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Wisconsin researcher claims another "breakthrough" -- but is he observing protocol with his labwork?

The noted and, to be fair, very capable virus researcher Yoshihiro Kawaoka, has released another research paper regarding the dreaded H1N1 influenza virus and its elusive "smoking gun" of lethality. Kawaoka is affiliated with the University of Wisconsin, which built and named a facility in his name, and with the University of Tokyo.

Researchers unlock secrets of 1918 flu pandemic

http://news.yahoo.com/s/nm/20081229/hl_nm/us_flu1918

WASHINGTON (Reuters) – Researchers have found out what made the 1918 flu pandemic so deadly -- a group of three genes that lets the virus invade the lungs and cause pneumonia.

They mixed samples of the 1918 influenza strain with modern seasonal flu viruses to find the three genes and said their study might help in the development of new flu drugs.

The discovery, published in Tuesday's issue of the Proceedings of the National Academy of Sciences, could also point to mutations that might turn ordinary flu into a dangerous pandemic strain.

Yoshihiro Kawaoka of the University of Wisconsin and colleagues at the Universities of Kobe and Tokyo in Japan used ferrets, which develop flu in ways very similar to humans.

Usually flu causes an upper respiratory infection affecting the nose and throat, as well as so-called systemic illness causing fever, muscle aches and weakness.

But some people become seriously ill and develop pneumonia. Sometimes bacteria cause the pneumonia and sometimes flu does it directly.

During pandemics, such as in 1918, a new and more dangerous flu strain emerges.

"The 1918 influenza pandemic was the most devastating outbreak of infectious disease in human history, accounting for about 50 million deaths worldwide," Kawaoka's team wrote.

It killed 2.5 percent of victims, compared to fewer than 1 percent during most annual flu epidemics. Autopsies showed many of the victims, often otherwise healthy young adults, died of severe pneumonia.

"We wanted to know why the 1918 flu caused severe pneumonia," Kawaoka said in a statement.

They painstakingly substituted single genes from the 1918 virus into modern flu viruses and, one after another, they acted like garden-variety flu, infecting only the upper respiratory tract.

But a complex of three genes helped to make the virus live and reproduce deep in the lungs.

The three genes -- called PA, PB1, and PB2 -- along with a 1918 version of the nucleoprotein or NP gene, made modern seasonal flu kill ferrets in much the same way as the original 1918 flu, Kawaoka's team found.

Most flu experts agree that a pandemic of influenza will almost certainly strike again. No one knows when or what strain it will be but one big suspect now is the H5N1 avian influenza virus.

H5N1 is circulating among poultry in Asia, Europe and parts of Africa. It rarely affects humans but has killed 247 of the 391 people infected since 2003.

A few mutations would make it into a pandemic strain that could kill millions globally within a few months.

Four licensed drugs can fight flu but the viruses regularly mutate into resistant forms -- just as bacteria evolve into forms that evade antibiotics.

Kawaoka has been fixated on the H1N1 Spanish Flu virus (and with Ebola) for awhile now, and press releases have followed Dr. Kawaoka with regularity since 2004. Any Google search with the following criteria "Kawaoka 1918 flu" will net you an impressive list of headlines.

Kawaoka's work has included a 2007 study in a Level 4 biolab in Canada where he infected apes with the 1918 pandemic virus; and this latest study, where he spliced the 1918 virus with current flu viruses and infected ferrets with various hybrid pandemic/seasonal variants until he came up with a few cocktails that induced severe and often fatal reactions in the ferrets.

Of concern to some is the fact that he is messing with gene splicing to begin with, thereby creating new flu variants using the 1918 virus. Recall that in September, 2007, Kawaoka was slapped hard for his playing fast and loose with the Ebola virus. In fact, as reported by the AP on September 20, 2007, the National Institutes for Health (NIH) actually suspended Kawaoka's work with Ebola due to inferior lab conditions.

Study of Ebola virus in U.S. lab halted

Facilities at Wisconsin university were not secure, NIH says

http://www.msnbc.msn.com/id/20892122/

MADISON, Wis. - University of Wisconsin-Madison research on the deadly Ebola virus was conducted for a year in a less-secure laboratory than required, until the National Institutes of Health alerted the school to the problem.

The deadly virus itself was never present in the laboratory, said Jan Klein, UW-Madison biological safety officer. Instead, DNA copies of the virus were being studied to better understand one of the world's most dangerous pathogens.

Klein said no one was ever at risk, though an infectious virus could have been produced if the research material had been combined with other components. "But that was not part of any planned experiment and would not be done by accident," she said.

The research was conducted there from 2005 until being halted in October 2006. Klein characterized the problem as a technical violation rather than a safety violation.

"NIH took a broader read of the guidelines than we were aware of and we were using," she said.

The researcher, Yoshi Kawaoka, a professor of virology in the School of Veterinary Medicine, said he immediately moved the research to a Canadian lab with higher security after the NIH said the UW-Madison laboratory was not secure enough for the research.

"We see this as a difference in interpretation" with the NIH, he said in an e-mail Thursday.

NIH spokesman Don Ralbovsky said he was looking into the matter and had no immediate comment.

Kawaoka is a leading researcher on infectious diseases such as bird flu and Ebola. The university retained him last year by promising to build a $9 million research institute after he received a lucrative offer elsewhere. (bold mine)

The university approved Kawaoka's study initially for a Biosafety Level 3, Klein said. Several of UW-Madison's laboratories are Level 3 labs, but none are Level 4, where the most stringent guidelines to contain the most dangerous pathogens are applied.

Klein said Kawaoka was pressing to conduct the research in a less restrictive Level 2 lab. When the university asked the NIH for guidance, it learned the material was restricted to a Level 4 lab.

I can best describe what Kawaoka was doing as working with a "fax" of the Ebola virus. But the point is that protocol was not observed, and that is why the NIH took the extreme steps of shutting down Dr. Kawaoka's research. He then moved the work to Canada, ostensibly to gain access to a level 4 lab, but to also perhaps extricate himself from the prying eyes of now-awake federal regulators.

It was this same Canadian lab which produced Kawaoka's last headline:

Study uncovers a lethal secret of 1918 influenza virus

Jan. 17, 2007

http://www.news.wisc.edu/13360

The study "proves the 1918 virus was indeed different from all of the other flu viruses we know of," says Kawaoka, a professor in the UW-Madison School of Veterinary Medicine and at the University of Tokyo.

The new study, conducted at the Public Health Agency of Canada's National Microbiology Laboratory in Winnipeg, Manitoba, utilized the 1918 flu virus, which has been reconstructed by researchers using genes obtained from the tissues of victims of the great pandemic in a reverse genetics process that enables scientists to make fully functioning viruses.

Upon infection, the virus grew rapidly in the infected animals, suggesting the agent somehow sets the stage for virulent infection. "Somehow, early in infection, this virus does something to the host that allows it to grow really well," says Kawaoka. "But we don't know what that is." (bold mine)

In the new study, conducted in a high-level biosafety laboratory (BSL 4) at the Public Health Agency of Canada's National Microbiology Laboratory, seven primates were infected with the reconstructed 1918 virus. Clinical signs of disease were apparent within 24 hours of infection, and within eight days, euthanization was necessary. The rapid course of the disease mirrors how quickly the disease ran its course in its human victims in 1918.

In addition to Kawaoka, authors of the new Nature paper include Darwyn Kobasa, Steven M. Jones, Hideki Ebihara, Friederike Feldman, Judie B. Alimonti, Lisa Fernando, Yan Li and Heinz Feldman of Canada's National Microbiology Laboratory; Kyoko Shinya of Japan's Tottori University; John C. Kash and Michael G. Katze of the University of Washington; John Copps of the Canadian Food Inspection Agency's National Centre for Foreign Animal Disease; and Yasuko Hatta, Jin Hyun Kim, Peter Halfmann and Masato Hatta of UW-Madison.

The new study was supported by the Public Health Agency of Canada, the Japanese Ministries of Education, Culture, Sports, Science and Technology, and private grants to Kawaoka.

But wait! Didn't Kawaoka figure out what "it" was back in 2004? Yet another breathless headline, this time from Science Daily:

Gene From 1918 Virus Proves Key To Virulent Influenza

http://www.sciencedaily.com/releases/2004/10/041007081335.htm

ScienceDaily (Oct. 7, 2004) — MADISON - Using a gene resurrected from the virus that caused the 1918 Spanish influenza pandemic, recorded history's most lethal outbreak of infectious disease, scientists have found that a single gene may have been responsible for the devastating virulence of the virus.

Writing today (Oct. 7, 2004) in the journal Nature, virologist Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo, describes experiments in which engineered viruses were made more potent by the addition of a single gene. The work is evidence that a slight genetic tweak is all that is required to transform mild strains of the flu virus into forms far more pathogenic and, possibly, more transmissible.

The results of the new work promise to help scientists understand why the 1918 pandemic, a worldwide outbreak of influenza that killed 20 million people, spread so quickly and killed so efficiently, says Kawaoka, who has studied influenza viruses for 20 years. The finding also lends insight into the ease with which animal forms of the virus, particularly avian influenza, can shift hosts with potentially catastrophic results.

"Replacing only one gene is sufficient to make the virus more pathogenic," says Kawaoka, a professor of pathobiological sciences at the UW-Madison School of Veterinary Medicine. In the Nature paper, Kawaoka and his colleagues describe how a Spanish flu gene that codes for a key protein changed a relatively benign strain of flu virus from a nuisance to a highly virulent form.

In the late 1990s, scientists were able to extract a handful of genes from the 1918 virus by looking in the preserved lung tissue of some of the pandemic's victims. Subsequently, the genes were sequenced, including two critical genes that make hemagglutinin and neuraminidase, the protein keys that help the virus enter and infect cells.

Using a comparatively mild form of influenza A virus as a template, Kawaoka's team added the two 1918 genes that code for hemagglutinin and neuraminidase and infected mice with the engineered viruses.

"Here we demonstrate that the [hemagglutinin] of the 1918 virus confers enhanced pathogenicity in mice to recent human viruses that are otherwise non-pathogenic in this host," Kawaoka and his colleagues write in the Nature report. Moreover, the viruses with the 1918 hemagglutinin gene caused symptoms in the mice - infection of the entire lung, inflammation and severe hemorrhaging - eerily similar to those exhibited by human victims of the 1918 pandemic.

Scientists and historians have long speculated about why the 1918 Spanish flu virus was so virulent. Theories range from lack of modern medical care and antibiotics, which had not yet been developed, to the already weakened state of many victims due to war and the tumultuous social conditions of the time.

"There also were people who thought the virus was different in terms of its virulence," Kawaoka says. The results of the new study tend to support the idea that the virus was inherently more dangerous.

Another important result of the new study is that it supports the idea that the 1918 Spanish flu virus was avian in origin, but already adapted to proliferate in humans. That insight is important as scientists and public health officials view birds as a primary reservoir of influenza A virus, strains of which can sometimes jump species to infect other animals, including humans.

According to Kawaoka, it's known that avian strains of the virus have slightly different receptors - key proteins on the surface of the virus that act like a key to unlock and infect host cells - from those on flu viruses that infect humans.

"That restricts transmission from avian species (to humans) to some extent, but not completely," Kawaoka notes.

The receptors on the virus with the gene from the 1918 virus, Kawaoka says, readily recognized their complements on human cells. "That tells you that there was a change in receptor recognition after introduction from avian species to humans. It recognized the human receptor even though it came from an avian species. That's why it transmitted so efficiently among humans."

A third and intriguing finding of the study is that blood from the now very elderly survivors of the 1918 pandemic had high antibody titers to the engineered virus, Kawaoka says.

"People who were infected with this virus in 1918 still have high antibodies, even after 80 years," he says.

That scientifically interesting finding, Kawaoka explains, suggests that another outbreak of flu like the 1918 pandemic would spare many very old people who had had a brush with the virus more than 80 years ago. The irony in that, according to Kawaoka, is that influenza often extracts its heaviest toll on the elderly.

I used to read scientific papers voraciously -- that is, until I had to start paying for them to gain access. I am sure Dr. Kawaoka is doing some really fine research up there in Madison. But I cannot help but feel I am reading the same headline over and over and over and over again. Kawaoka claims that he found that "single gene" back in 2004 when he spliced 1918 genes onto common seasonal influenza A. Then he said in 2007 that he didn't know what "it" was. Then in December 2008, he says he has found "it" again! And this time, "it" is three genes.

And forgive me, I cannot help but feel that somehow, grant dollars are tied to these headlines.  "Publish or perish" is the mantra when it comes to these types of careers.  But can someone tell me in terms I can understand what the difference is between these three studies?  I am reminded of Omar Bradley's comment that giving Patton a headline meant he was good for another twenty miles.  Now substitute the word "grant" for "miles."

Also let me ask the question no one else seems to be asking:   What assurances are there, given Dr. Kawaoka's apparent belief that he knows better than the authorities what level of biosecurity is proper for these experiments, that someone with a kill switch is looking over his shoulder? 

Dr. Robert Webster has stated publicly that he believes the 1977 "age-specific pandemic" (my words) of H1N1 was the result of a Soviet lab accident.  Wouldn't it be terribly ironic if a hybrid pandemic virus was foisted upon society by those looking to solve its lethality who moved their ops to another nation because they perhaps didn't like who was peering over their shoulder?