The AP (via The NY Times) is reporting that the Avian Flu has been confirmed as the cause of death of a young woman in Iraq. Patients displaying symptoms consistent with the flu have been admitted to local hospitals.
January 2006 Archives
Declan Butler is reporting in tomorrow's Nature that the H5N1 strains currently circulating in Turkey carry mutations, "likely to make the virus better adapted to humans." According to Dr. Butler:
The Turkey outbreak is unusual, because of the large family clusters of cases; the fact that many of those infected have only mild symptoms; and the speed with which infections have arisen — twenty cases, including four deaths, in less than two weeks. So scientists are urgently trying to establish whether the virus is behaving differently in this outbreak from previous ones in Asia. In particular, international teams are investigating the possibility that the virus is moving between people.
I speculated briefly last week about the odd behavior of the Turkey strain, and with 20 cases and 4 fatalities in two weeks, there may be reason for concern that the virus has changed its tropism to favor humans. One of the mutations, in the polymerase gene, is said to be among the ten that caused the 1918 pandemic strain to be so problematic. The other mutation is in the HA gene, which enables the virus to better target epithelial receptors in the nose and throat.
Dr. Butler reports that together these mutations may make it easier for the virus to be transmitted between humans. If this were a pandemic strain we would probably know it already. Unfortunately, human morbidity and mortality are likely the only clues we are going to have; as I've described previously, there is presently no scientific basis to predict the course of the flu. Alas, human institutions are complicating the process of gathering better data. Dr. Butler writes that:
Researchers are sequencing more strains from the Turkey cases, to see whether they share the mutations and to check for further changes. Samples were expected to arrive in London on 18 January, after being held up for more than a week in Turkey because of the Eid ul-Adha holiday period.
Given the threat, and the potential for rapid transmission beyond Turkey's borders, why didn't the WHO have a guy (or better yet, a dozen) on the ground chasing samples, with a private jet waiting to fly them to fully outfitted labs in western Europe? Or perhaps celebration of Eid prevented even the Turks from grasping how the situation was changing? In any event, I suspect we can ill afford to be without better intelligence from the field. The AP is just now reporting that Iraq is investigating a potential human death from H5N1, which occurred in a migratory flyway out of Turkey. One can only hope some of the $1.9B pledged today to fight the bird flu is spent on better surveillance.
This is an important paper. "Epidermal DNA vaccine for influenza is immunogenic in humans," is "in press" at Vaccine (PubMed), accessible online even though it is undergoing final review. The manuscript describes initial results from vaccination with a plasmid-based vaccine containing the HA domain of the H3 Panama strain. I wrote briefly about this last year.
- The vaccine appeared well tolerated, with some reaction to the physical effects of the vaccine that amounted to at most a slight rash. Standard reactions to flu vaccination were observed, including fatigue, fever, headaches. No antibodies to the double-stranded vaccine itself were detected.
- The antibody titers are as reported previously, and this paper claims, "The present study is the first successful demonstration of immunogenicity of an influenza DNA vaccine in humans."
- Increasing doses of the vaccine (up to 4 micrograms) induced increasing antibody titers, with only the largest dose meeting the 21 license requirement of the Committee for Proprietary Medical Products in the European Union. I would observe that this is still a factor of 250 lower than any intramuscular DNA vaccine up to this point, and well within doses reasonable for widespread manufacturing and inoculation. The specific antibody kinetics of vaccination with DNA are still unclear, and the authors note that, "The immune response to the DNA vaccine in humans may be qualitatively different than the response to protein vaccines." Something that requires further study, to be sure.
In addition to the speed, manufacturing, and distribution advantages of DNA vaccines over egg- or cell culture-based approaches, it should be possible to achieve vaccination against multiple strains with one shot. This could be accomplished either by including plasmids coding for multiple antigenic domains or by tailoring sequences to achieve cross-protection from the same antigen. That is, it appears careful choice of the antigenic domain can result in the production of antibodies that neutralize more than one strain of a pathogen.
Given that 1) we very likely cannot know ahead of time the sequence of the virus that results in a pandemic, 2) flu viruses have been demonstrated to escape vaccines within 12 months, and 3) traditional vaccines aren't up to the job anyway, DNA vaccines may provide a way to inoculate people against more than one strain. Because we are slowly developing the capability to monitor the virus in bird populations as well as humans (an endeavor that should have been given a much higher priority in the recent supplemental budget request), it may soon be possible to include a distribution of antigenic sequences in any given round of inoculations. This is speculative, to be sure, because there are currently no demonstrated ways of estimating which sequences are likely to be produced by mutation or recombination, but in principle we could produce vaccines effective against a whole range of pathogens, even those that have yet to appear in nature.
However, it is clear we have a lot to learn before this is possible. A recent review paper in the Japanese Journal of Infectious Disease explores, "Mechanisms of Broad Cross-Protection Provided by Influenza Virus Infection and Their Application to Vaccines."
Hmmm...I was about to write a short summary of this paper, but I'm realizing it will take a bit me longer to digest the contents and do the subject justice. So, I'll post again on cross-protection and the flu when I have a better grasp of it.
I've resisted writing about Hwang Woo Suk's fraudulent paper in Science about producing patient specific stem cells. It just isn't really that big a deal. A guy who claimed proficiency with chopsticks was directly correlated with producing cutting edge science -- surprise! -- turned out to be not so credible. He was found out. Science wins. Science will always win, eventually.
Yet the affair provides an interesting context for thinking about the tenuous standing of cutting edge science. Uncovering the fraud is frustrating to those waiting for cures for disease or injury, annoying to those waiting for life extension technologies, and disappointing to almost everyone for whom scientific inquiry is the closest approximation to a pursuit of truth; all true. But guess what? Science is a human institution, practiced by humans with all of their faults. It is simply inevitable that those faults affect scientific results and publications.
But what distinguishes science from other human institutions, notably politics, religion, and business, which have all experienced extraordinary fraud and malfeasance recently in the U.S., is that fundamentally science finds its foundations in the physical world. The progress of science, and its authority, are tied to what is measurable. Moreover, those measurements must be repeatable. That is, a result must be testable and verifiable by others to become accepted. True, uncovering the Hwang fraud took almost two years, but Hwang's fall was inevitable because the requirement for repeatability means that science is self-correcting. It happens that the holes in the original Science paper appeared not because of questions emerging from labs trying to repeat the work, but rather from suspicious aspects of the paper itself, such different figures of supposedly different cell lines containing similar images.
The scrutiny of these images and other details of the paper applied by scientists within South Korea, fed by suspicion of the great height to which Hwang aspired, only strengthens the process of science. We didn't actually have to wait for the results of long and laborious experiments, nor did we have to spend money to repeat Hwang's work. The fraud fell apart under its own weight. This is a success.
I, like every other practicing scientist, have to wonder how this episode will affect the public perception of science. I come to the conclusion that the airing of dirty laundry will only improve the position of science in the long run. There is no other human institution so ruthless in chopping out the dead wood. After all, if you are lying or pulling a fast one, the very last thing you want to do is get a bunch of really smart people trying to catch you out, all of whose professional standing improves if they do.
The public perception of all this is complicated slightly by the fact that there is a difference between the science you read in textbooks, and the science reported in journals or on the front page of newspapers and news magazines. In today's New York Times, Nicholas Wade has a very nice article exploring this issue, prompted by the stem cell fraud:
The contrast between the fallibility of Dr. Hwang's claims and the general solidity of scientific knowledge arises from the existence of two kinds of science - a distinction that is often blurred when new advances are reported first by scientific journals and then by the news media. There is textbook science and frontier science, and the two types carry quite different expiration dates.
Textbook science is material that has stood the test of time and can be largely relied upon. It may include findings made just a few years ago, but which have been reasonably well confirmed by other laboratories.
Science from the frontiers of knowledge, on the other hand, is wild, untamed and often either wrong or irrelevant to future research. A few years after they are published, most scientific papers are never cited again.
I find this latter point the most problematic of the scientific enterprise. Of the papers with short lifetimes, some are not read or cited because they aren't very good or very interesting, some are only minor improvements on previous work, and some fall by the wayside because they describe dead ends. In all cases, very little science that gets done, and even less that is finally reported in journals, actually affects the world in a meaningful way. How can you not feel a bit ambivalent about this? Isn't this emblematic of some sort of waste, inefficiency, or a Proxmire-attracting, willful misappropriation of funds? Emphatically not! This is a cost we must bear as part of the never-ending effort to banish our ignorance and improve the human condition. At both the institutional and the personal level this cost is intrinsic to science. Every scientist, and every technologist and inventor, for that matter, has plentiful experience with choosing the wrong path. Alas, the dominant social structures governing funding decisions and career advancement are based predominantly on the number of papers published, rather than upon their content, which means that often the wrong path, the marginal improvement, and the simply boring result in the lab are gussied up for publication to look far more significant that they really are.
The only real defense against this profusion of craptastic papers is the choice of individuals not to write and publish them. So I have little hope of progress there. Enough said about that.
A weaker, but necessary, defense lies in peer review. In lieu of the sudden popularity of all scientists becoming harsh and discerning critics of our own efforts, we must all keep watch on science as a whole, trying to catch mistakes and fraud before publication. Yet this process, too, is far from perfect. Too many anonymous reviewers have political reasons for rejecting papers, and many more just don't do a good job of reading the paper they are judging. I don't really have a solution to this problem, but I have to wonder if removing anonymity from the review process would clean things up. Yes, you would have the problem that younger scientists reviewing the work of their elders would be exposed to wrath from above. But what we have now definitely needs improvement. Witness the Hwang paper.
Mr. Wade explores the notion of improving the quality of papers through requiring authors to state their contributions to a paper, and by requiring all authors to state their explicit agreement with all conclusions in a paper. I don't have any problems with the latter, but I can say from personal experience that writing an author contribution statement can be extraordinarily painful, a struggle to carve out sufficient acknowledgments of your own efforts and give perspective on another's efforts, particularly when control of the text lies with someone else. Still, it's worth a try. And I support the inclusion of author's contributions for the time being.
Alas, this doesn't help with the review process itself, because it doesn't do anything about biases or laziness of reviewers. Mr. Wade thus incorrectly suggests that clarifying the author's roles in research has anything to do with the decision-making process during review at a journal. Nonetheless, save conflation of the review process with writing and attribution, his conclusion is right on the money:
Tightening up the reviewing system may remove some faults but will not erase the inescapable gap between textbook science and frontier science. A more effective protection against being surprised by the likes of Dr. Hwang might be for journalists to recognize that journals like Science and Nature do not, and cannot, publish scientific truths. They publish roughly screened scientific claims, which may or may not turn out to be true.
And thus we must labor on, and through those labors attempt to keep science honest and thereby produce a better world. Science will always win, eventually.
I've just been playing with the Google Earth mashup of 1800 avian flu outbreaks from the last two years, constructed by Declan Butler for Nature. Jamais Cascio has a good write up of the thing over at WorldChanging.
Butler describes the challenges of producing the mashup on his blog (link at WorldChanging). I think the most interesting part might be his difficulty in acquiring data sets that played well together. Each agency may use a different format, and require specific individual permission to access the detailed data, making production of a unified data set rather a pain. Let alone trying to make sure the data is actually comparable between sets, is represented using the same system of units, etc. Obviously an area of improvement for collaboration and cooperation to improve our understanding of influenza, and for getting sufficient information to make policy decisions within goverments and corporations. But a challenge for the moment.
Bravo to Dr. Butler for making as much progress as he did.
CNN is reporting that infection with an avian flu strain has resulted in the death of a 3rd child in Turkey. The three siblings evidently contracted the virus from sick poultry, domesticated chickens that had been killed and cooked after falling ill. The WHO is still waiting for confirmation on whether the strain is H5N1.
The simple explanation for the appearance in Turkey of H5N1 is transmission by migratory birds. However, a recent AP story by Andrew Bridges suggests that, "Avian Flu [is] Not Spread by Bird Migration" (at LiveScience):
Bird flu appears more likely to wing its away around the globe by plane than by migrating birds. Scientists have been unable to link the spread of the virus to migratory patterns, suggesting that the thousands of wild birds that have died, primarily waterfowl and shore birds, are not primary transmitters of bird flu.
If that holds true, it would suggest that shipments of domestic chickens, ducks and other poultry represents a far greater threat than does the movement of wild birds on the wing.
...Reports this summer and fall of the spread of the H5N1 strain strongly suggested wild birds were carrying the disease outward from Asia as they followed migration patterns that crisscross the Earth. The timing and location of outbreaks in western China, Russia, Romania, Turkey and Croatia seemed to point to wild birds en route to winter grounds.
Since the early fall, however, there have been only scattered reports of more outbreaks. The disease has been glaringly absent, for example, from western Europe and the Nile delta, where many presumed it would crop up as migrating birds returned to winter roosts.
...That has made increasing the understanding of the migratory routes followed by birds more important than ever. It also draws attention to how little is still known about the routes.
This last point is the most important observation of the whole article. We simply don't know enough about the virus or its wild reservoir, and we definitely aren't spending enough to remedy our ignorance.
But assume for a moment the virus now killing people in Turkey is H5N1, then here's the thing: if the virus is spread more by human travel or by shipments of birds, as Mr. Bridges' article suggests, how the hell did it wind up in a relatively remote village in Turkey? Is there sufficient poultry trade or human travel between southeastern Anatolia and SE Asia to serve as a conduit for an avian influenza virus? This trade and travel must be only a small fraction of that between SE Asia and North America, Europe, and Japan.
This means that either the virus "got lucky" this time, based on whatever trade and travel does exist between SE Asia and Anatolia, or that the virus is much easier to spread than we now believe. But if it is really spread mostly by human action, then it should be all over the globe by now, or it soon will be. Which leads me to suspect that migratory birds are in fact the vector, and that we need to do a much better job of understanding the virus in the wild.
A potential reason why the virus has not spread as much as feared this year can be found in an article by Howard Markel in the last Week in Review section of The New York Times. In a short piece entitled, "If the Avian Flu Hasn’t Hit, Here’s Why. Maybe.", Dr. Markel, a professor of pediatrics and communicable diseases at the University of Michigan, suggests that, "Wild birds have completed their seasonal migration, and it appears that the United States has dodged the avian flu threat for now. The pattern of the semiannual migration itself provides some protection."
The article is accompanied by a graphic illustrating the mostly north-south orientation of migratory pathways. Dr. Markel's hypothesis is that because there is very little east-west overlap of flyways, there is only a small chance every year for the virus to be transmitted to birds in adjacent flyways.
I think we don't have the geographical/migration data to be so confident about the boundaries of flyways. All those charts have a very "drawn by hand" feel to them. Moreover, this is just one component of our ignorance. Thus while Dr. Markel may well be correct, it is quite difficult to presently sort out the effects of species tropism from geographical distribution and spread. Then there is all of our ignorance about the basic molecular biology of the virus, and whether this is the big one or not, about which I have written many posts.
Dr. Markel concludes, "It is possible that avian flu may never pose an epidemic threat to humans. But for now, the best way to reduce the danger is to keep watching the birds."
Here is Carolyn Abraham's article about Synthetic Biology from the Toronto Globe and Mail, "Playing God in Running Shoes (subscription required to get past the first page)." Full text here, no subscription required. Note: I'm not a professor at the UW, as suggested in the article, but rather a senior scientist in the Electrical Engineering Department. Otherwise, a fine article that goes into not just the technical difficulty inherent in building new organisms but also explores ethical implications of the whole endeavor. I'm not so sure, though, how Drew Endy is going to feel about being described in the story title that way...