasonal virus,” the paper quoted Dr. Fouchier as saying. “This is very bad news, indeed.”

The meeting wasn’t secret. Journalists were there, and some even wrote about it. New Scientist ran a piece about the research, as did Scientific American.

If this much information is already out there, might it just be possible that a “rogue scientist” could come up with much, much more? And is the National Science Advisory Board for Biosecurity really suggesting that only two scientists in all the world have so advanced this virus?

It might even be possible that there are labs in other countries working on the same thing. And that some of those countries might want to suppress important findings — holding them close the vest to “protect” the populace.

We wouldn’t want that now. Would we?

—Michele G. Sullivan

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