The Debate Over Gain Of Function Studies Continues

BSL-4 Lab Worker - Photo Credit –USAMRIID

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`Gain of Function’ research (aka GOF) seeks to enhance the virulence, transmissibility, or host range of potentially deadly microorganisms. Proponents believe this could give us an early warning system for the next pandemic, and could aid in the timely creation of a vaccine.  

 

Opponents say those benefits are likely overstated, and there is a small - but genuine - risk that one of these `engineered’ pathogens could escape the lab, and actually cause the pandemic it was supposed to mitigate.

 

While GOF research isn’t new, the bioengineering tools we have today make possible tasks that would have been considered literally impossible a couple of decades ago.

 

All of this really came to a head about three years ago, when Dutch Virologist and flu researcher Dr. Ron Fouchier announced, at the 2011 ESWI Influenza Conference in Malta, that he’d created a `more transmissible’ form of the H5N1 virus (see Debra MacKenzie’s New Scientist: Five Easy Mutations).

 

At roughly the same time we saw a similar announcement from Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine, that together set alarm bells ringing in the world of biosecurity.

 

The early reaction outside of academia was fairly negative, with scathing editorials like An Engineered Doomsday  appearing in the New York Times. There was a year-long self imposed moratorium by a group of major researchers, to allow time for `public discussion and scientific debate’ of the issue, but in the end, very little of that actually took place. 

 

Instead, the moratorium was quietly lifted in early 2013, and research resumed, often in Biosafety level 3+ (Ag) facilities – not – as some have recommended, restricted to the highest containment Biosafety level 4 facilities. 

The revelation two weeks ago of a major breach in biosafety at a CDC lab in Atlanta (see CDC Statement On Possible Lab Exposure To Anthrax), along with the announcement earlier this month that Dr. Kawaoka had recreated viruses similar to the 1918 pandemic strain in his lab (see Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential) has helped to reignite the debate.

 

Today the Wisconsin State Journal carries a long article on concerns raised by University of Wisconsin biosafety expert.

 

UW-Madison flu studies raise risk more than prevent it, biosafety panelist says

By David Wahlberg | Wisconsin State Journal

UW-Madison scientist Yoshihiro Kawaoka says he’s creating potentially deadly flu viruses to help prevent a pandemic, but a campus biosafety panel member says the research could cause more harm than good because the viruses could escape from the lab.

“You’re increasing the probability of having a pandemic rather than decreasing the probability,” said Tom Jeffries, a member of the university’s Institutional Biosafety Committee, which reviews sensitive research.

Jeffries said the flu viruses Kawaoka creates in his lab at University Research Park on Madison’s West Side should be genetically modified to minimize the risk to humans. Kawaoka said doing that would undermine his studies, aimed at identifying troublesome flu viruses that could arise in nature.

(Continue . . .)

 

Late last week, the Journal Nature – which published Dr. Kawaoka’s H5N1 study in 2012 – published a cautionary opinion piece on the risks of doing this type of research.  Follow the link to read it in its entirety.

Nature | Editorial

Biosafety in the balance

An accident with anthrax demonstrates that pathogen research always carries a risk of release — and highlights the need for rigorous scrutiny of gain-of-function flu studies.

25 June 2014

The news last week of an accident involving live anthrax bacteria at the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, is troubling. Some 84 workers were potentially exposed to the deadly Ames strain at three CDC labs. But the incident will cause much wider ripples: it highlights the risks of the current proliferation of biocontainment labs and work on dangerous pathogens. If an accident can happen at the CDC, then it can happen anywhere.

(Continue . . . )

 

As you might imagine, speaking out against this sort of research isn’t exactly popular in academia, as these research projects can bring in large government grants, along with substantial publicity and prestige to Universities.

 

Suggestions that this sort of research be confined to biosafety level 4 facilities are often met with stiff resistance, since that would exclude most of the University based labs in this country.

 

Last November, in BMC Medicine: Containing Laboratory Escape Of Pandemic Viruses, we looked at a report that found the risks of seeing an accidental release from one of these labs is far from zero.

 

They calculated a .3% chance of release from any given lab each year, which works out to be roughly one every 100 years of lab operation.  With hundreds of of BSL-3 and BSL-4 labs around the world, the odds of seeing an accident in any given year somewhere in the world go up substantially.

While one can certainly argue with the methodologies used to come up with estimates for future events, we do know that between 2003 and 2009, US government laboratories had 395 incidents that involved the potential release of select agents  (see CIDRAP News  report Report: 395 mishaps at US labs risked releasing select agents).

 

While only 7 related infections were reported, this does add weight to the concerns being expressed by GOF research critics.   As does the most recent breach at the CDC lab in Atlanta.

 

For more background on all of this, you may wish to revisit a presentation by Dr. Marc Lipsitch on the the risks of these types of experiments from last September, while last December (see The Call For Urgent Talks On `GOF’ Research Projects), we saw  a letter – signed by 56 scientists – and published both in SciAm and the journal Nature - calling for `urgent talks’ over the future course of GOF research on influenza viruses, and other pathogens.

 

And more recently, we’ve seen the debate renewed, first in the pages of PLoS Medicine last month:

 

Lipsitch & Galvani: GOF Research Concerns

 

The debate then moved to CIDRAP News, where Kawaoka & Fouchier responded to this paper:

Experts call for alternatives to 'gain-of-function' flu studies

 

And most recently, a response back by Lipsitch & Galvani, again at CIDRAP.

 

COMMENTARY: The case against 'gain-of-function' experiments: A reply to Fouchier & Kawaoka

Marc Lipsitch, DPhil, and Alison P. Galvani, PhD

 

Unfortunately, despite the ongoing debate, this issue doesn’t seem to be any closer to resolution than it was two and half years ago when the fate of the Fouchier & Kawaoka H5N1 papers was still in doubt.

Cell Host & Microbe: 1918-like Avian Viruses Circulating In Birds Have Pandemic Potential

BSL-4 Lab Worker - Photo Credit –USAMRIID  

 

 

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Last year, in H2N2: What Went Around, Could Come Around Again, we looked at a cautionary report from researchers at St. Jude Children's Research Hospital that warned that avian H2N2 viruses – similar to the one that sparked the 1957 pandemic – continue to circulate in the avian species.

 

Those born after 1968 – when H2N2 was supplanted in the human population by the H3N2 virus – are likely to have little immunity to an H2 flu virus, and so concerns remain that the virus could re-emerge as a pandemic.

 

The H1N1 virus – which disappeared for 20 years after H2N2 arrived on the scene – returned in 1976, and has co-existed with H3N2 ever since. Given the near-universal exposure we all have to H1N1, few scientists thought another H1N1 could pose a substantial pandemic risk.  

 

That theory was disposed of when, in 2009, a `new’  H1N1 variant appeared and did just that. 

 

All of which brings us to a new study, published today in Cell Host & Microbe, that begins by looking at the current reservoir of avian flu viruses in the wild for gene segments similar to those found in the deadly 1918 H1N1 pandemic virus. And as you might expect, they found what they were looking for. 

 

Gene segments with a `high homology’ to the 1918 virus still exist in the wild, and given the ability of flu viruses to reassort, may pose a future pandemic risk.

How big that risk is, is unknown.

 

This story gets more complicated, when - in what some scientists consider a risky step -  the researchers assembled their own version of the 1918 pandemic virus using these different gene segments, and proceeded to test it on ferrets.

 

This virus was `close’ to the 1918 version – but not an exact match -  off by a few amino acid substitutions. And so the virus didn’t kill or spread between the ferrets. 

 

These researchers then introduced a small number of mutations (and some arose spontaneously), that increased both the virus’s transmissibility and virulence, making the virus deadly (at least to ferrets).

A press release from the University of Wisconsin-Madison describes the experiment:

 

Genes found in nature yield 1918-like virus with pandemic potential

(EXCERPT)

To assess the risk posed by a virus that could acquire all eight of the 1918-like genes, the team used reverse genetics methods to generate a virus that differed from the 1918 virus by only 3 percent of the amino acids that make the virus proteins. The resulting virus was more pathogenic in mice and ferrets that an ordinary avian flu virus, but was not as pathogenic as the 1918 virus and it did not transmit in ferrets via respiratory droplets, the primary mode of flu transmission.

Since pandemic risk escalates when a virus become transmissible, Kawaoka's group then conducted additional experiments to determine how many changes would be required for the avian 1918-like virus to become transmissible in ferrets, a well accepted model for influenza transmission studies. The researchers identified seven mutations in three viral genes that enabled the pathogen to transmit as efficiently as the 1918 virus. The resulting virus, composed of genetic factors circulating in wild and domesticated birds, demonstrates that the genetic ingredients for a potentially deadly and pandemic pathogen exist in nature and could combine to form such a virus, according to Kawaoka.

<SNIP>

The transmission studies were conducted under specially designed high-containment conditions, using commensurate biosafety practices, at UW-Madison with approval of the university's Institutional Biosafety Committee. The draft manuscript was reviewed by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), in keeping with the institute's implementation of the United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern.

(Continue . . . )

First, the link to the article, then I’ll have a little bit more on the controversy that surrounds Gain of Function (GOF) research. 

 

Circulating Avian Influenza Viruses Closely Related to the 1918 Virus Have Pandemic Potential

Tokiko Watanabe^12,Gongxun Zhong^12, Colin A. Russell¹² , Noriko Nakajima , Masato Hatta , Anthony Hanson ,  Ryan McBride , David F. Burke , Kenta Takahashi ,  Satoshi Fukuyama ,  Yuriko Tomita ,  Eileen A. Maher ,  Shinji Watanabe , Masaki Imai ,  Gabriele Neumann ,  Hideki Hasegawa ,  James C. Paulson ,  Derek J. Smith ,  Yoshihiro Kawaoka

DOI: http://dx.doi.org/10.1016/j.chom.2014.05.006

Highlights

• •Current circulating avian flu viruses encode proteins similar to the 1918 virus
• •A 1918-like virus composed of avian influenza virus segments was generated
• •The 1918-like virus is more pathogenic in mammals than an authentic avian flu virus
• •Seven amino acid substitutions were sufficient to confer transmission in ferrets

(Continue . . . )

Despite the safety precautions taken, there is considerable concern among some in the scientific community over the safety of these so called `gain of function’ (GOF) experiments, and that has led to increasingly heated exchanges and increasing polarization in academia.

 

Proponents argue that these experiments can help us discover what strains have the most pandemic potential, and could help in the early development of a vaccine.  Opponents argue that these potential benefits are overstated, and the risks of an accidental release from the lab are too great.

 

This is an area where reputable – indeed, world renown – scientists and researchers do not agree. I’ve covered both sides of this issue previously, including:

 

Lipsitch & Galvani: GOF Research Concerns

Laurie Garrett On Biosecurity Reforms

H7N9: Reigniting The `Gain Of Function’ Research Debate

mbio Science Should Be in the Public Domain

 

Unfortunately, despite considerable debate over this issue, we seem no closer to a consensus than we were two and half years ago when fate of the Fouchier H5N1 Ferret studies was still on the table. Worse, the long promised `thorough public discussion of the risks and benefits involved; has yet to happen in any substantive way. 

 

We seem to have reached a sort of equilibrium, an uneasy state of status quo on this issue, where nothing really changes.

 

Which pretty much assures that a month, perhaps two from now, we’ll likely see another controversial GOF study released, followed by another round of criticism and concern.  Ad infinitum.

 

Perhaps not the worst possible state of affairs, but it does tend  to make a mockery of the phrase `scientific progress’.

H7N9: Reigniting The `Gain Of Function’ Research Debate

 

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

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Most readers will recall that, beginning in the fall of 2011 and extending well into the summer of 2012, the global scientific community was roiled by controversy over the wisdom of conducting – and publishing – Gain of Function (GOF) research on the avian H5N1 virus.

 

Objections were raised initially after the 2011 ESWI Influenza Conference in Malta, where Dutch researcher Ron Fouchier revealed that he’d created a more `transmissible’ form of the H5N1 virus (see Debra MacKenzie’s New Scientist: Five Easy Mutations).

 

That discovery, along with similar news coming from Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine, set alarm bells ringing in the biosecurity community.

 

By December of 2011 The Biosecurity Debate On H5N1 Research reached fevered pitch, which led to a group of internationally renowned Scientists to Announce a 60 Day Moratorium On Some H5N1 Research in January, 2012. That moratorium was subsequently extended until January of 2013 (see NIH Statement On Lifting Of The H5N1 Research Moratorium).

 

In the meantime, after much heated debate, last summer Science Published The Fouchier Ferret Study and Nature Published The Kawaoka H5N1 Study. 

 

In March of 2012 the NIH - which funds many of these research projects - promulgated new DURC Oversight Rules (Dual Use Research of Concern), which also includes some types of GOF research.

 

For those unfamiliar with the lexicon of biomedical research, DURC in this new policy is defined as:

. . . life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment,

 

Since then the debate has continued, mostly in academia, over what restrictions (if any) should be placed on potentially dangerous gain of function research.

 

  A couple of recent examples include:

 

Nature: H5N1 viral-engineering dangers will not go away

Morens & Taubenberger - Influenza Viruses: Breaking All the Rules

 

Today, in a bid to head off the kind of controversy they encountered with the surprise announcement of H5N1 GOF studies in 2011, 22 respected international scientists have published a pre-emptive letter (in the Journal Science and the Journal Nature) calling for gain of function research using the H7N9 virus.

 

In this letter they outline the benefits they believe such studies will provide along with the biosecurity measures they will work under.

 

Many of the signatories to this letter are well known to the readers of this blog.

 

RON A. M. FOUCHIER, YOSHIHIRO KAWAOKA, CAROL CARDONA,  RICHARD W. COMPANS, ADOLFO GARCÍA-SASTRE,  ELENA A. GOVORKOVA, YI GUAN, SANDER HERFST, WALTER A. ORENSTEIN, J. S. MALIK PEIRIS, DANIEL R. PEREZ,  JUERGEN A. RICHT, CHARLES RUSSELL, STACEY L. SCHULTZ-CHERRY, DEREK J. SMITH, JOHN STEEL,  S. MARK TOMPKINS, DAVID J. TOPHAM, JOHN J. TREANOR, RALPH A. TRIPP, RICHARD J. WEBBY,  ROBERT G. WEBSTER

 

You can read the full letter here or at the following link:

 

Published Online August 7 2013

Science DOI: 10.1126/science.1243325

Letters

Gain-of-Function Experiments on H7N9

*Corresponding author. E-mail: r.fouchier@erasmusmc.nl (R.A.M.F.); kawaokay@svm.vetmed.wisc.edu (Y.K.)

• Abstract

Since the end of March 2013, avian a influenza viruses of the H7N9 subtype have caused more than 130 human cases of infection in China, many of which were severe, resulting in 43 fatalities. Although this A(H7N9) virus outbreak is now under control, the virus (or one with similar properties) could reemerge as winter approaches. To better assess the pandemic threat posed by A(H7N9) viruses, NIAID/NIH Centers of Excellence in Influenza Research and Surveillance (CEIRS) investigators and other expert laboratories in China and elsewhere have characterized the wild-type avian A(H7N9) viruses in terms of host range, virulence, and transmission, and are evaluating the effectiveness of antiviral drugs and vaccine candidates. However, to fully assess the potential risk associated with these novel viruses, there is a need for additional research including experiments that may be classified as “gain-of-function” (GOF). Here, we outline the aspects of the current situation that most urgently require additional research, our proposed studies, and risk-mitigation strategies.

 

 

But as you might expect, not everyone is in agreement on the value, or the safety, of doing these studies.  In an accompanying news and analysis article in Science Magazine, David Malakoff writes:

 

Avian Influenza

Critics Skeptical as Flu Scientists Argue for Controversial H7N9 Studies

David Malakoff

<EXCERPT>

The openness offensive isn't quieting critics. “The scientific justification presented for doing this work is very flimsy, to put it mildly, and the claims that it will lead to anything useful are lightweight,” says Adel A. F. Mahmoud, an infectious disease specialist at Princeton University and the former president of Merck Vaccines. And the security precautions are “insufficient and amazingly lame,” says molecular biologist Richard Ebright of Rutgers University in Piscataway, New Jersey.

 

(Continue . . . )

 

The NIH, responding to today’s letter, has published their position regarding additional oversight they will require for H7N9 influenza virus gain-of-function research.

 

Extra Oversight for H7N9 Experiments

Harold Jaffe, Amy P. Patterson, Nicole Lurie

The U.S. Department of Health and Human Services (HHS) announces a new review process for certain gain-of-function (GOF) experiments with the avian influenza A (H7N9) virus, some of which are proposed this week by influenza scientists (1). Specifically, before being undertaken using funds from the HHS, proposed studies that are reasonably anticipated to generate H7N9 viruses with increased transmissibility between mammals by respiratory droplets will undergo an additional level of review by the HHS.

(Continue . . . )

 

 

Ed Yong – writing for The Scientist – has penned an excellent overview of this controversy, including extended remarks from a number of experts, including CIDRAP director Michael Osterholm.

 

 

Bird Flu Experiments Proposed

In a bid to avoid the controversy that dogged H5N1 research last year, flu researchers have published a letter proposing how to approach potentially dangerous research on H7N9.

By Ed Yong | August 7, 2013

 

And for a last stop, we have the always reliable Helen Branswell, who writes:

 

Flu researchers propose controversial 'gain-of-function' studies for H7N9 virus

By Helen Branswell, The Canadian Press August 7, 2013 10:30 AM

 

 

Whether this controversy will reach the contentious levels we saw last year with H5N1 research is difficult to predict, but there are strong feelings on both sides of this issue.

 

Stay tuned.

Peter Sandman: Outrage On Both Sides

 

 

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Dr. Peter Sandman is a world renown expert on crisis communications, and along with his wife and colleague Dr. Jody Lanard, provide consulting services to individuals, organizations, and companies – often during their worst public relations nightmares.

Together they also produce a wealth of invaluable risk management advice on their website, which quite frankly should be second home for anyone involved in public relations or risk communications.

 

 

I’ve highlighted Peter and Jody’s work often in the past, including:

 

Peter Sandman: Swine Flu For Grownups

Experts: `Mild’ Is A Misleading Term For This Pandemic

Peter Sandman On Pandemic Risk Communication

 

 

When you think about `risk communications’ and `flu’, very little comes close to the often unseemly debate of the past few months over the publication of the Kawaoka and Fouchier H5N1 transmissibility papers.

 

 

For those that need a refresher:

 

Last September, Ron Fouchier from the Netherlands (and almost simultaneously Professor Yoshihiro Kawaoka from Wisconsin) announced success in creating enhanced strains of the H5N1 avian flu virus in the laboratory that can transmit efficiently among ferrets, which quickly sparked biosecurity concerns.

 

For some background, see Katherine Harmon’s Sci-Am article , New Scientist: Five Easy Mutations, & NPR: Bio-Terrorism Concerns Over Bird Flu Research.

 

 

The fate of these two papers has now been decided; Kawaoka’s was published earlier this month (see Nature Publishes The Kawaoka H5N1 Study), and a revised version of Fouchier’s paper is due out anytime.

 

While the original focus of this debate has been settled, we are left with nagging questions regarding the way this debate was handled, and concerns over what happens when this sort of situation inevitably occurs again.

 

Which brings us to a long, detailed, and very informative analysis of the risk communication missteps made by both sides of this debate, posted by Dr. Sandman on his website in response to a reader’s comment.

 

It is called:

 

Risk communication aspects of the debate over H5N1 transmission studies

 

 

I’ll not try to summarize this well reasoned and detailed examination of the events of the past few months, as to do so would be a disservice.

 

This article deserves to be read in its entirety. 

 

Highly recommended.

Renewed Respect For Wild H5N1

 

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Part of the fallout from the publication of Yoshiro Kawaoka’s research paper (see Nature Publishes The Kawaoka H5N1 Study) has been renewed concerns over the progress the avian flu virus is making in the wild and its potential for sparking a pandemic.

 

A few headlines from the past 24 hours include:

 

Once-Banned Bird Flu Study Suggests Pandemic Threat Is Real Newsday.com

 

Bird flu viruses have potential to cause a ‘human pandemic' The Hindu

 

Study Shows How Bird Flu Could Jump to Humans - MedPage Today

 

Pandemic Potential? Bird Flu Becomes Airborne With Just 4 Mutations LiveScience.com

 

 

Kawaoka showed that it would take perhaps only 3 or 4 mutations to turn the H5N1 virus into a mammalian transmissible influenza, and noted that similar genetic changes have already been observed in virus samples collected from the middle east.

 

The `money quote’ from his paper was:

 

Therefore, these viruses may be several steps closer to those capable of efficient transmission in humans and are of concern.

 

 

Kawaoka references a 2011 study that found that several new H5 sublineages have emerged in Egypt with an increased affinity for (human) α2,6 SA receptor cells while still retaining their binding ability to (avian) α2,3 SA receptor cells.

 

We looked at this paper roughly a year ago in PLoS: Human-Type H5N1 Receptor Binding In Egypt.

 

Of note, in 2011 the authors found `increased attachment and infectivity in the human lower respiratory tract, but not in the larynx.’

 

Many scientists believe the virus must learn to bind to, and replicate in, the upper airway (nose, larynx, pharynx, trachea)  of humans in order to transmit efficiently from human to human. 

 

And that hasn’t happened in the wild yet.

 

Of concern, one of Kawaoka’s discoveries is a single mutation that `stabilizes’ the virus so that it can replicate within the pH range normally found in the trachea.

 

Some scientists worry that this pH stabilization might be one of the last big hurdles the virus must clear before becoming more of a human threat.

 

Whether the `right’ mutations will occur in nature, and at a time and place conducive for sparking a pandemic, is subject to debate. 

 

Some scientists argue that if it hasn’t happened by now, it isn’t likely to.

 

But it now appears that the number changes needed for the H5N1 virus to make a leap from being an avian-specific virus to a human-adapted one may be fewer than previously suspected.

More Reaction To The Kawaoka Paper

 

 

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As promised, some additional reports on the publication in Nature today of Yoshiro Kawaoka’s H5N1 study (see Nature Publishes The Kawaoka H5N1 Study).

 

First from Carl Zimmer, an in-depth (and extremely well done) explainer of the issues surrounding the publication of this study.

 

Behold The Forbidden Flu: A Loom Explainer

 

 

Ed Yong for Discover Magazine writes:

 

Mutant flu paper is finally published, reveals pandemic potential of wild viruses

 

 

And the journal Nature runs an editorial:

 

Nature | Editorial

Publishing risky research

Nature 485,5 (03 May 2012)

doi:10.1038/485005a

Imperfect global biosafety standards and a threat to researchers' motivations from biosecurity concerns are among the significant risks in current flu research.

 

 

Via The Scientist we get the following.

 

Bird Flu Transmission in Mammals

After much ado, Nature publishes the first report of a bird flu virus adapted for transmission in ferrets.         By Ruth Williams | May 2, 2012

And lastly, from Science Magazine:

 

One of Two Hotly Debated H5N1 Papers Finally Published

by Martin Enserink and Jon Cohen on 2 May 2012, 1:18 PM

 

Nature Publishes The Kawaoka H5N1 Study

 

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

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Although it was Ron Fouchier’s announcement last September (see New Scientist: Five Easy Mutations) of his successful manipulation of the H5N1 virus to make it transmissible among ferrets that set off biosecurity alarm bells (see NPR: Bio-Terrorism Concerns Over Bird Flu Research) and instigated an international debate, in a laboratory halfway around the world Dr. Yoshiro Kawaoka was quietly duplicating the feat.

 

Today (the embargo having lifted at 1pm) the journal Nature publishes Kawaoka’s study, which details how he created a modified H5N1 – H1N1 hybrid that transmits via respiratory droplets among ferrets.

 

While its virulence in ferrets was reduced over that of its parental H5N1 virus (exactly why is unknown), the big news is that it only took the introduction of 4 mutations into the H5N1’s hemagglutinin (HA) to allow it to bind efficiently to the alpha (2-6) sialic acid receptors found in ferret (and human) upper respiratory tracts.

 

Three of these mutations were directly involved in the binding to the a2,6 receptor cell, while the 4th stabilized the virus to fuse with receptor cells at pH levels typically found in the upper respiratory tract. 

 

An affinity for a2,6 receptor cells has long been thought vital for the virus to adapt to humans, but this 4th mutation - that facilitates virus-cell fusion - may prove equally important.

 

Given its highly public and bumpy road to publication, Kawaoka’s study (see below) is certain to receive an inordinate amount of scrutiny and review over the next couple of days.

 

 

Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to areassortant H5 HA/H1N1 virus in ferrets

 

doi:10.1038/nature10831

Masaki Imai, Tokiko Watanabe, Masato Hatta, Subash C. Das, Makoto Ozawa, Kyoko Shinya, Gongxun Zhong, Anthony Hanson, Hiroaki Katsura, Shinji Watanabe, Chengjun Li , Eiryo Kawakami , Shinya Yamada, Maki Kiso5,Yasuo Suzuki , Eileen A. Maher, Gabriele Neumann & Yoshihiro Kawaoka

 

Kawaoka’s 11-page study is, as you might imagine, highly technical and may prove tough sledding for those without a solid background in virology.

 

Nature published a 2-page synopsis by Hui-Ling Yen & Malik Peiris that helps to explain some of the details, but this is a pay-to-view article.

 

 

Bird flu in mammals

An engineered influenza virus based on a haemagglutinin protein from H5N1 avian influenza, with just four mutations, can be transmitted between ferrets, emphasizing the potential for a human pandemic to emerge from birds. 

 

 

According to Malik Peiris, this study reaffirms the pandemic potential of the H5N1 virus, and reinforces the need for better surveillance of the virus in the wild.

 

While Kawaoka identified several mutations in the H5 HA that allowed the virus to bind to a2,6 receptors there are likely other combinations that could lead to greater transmissibility.

 

For the best all-around coverage of this story, we can always rely on Helen Branswell of The Canadian Press. Helen has just posted the following article on this research’s publication.

 

 

Bird flu study: Three mutations might give virus ability to transmit to humans

By: Helen Branswell, The Canadian Press

 

 

There will, undoubtedly, be a large number of stories and opinion pieces regarding the publication today of Kawaoka’s research.

 

Already I note  that Vincent Racaniello has blogged on this publication:

 

Kawaoka paper published on aerosol transmission of H5 influenza virus in ferrets

2 May 2012

Meanwhile Laurie Garrett  takes a more cautionary route in:

 

Manmade H5N1 Paper Finally Published, And Worrying

 

 

I’ll update this blog with more links to articles and opinion pieces on this research later today or tomorrow.

Nature: Yoshihiro Kawaoka Talks About His H5N1 Research

 

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

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Although two scientists, working independently and a half-a-world-apart have recently created a more transmissible version of the H5N1 virus, it has been the work of Ron Fouchier at Erasmus University that has garnered the most press.

 

The reason is pretty simple.

 

Fouchier announced his findings at a scientific conference late last summer (see Katherine Harmon’s Sci-Am article and in a follow up to this story in New Scientist: Five Easy Mutations), while Yoshihiro Kawaoka has – until now - refrained from discussing his work publicly.

 

Today in a Nature commentary, flu virologist Yoshihiro Kawaoka breaks his silence and talks about his research into the H5N1 virus, and why such research should continue.

 

H5N1: Flu transmission work is urgent

• Yoshihiro Kawaoka

Nature (2012)

doi:10.1038/nature10884 Published online

25 January 2012

Yoshihiro Kawaoka explains that research on transmissible avian flu viruses needs to continue if pandemics are to be prevented.

 

Taking a different approach than that used by Fouchier, Kawaoka created a reassortant virus combining H5N1 and the 2009 H1N1 virus, which while transmissible between ferrets, was no more pathogenic than regular flu.

 

As you might expect, Helen Branswell is already all over this story, and you can find her take on it at:

 

The Canadian Press - ONLINE EDITION

Researcher at heart of bird flu studies controversy reveals details of his findings

By: Helen Branswell, The Canadian Press