Lethal Virus from 1918 Genetically Reconstructed

Lethal Virus from 1918 Genetically Reconstructed
US Army scientists create "Spanish Flu" virus in laboratory - medical benefit questionable

(Austin and Hamburg, 9 October 2003) – The 'Spanish Flu' influenza virus that killed 20-40 million people in 1918 is currently under reconstruction. Several genes of the extraordinarily lethal 1918 flu virus have been isolated and introduced into contemporary flu strains. These proved to be lethal for mice, while virus constructs with genes from a current flu virus types had hardly any effect. These experiments may easily be abused for military purposes, but provide little benefit from a medical or public health point of view.

The 1918 Spanish Flu was highly infectious and – in comparison to contemporary flu viruses – killed a very high percentage of those infected, including many younger people. The Spanish Flu alone caused the medium life expectancy in the US in 1918 to drop by 10 years. Hence, flu viruses are perceived today as a serious biological warfare threat. Just two weeks ago, a 15 million dollar research grant was awarded in the US to develop protective measures especially against a bioterrorist attack with flu viruses.

Despite the very dangerous nature of the 1918 virus, efforts to reconstruct it started in the mid 1990s, when Dr Jeffrey Taubenberger from the US Armed Forces Institute of Pathology in Washington DC succeeded in recovering and sequencing fragments of the viral RNA from preserved tissues of 1918 victims. In the current issue of the scientific journal Emerging Infectious Diseases new genetic details of the 1918 flu virus will be published.

But after (partially) unravelling the genetic sequence of the virus, the scientists went a step further and began bringing the Spanish flu back to life. Unnoticed by the public, they succeeded in creating a live virus containing two 1918 genes that proved to be very lethal in animal experiments. This experiment is only one genetic step away from taking the 1918 demon entirely out of the bottle.

A resuscitation of the Spanish flu is neither necessary nor warranted from a public health point of view. Allegedly, the recent experiments sought to test the efficacy of existing antiviral drugs on the 1918 construct. But there is little need for antiviral drugs against the 1918 strain if the 1918 strain had not been recreated in the first place "It simply does not make any scientific sense to create a new threat just to develop new countermeasures against it." says Jan van Aken, biologist with the Sunshine Project, "Genetic characterization of influenza strains has important biomedical applications. But it is not justifiable to recreate this particularly dangerous eradicated strain that could wreak havoc if released, deliberately or accidentally."

Construction of new maximum security (BSL-4) laboratories for biodefense research has been justified in part by citing the potential of the Spanish Flu as a biological weapon. Influenza usually requires a low level of containment; but when scientists begin recombining virulence-related genes, the danger dramatically increases. The University of Texas Medical Branch's BSL-4 plans influenza 'gene reassortment' experiments in maximum containment. "This kind of research is creating a vicious circle, and could prompt a race by biodefense scientists to genetic engineer unthinkable diseases", says Edward Hammond of the Sunshine Project, "What disease comes after influenza? Biodefense laboratories must not become self-fulfilling prophesy centers. The world does not need biodefense programs to create a 'genetically engineered disease gap'."

From an arms control perspective it appears to be particularly sensitive if a military research institution embarks on a project that aims at constructing more dangerous pathogens. "If Jeffery Taubenberger worked in a Chinese, Russian or Iranian laboratory, his work might well be seen as the 'smoking gun' of an offensive biowarfare program," says van Aken.

Genetic study links 1918, '97 flu outbreaks
Clues indicate virus leaped from animals

Sabin Russell, Chronicle Medical Writer Friday, September 7, 2001

Using the latest tools of genetic engineering, researchers have discovered tantalizing clues to explain two outbreaks of influenza nearly 80 years apart.

The first epidemic was the Spanish flu of 1918, which killed at least 20 million people, and the second, just four years ago in Hong Kong, might have been just as deadly -- but was stopped by the slaughter of a million chickens that may have harbored the virus.

In each case, changes in the genetic makeup of an influenza virus apparently allowed the disease to jump from animals to people, exposing them to a microbe that the human immune system had not encountered before.

Both investigations are chronicled in today's issue of the journal Science. While the discoveries described by scientists are different and apparently unrelated, they underscore how researchers are gaining valuable -- and potentially dangerous -- knowledge about one of the most threatening diseases on the planet.

'MOLECULAR WHODUNIT'
"This is a molecular whodunit," said Robert Webster, a virologist at St. Jude Children's Research Hospital in Memphis, who wrote a commentary accompanying the articles in Science. "We've got some of the clues, but there's a few more clues to come in."

With new insights, however, comes a caution. Scientists are learning so much about the inner workings of the deadliest flu viruses that it is now possible to create them in the lab.

"When the complete sequence of the 1918 virus is obtained, it may be possible to create the virus anew," Webster wrote. "Such a study should be attempted only if its benefits warrant the risk, and if high-level biosafety laboratories are used."

The Science articles are the latest evidence of a growing fascination with the 1918 flu, which study author Mark Gibbs and colleagues at Australian National University describe as "the most severe recorded outbreak of acute human disease."

AUSTRALIAN RESEARCH
In their article, the Australian researchers presented a new and highly controversial theory that the Spanish flu was triggered when a gene segment from pig influenza somehow swapped with a gene segment in a flu virus infecting humans -- an event called recombination.

The new virus, according to the Australian team, was a natural version of the kind of recombinant viruses that can be crafted in a modern gene-splicing lab. The hybrid gene would have produced on the surface of the Spanish flu virus a docking protein that resembled human influenza at its roots, but a pig variant at the top where it grabs onto a target cell.

Gibbs' findings are based on a re-examination of gene fragments of the 1918 flu virus extracted from preserved tissue of two soldiers who died of it and from an Inuit woman who also died from the flu and was buried in the Alaskan permafrost. They used computers to compare genetic signatures of the fragments with those of more recent human and swine flus, and plotted the likely evolution of the 1918 strain.

Their conclusion: the gene segment from the pig flu virus entered the human flu lineage just prior to the outbreak of Spanish flu in 1918.

Gibbs said via e-mail that pathologists who discovered the old viral fragments did not spot the spliced gene in their initial analysis because there was no reason to look for such a major shift. "It was believed that influenza viruses couldn't recombine in this way," he said. "It took special software to spot the changes," he added.

Skeptics are not convinced. "There is absolutely no evidence for recombination in influenza," Webster said. He called Gibbs' conclusions "a stretch."

HONG KONG CHICKEN FLU
The evidence uncovered by studies of the Hong Kong chicken flu virus, Webster contends, are much more compelling.

Veterinarians at the University of Wisconsin at Madison obtained two different strains of the Hong Kong virus that killed six of 18 infected people in 1997. One was found to be lethal to laboratory mice, and the other was not. Using a new laboratory technique called reverse genetics, they were able to pinpoint two mutated genes in the lethal strain.

To scientists trying to find out why some flu viruses are so much more virulent than others, this is an exciting discovery. "Now, the tools are beginning to get into place that can work out what makes a virus mild, and what makes it nasty," Webster said.

E-mail Sabin Russell at srussell@sfchronicle.com

This is hardly secret nor would constitute "a smoking gun" of a bio-warfare program. Leftists love to say stuf like that though.

Here is their recent abstract on their work:
_________________

Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13849-54. Epub 2002 Oct 04.

Existing antivirals are effective against influenza viruses with genes from the
1918 pandemic virus.

Tumpey TM, Garcia-Sastre A, Mikulasova A, Taubenberger JK, Swayne DE, Palese P,
Basler CF.

Southeast Poultry Research Laboratory, United States Department of Agriculture,
Athens, GA 30605, USA.

The 1918 influenza pandemic caused more than 20 million deaths worldwide. Thus,
the potential impact of a re-emergent 1918 or 1918-like influenza virus, whether
through natural means or as a result of bioterrorism, is of significant concern.
The genetic determinants of the virulence of the 1918 virus have not been
defined yet, nor have specific clinical prophylaxis and/or treatment
interventions that would be effective against a re-emergent 1918 or 1918-like
virus been identified. Based on the reported nucleotide sequences, we have
reconstructed the hemagglutinin (HA), neuraminidase (NA), and matrix (M) genes
of the 1918 virus. Under biosafety level 3 (agricultural) conditions, we have
generated recombinant influenza viruses bearing the 1918 HA, NA, or M segments.
Strikingly, recombinant viruses possessing both the 1918 HA and 1918 NA were
virulent in mice. In contrast, a control virus with the HA and NA from a more
recent human isolate was unable to kill mice at any dose tested. The recombinant
viruses were also tested for their sensitivity to U.S. Food and Drug
Administration-approved antiinfluenza virus drugs in vitro and in vivo.
Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were
inhibited effectively in both tissue culture and mice by the NA inhibitors,
zanamivir and oseltamivir. A recombinant virus possessing the 1918 M segment was
inhibited effectively both in tissue culture and in vivo by the M2 ion-channel
inhibitors amantadine and rimantadine. These data suggest that current antiviral
strategies would be effective in curbing the dangers of a re-emergent 1918 or
1918-like virus.

Excellent post. I found this fascinating:

Gibbs said via e-mail that pathologists who discovered the old viral fragments did not spot the spliced gene in their initial analysis because there was no reason to look for such a major shift. "It was believed that influenza viruses couldn't recombine in this way," he said. "It took special software to spot the changes," he added.

I think this speaks to the concerns I have. Mapping and recreating the 1918 mutation would not protect us against anything but a 1918 clone. If a new piece of code is spliced in either naturally as Gibbs postulates, or purposefully as researchers monkey with it, our immune systems may be like the Maginot line. Check the links in post 49. One of those discusses how certain aspects present in one variant made it "invisible" to the body's immune system. (Great tag line BTW!)

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