Tuesday, May 15, 2007

Millions dead within weeks

I became interested in primate research at the university of Wisconsin in 1997, after learning about some of the research at the Oregon and Washington Regional Primate Research Centers. Since then, I have been a fairly close observer of primate research in the United States.

Among the National Institutes of Health's National Primate Research Centers, Wisconsin stands out for a couple of reasons. Harry Harlow started the lab that bears his name, and he was the first director of the Wisconsin Regional Primate Research Center, which sits next door. (In April 2002, the Regional Primate Research Centers were renamed National Primate Rersearch Centers.) Many people remember Harlow as the scientist associated with the black and white photos of the baby monkeys clinging to a cloth-covered surrogate mother. Harlow was one of the promoters and architects of the country’s current system of publicly funded primate research centers. At Wisconsin, primate research seems homegrown.

Wisconsin’s setting is unique. The other primate centers are shielded from public view. Yerkes, Oregon, California, New England, Tulane, and Southwest are located on large acreages and more or less impossible to see from the road, while Washington presents itself as a single door along one of a labyrinth of hallways in the Magnuson Health Sciences Center (once billed as the largest area under one roof in the world.)

Wisconsin is comprised of two buildings immediately next door to a third monkey lab (Harlow) on the edge of campus. A short street bisects the center; it is sometimes possible to see monkeys being carried between the buildings. At Wisconsin, you can see people working at their desks on the ground floor of one building, although the buildings are otherwise nearly windowless.

All of the centers have closets filled with multiple USDA violations and scandal. But here too, Wisconsin is a stand out. Briefly, they lied in writing repeatedly to the county in regard to their use of protected monkeys at the county zoo; a director was involved in an abusive sex scandal with a graduate student; they paid off a veterinarian to keep quiet about the lack of medical care the monkeys were receiving; USDA inspectors discovered many instances of neglect and lack of oversight. I have detailed these and other unique features of Wisconsin elsewhere.

My observation of the industry has led me to realize that much of what they say publicly is a surreal abstraction of the truth and sometimes has little similarity to reality. I now read anything written by those associated with the Wisconsin animal labs with a skepticism born from their history of lying to the public to protect or promote their own interests.

So I was primed to doubt much in the featured article in the alumni magazine about Yoshiro Kawaoka and his research; especially because he had jut made national news by demonstrating that exposure to the reconstituted previously extinct 1918 Spanish flu quickly leads to an agonizing death in monkeys.

Since I first wrote about seeming contradictions in the article, a letter to the editor appeared in a local paper, and some behind-the-scenes correspondence has taken place between the magazine’s editors and James W. Tracy an official responsible for the university’s select agent program.

Select agents are things like germs or spores that could cause public health problems if they escaped from a laboratory.

In reply to the recent letter to the editor, [Capital Times 5/12/2007] Tracy had this to say:
Dear Editor: Melissa Tedrowe's letter regarding the work of Dr. Yoshihiro Kawaoka contains serious inaccuracies. It misrepresents not only a very important line of research intended to mitigate the effects of potential future flu pandemics, but also the processes and mechanisms in place to oversee work involving serious pathogens such as influenza.

The most serious inaccuracy is the assertion that Dr. Kawaoka's group has been conducting work on campus with live 1918 or Spanish flu virus. Dr. Kawaoka's group has indeed reconstituted the virus, but work with the live, infectious agent has not taken place on the Madison campus. That work was conducted in Canada, in high-level biosafety facilities that do not exist in Wisconsin.

The virus was first reconstituted by researchers at the U.S. Centers for Disease Control in laboratory settings a safety level below the laboratory where Dr. Kawaoka's work was performed. Dr. Kawaoka's experiments, which received considerable international publicity, are critical to understanding the nature of influenza viruses such as the 1918 virus, and insight gleaned from those experiments is already being utilized to help prepare for future flu pandemics, which will inevitably occur.

That the UW-Madison Institutional Biosafety Committee raised questions about Dr. Kawaoka's influenza work simply shows that the oversight process is vigorous and thorough. All such work undergoes scrutiny and must be approved before it is undertaken. We would be concerned if such questions were not raised.

Ms. Tedrowe also implies that the public is somehow uninformed about such work. No doubt the inspiration for her letter was the cover story about Dr. Kawaoka in the winter issues of On Wisconsin, the university's alumni publication. Sharing the important work done by Dr. Kawaoka and his colleagues with 300,000 of our closest friends seems like a good way to make this a part of public conversation.

James W. Tracy, Ph.D., Select Agent Program, University of Wisconsin-Madison
It seems to be true that some experiments with the 1918 Spanish flu were conducted in Canada at a lab with a relatively high level of biosafety and that Kawaoka was associated with them. And, it is true that the experiments received considerable international publicity. And, it is true that an article appeared in On Wisconsin. But on this scaffold of true statements, Tracy has hung a number of misleading claims.

If we were talking about most diseases, this would all be fairly academic; the university’s lies might serve to shine its image, they might serve to deflect public concern over the animals’ suffering, but they would not be putting the public at such a profound risk.

The risk associated with the 1918 Spanish flu is unlike the risks associated with any other infectious agent. Let me repeat that: The risk associated with the 1918 Spanish flu is unlike the risks associated with any other infectious agent.

When the disease first appeared, the United States government was well prepared for an epidemic. Medical experts knew that disease, at that time in history, accounted for more losses during a time of war than did the fighting itself. As the country geared up to fight the Great War, military doctors and public health experts put procedures in place that they felt would be needed when disease broke out, as they knew it would.

When the first cases showed up, quarantine was almost immediate. It is unlikely that such a rapid response would occur today.

By the time people showed any symptoms, they had been infectious for a few days and had already spread the virus. Pre-planned and vigorous quarantine had little affect on the spread of the disease.

John M. Barry, in his book The Great Influenza says:
Although the influenza pandemic stretched over two years, perhaps two-thirds of the deaths occurred in a period of twenty-four weeks, and more than half of those deaths occurred in even less time, from mid-September to early December 1918. Influenza killed more people in a year than the Black Death killed in a century; it killed more people in twenty-four weeks than AIDS has killed in twenty-four years.
Over half of those who died in the 1918 pandemic were in their 20s and 30s, in the prime of their lives, not the elderly.

Keeping in mind the government’s response to hurricane Katrina, it seems unlikely that a response to an outbreak of 1918 Spanish flu would come in time to contain it. Whether we even could contain it, even if we were ready for it, seems like a gamble that only a fool would take.

Estimates of the number of deaths cause by the epidemic vary from 20 to 100 million. This was prior to air travel and among a smaller population. The death toll today could be much higher. Betting it will be lower next time rests on an unwarranted faith in local, state, and world governments' timely and intelligent responses. Some scientists think that the world's population might now have a natural immunity to the virus. Should we test this conjecture?

Government’s wisdom regarding the 1918 Spanish flu is suspect at best. Once the epidemic ran its course, it all but completely disappeared. J. van Aken of the Research Group for Biological Weapons and Arms Control at the University of Hamburg, writes:
Recently, a team of US scientists resurrected a virus that has since been labelled 'perhaps the most effective bioweapons agent now known' (von Bubnoff, 2005). In 1918, a highly virulent strain of influenza virus killed up to 50 million people worldwide. The virus – later dubbed the Spanish Flu – killed more people than any other disease of similar duration in the history of humankind. Until last year, this virus was extinct, preserved only as small DNA fragments in victims buried in Alaskan permafrost, or in tissue specimen of the United States Armed Forces Pathology Institute. Now the full sequence of the Spanish Flu virus has been published (Taubenberger et al., 2005) and the virus itself reconstructed. It proved to be as fatal as the original….[Risks of resurrecting 1918 flu virus outweigh benefits. Heredity. 2007. 98, 1–2; published online 11 October 2006.]

So, with all these encouraging facts before us, look again at James Tracy’s letter. His main assertions are these:

“[W]ork with the live, infectious agent has not taken place on the Madison campus.”

This “work was conducted in Canada, in high-level biosafety facilities that do not exist in Wisconsin.”

The work that took place in Canada was reported in the journal Nature (the journal has been criticized for doing so): Kobasa D, Kawaoka Y. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007 Jan 18;445(7125):319-23.

But the real question is whether all the experiments leading up to this one were also conducted in the Canadian lab, and what was the nature of those that were conducted at Wisconsin?

In 2004, Kawaoka reported that inserting genes from the 1918 Spanish flu into contemporary flu viruses caused them to become deadly in mice: “these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and … resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic.” [Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature. 2004 Oct 7;431(7009):703-7.] This research probably took place in Madison.

The most telling evidence to date is the UW-Madison Institutional Biosafety Committee minutes from November 2, and December 7, 2005. On November 2, the committee reviewed Dr. Kawaoka's planned experiments, which are succinctly described: "Virulence and pathogenicity of the 1918 and reassortant strains will be tested in mice, ferrets, and NHP [nonhuman primates]."

(The minutes cited here are from the Sunshine Project's large archive of biosafety committee minutes from a large number of institutions engaged in research that could be associated with biological weapons.)

The committee minutes of December 7, 2005, indicate that the experiments were approved but stipulated that the lab should pour disinfectant down the floor drains.

Apparently, leading up to his experiments in Canada, Kawaoka was experimenting with various genetically engineered influenza viruses containing various combinations of genes from the reconstituted 1918 original. Along the way, he demonstrated that one of his designer versions was deadly to mice (Nature 2004, above.) He also uses ferrets and monkeys in his lab, as the biosafety committee minutes make clear, yet he published nothing regarding the effect of these genetic constructs on mice, ferrets or monkeys between 2004 and 2007 [Kawaoka Y. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007 Jan 18;445(7125):319-23.] The Kawaoka lab is incredibly prolific. In the same period, they published at least 45 other virology papers.

At some point between October 2004 and January 2007, he reconstituted the entire virus. It seems unlikely that Kawaoka was working in the Canadian lab for the intervening two years. The probability that much of the research was done somewhere other than in his Wisconsin lab seems low, given the committee’s approval. The anxious desire to build him a new high security lab, explained in the alumni magazine, where he can “safely” continue his research, is cause for serious concern about what is and has been going on in his present lab.

Tracy says that Kawaoka’s work with the 1918 Spanish flu was conducted in Canada because no similarly secure lab exists in Wisconsin. There is no such lab in Wisconsin, but such a lab does exist at the Wisconsin primate center’s sister facility in San Antonio (Southwest) and there are a few others scattered throughout the country.

There is also the problem associated with the university's oversight of research on animals. Tracy was not present at the November 2, or the December 7, 2005 committee meetings. Given the failure of university oversight in the Terasawa affair, there isn't much reason to believe that he is or was fully cognizant of the research taking place on campus.

Tracy makes an outlandish claim at the end of his letter when he says: “Sharing the important work done by Dr. Kawaoka and his colleagues with 300,000 of our closest friends [subscribers to On Wisconsin] seems like a good way to make this a part of public conversation.”

Public conversation about the reconstitution of the 1918 Spanish flu should have occurred prior to Kawaoka being given the go-ahead to do so. (See here, too. And here.) Public conversation should have occurred prior to the university promising to build him a new more secure lab. Telling the public what was done and decided after the fact is just more gross arrogance by university officials who seem to believe that their neighbors are too stupid to notice the spin.

The university is generally loath to entertain much public conversation about matters having to do with its animal experimentation. It is also uninterested in much discussion regarding its research into highly infectious diseases, if the NBAF meetings were a fair measure. In this instance, these two controversies -- hurting animals and conducting controversial and suspect highly dangerous infectious disease experiments -- combine to create a situation that they understandably don't want to address in depth.

2 comments:

Anonymous said...

Dear Ms. Tedrowe,

I admire your dedication to the cause of animal rights and your deep concerns about the ethical conundrums that lie at the center of many facets of modern biological research. However, many of your claims in this blog post are, at best, misinformed. I was a graduate student under Dr. Kawaoka through December, 2006, when I received my Ph.D. I am very familiar with the research that is performed in Dr. Kawaoka’s laboratory. With respect to the laboratory’s work on select agents, Dr. Kawaoka is a conscientious investigator who complies to the best of his abilities with all federal and state regulations. Instead of engaging in a complicated debate about the biology/epidemiology of the 1918 influenza virus or the fairness of such phrases as “the university’s lies”, I will directly address your comments about which I have intimate knowledge.

You state: “It seems to be true that some experiments with the 1918 Spanish flu were conducted in Canada at a lab with a relatively high level of biosafety and that Kawaoka was associated with them.”

The National Microbiology Laboratory in Winnipeg, Manitoba, Canada is not just a “relatively high level” biosafety facility. It is a modern, biosafety level 4 facility that is fully approved for the handling of select agents by the Canadian government. The Kawaoka laboratory has collaborated with the NML for several years.

You state: “But the real question is whether all the experiments leading up to this one were also conducted in the Canadian lab, and what was the nature of those that were conducted at Wisconsin? In 2004, Kawaoka reported that inserting genes from the 1918 Spanish flu into contemporary flu viruses caused them to become deadly in mice: “these highly virulent recombinant viruses expressing the 1918 viral HA could infect the entire lung and … resulted in infiltration of inflammatory cells and severe haemorrhage, hallmarks of the illness produced during the original pandemic.” [Enhanced virulence of influenza A viruses with the haemagglutinin of the 1918 pandemic virus. Nature. 2004 Oct 7;431(7009):703-7.] This research probably took place in Madison.”

ALL work involving infectious reassortent viruses with genes from the 1918 virus was performed at the NML in Winnipeg. A large portion of the work involved in these types of projects is basic molecular biology. Classical cloning technology is employed by members of the Kawaoka laboratory to construct the plasmids that encode the genes and/or genomes of various viruses, including the recombinant 1918 viruses. This work is performed on a daily basis on the Madison campus in BSL-2 conditions as is standard worldwide. Before infectious viruses can be produced, these plasmids must be combined with several other reagents, as well as mammalian cells in culture. It is this work that is performed in high-security conditions (in this case at the NML in Winnipeg). It is misleading to insinuate that the mouse experiments described in the Nature paper you reference were performed in Madison. That is simply not true.

You state: “Apparently, leading up to his experiments in Canada, Kawaoka was experimenting with various genetically engineered influenza viruses containing various combinations of genes from the reconstituted 1918 original. Along the way, he demonstrated that one of his designer versions was deadly to mice (Nature 2004, above.) He also uses ferrets and monkeys in his lab, as the biosafety committee minutes make clear, yet he published nothing regarding the effect of these genetic constructs on mice, ferrets or monkeys between 2004 and 2007 [Kawaoka Y. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007 Jan 18;445(7125):319-23.] The Kawaoka lab is incredibly prolific. In the same period, they published at least 45 other virology papers. At some point between October 2004 and January 2007, he reconstituted the entire virus. It seems unlikely that Kawaoka was working in the Canadian lab for the intervening two years. The probability that much of the research was done somewhere other than in his Wisconsin lab seems low, given the committee’s approval. The anxious desire to build him a new high security lab, explained in the alumni magazine, where he can “safely” continue his research, is cause for serious concern about what is and has been going on in his present lab.”

The Kawaoka laboratory does not do monkey work in Madison. As for your question about the gap between the 2004 and 2007 publications, you must understand that numerous mitigating factors prevented the work from being completed sooner. For example, complete sequence information from the 1918 virus was not available until 2005. Once such data is made available, it takes several months just to perform the grunt work required before actual experiments can be performed. In addition, space at the NML in Winnipeg is limited, as most of the facility is devoted to diagnostic work, so experiments requested by Dr. Kawaoka are sometimes delayed for significant periods until space becomes available. Because Dr. Kawaoka followed all safety protocols conscientiously, the research reported in the January, 2007 paper was slowed by these constraints. Finally, the new laboratory facilities being constructed in Madison will not contain a “high security lab” as you indicate. The buildings will house several BSL-3 labs, but the main UW-Madison campus already houses several BSL-3 labs. Your insinuation that Dr Kawaoka’s research should be a subject of “serious concern” is hyperbolic and conspiratorial if you cannot support such a claim with actual evidence.

You state: “Tracy makes an outlandish claim at the end of his letter when he says: ‘Sharing the important work done by Dr. Kawaoka and his colleagues with 300,000 of our closest friends [subscribers to On Wisconsin] seems like a good way to make this a part of public conversation.’ Public conversation about the reconstitution of the 1918 Spanish flu should have occurred prior to Kawaoka being given the go-ahead to do so. (See here, too. And here.) Public conversation should have occurred prior to the university promising to build him a new more secure lab. Telling the public what was done and decided after the fact is just more gross arrogance by university officials who seem to believe that their neighbors are too stupid to notice the spin.”

I fully agree with you that “public conversation about the reconstitution of the 1918 Spanish flu” is a worthy goal, and Dr. Tracy’s statement in reference to On Wisconsin is a bit silly. However, work on the 1918 virus is not just being conducted in Madison. Several laboratories across the country are studying this virus and all are receiving federal grant dollars in support of this work. In addition, as no work posing any danger to the residents of Madison has taken place in the laboratory of Dr. Kawaoka, it is unfair to propose a public debate on the grounds of safety, when the real grounds of the debate are on a larger, ethical and public policy scale. Finally, university official are certainly guilty of “gross arrogance” on many occasions. However, the public must not be left off the hook. The gross arrogance of officialdom is matched by the gross ignorance of basic science by the public. As someone who obviously cares very much about the impact of science on the public, I imagine this is a point on which we can agree.

Sincerely,
Luke D. Jasenosky
Brookline, MA

Rick Bogle said...

Luke,

Ms. Tedrowe is not the author of this blog, she was the author of a letter to the editor of a local paper.

Thank you for your response.

Your writing seems authentic to me and comes across as if written honestly.

By now, I hope you will have found the other entries associated with Kawaoka. I hope you took a look at the two IBC Closed Session Minutes I included in the orginal essay. These are here:
http://www.madisonmonkeys.com/biosafety/11-2-05.pdf

and here:

http://www.madisonmonkeys.com/biosafety/12-7-05.pdf

These documents strongly suggest a situation contrary to that which you describe, or perhaps, that you were aware of.

I'd love to read your explanations of the IBC minutes.

Again, thanks for writing.

[One thing, the university has a history of lying about matters associated with its use of animals. Check out http://www.primateresearch.com and check out the Vilas monkey affair. Once one has discovered that someone is willing to lie, and lies frequently, I think it prudent to assume that any utterance might be a lie. I think it fair to call a lie a lie.]

Rick Bogle