Forum: H 5 N 1 Evolving Towards Pandemic Strain

There has been much discussion as to whether sequence data indicates that H5N1 is getting closer to a pandemic strain. A paper I recently read removes any question of this in my mind. It appeared in the journal Science as an express article on March 16 2006.

The paper is: Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus.

by Stevens J, Blixt O, Tumpey TM, Taubenberger JK, Paulson JC, Wilson IA.

the link takes you to the abstract. You need a subscription to read the whole article. If you have one, don’t forget to get the Supporting Online Material. Alignments are there

Some relevant quotes:

“The hemagglutinin (HA) structure at 2.9 angstrom resolution, from a highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA”

The 3D structure of a protein is the best indicator of its function. This means that the HA protein of H5N1 has changed significantly since 1997 and is now more similar in function to the 1918 strain than it is the original H5N1 strain that emmerged in 1997.

“…mutations that can convert avian H2 and H3 HAs to human receptor specificity, when inserted onto the Viet04 H5 HA framework, permitted binding to a natural human alpha2–6 glycan that suggests a path for this H5N1 virus to gain a foothold in the human population.”

This addresses the question as to whether its possible for H5N1 to become a pandemic strain. We now know the answer to this question is likely yes.

I cannot overstate the importance of this paper. My threat level has gone way up since reading it. Although I’m not quite ready to say a severe pandemic is inevitable, I’m getting close to that.

I have been wanting a thread on this report. Does it look like the tests imply that there needs to be a H2 and H3 transmutation because H5 and H1 won’t work? If so, does that have to happen in swine, or in a “sick with both virus” person?

I just wanted to remind everyone, if you don’t have access to Science call your local public library and they should be able to help. If they can’t assist you, try your local public university library. Most are open to the public and should be willing to let you have a look at the print jounral if you visit the library.

/end librarian mode

NJ. Preppie. They generated a panel of mutants to see which sequences would be mostly likely to result in binding to human alpha2–6 glycan which, as you know, is thought to be necessary for efficient transmission of an influenza virus in humans.

Another quote which addresses your question:

“Our conclusion is that the mutations that cause a shift from avian type to human type specificity on the H1 and H3 frameworks do not cause an equivalent shift in specificity on the H5 framework of the Viet04 isolate. However, the mutations that give rise to alpha2–6 specificity in H3 HAs do in fact reduce avidity to alpha2–3 sialosides, and increases specificity for alpha2–6 linked biantennary N-linked glycans that could serve as receptors for the virus on lung epithelial cells. These combined effects could allow the Viet04 virus to escape entrapment by mucins, and increase the likelihood of binding to and infection of susceptible epithelial cells.”

The bottomline is that the virus isolated in 2004 in Vietnam did not yet have all the necessary changes for efficient H2H transmission. However, the mutations that shifted H3 from avian to human hosts might also shift H5 from avian to human. Only two mutations were necessary to make avian H3 a human adapted virus.

Now, wouldn’t it be nice to know what the HA sequence is from the H5N1 virus isolated in 2006 from patients in Turkey? Oh wait, I forgot, those are locked up in a secret WHO database.

Monotreme - I commented yesterday that I thought by using an 2004 virus that we are behind the curve, so to speak, and that the only way to see how this info applies is to look at all the current sequences so scientists can asses the virus as it looks today. While 2004 virus info is important and helpful, the strains cirulating now are the threat and we need to be able to see what changes they have undergone. Yes?

Even more urgent need for all sequences to be released for analysis.

P.S. Your interpretation of the article was much more helpful than the one posted yesterday. Thanks much.

The Webster paper citing NS protein as another major factor needs to be added. The point is that it isn’t just HA, and that there are many paths to pandemic, nit just following 1918 or 1957 or 1968.

But anything that mimics 1918 is of note. So is any paper by Webster or Taubenberger.

This CE thread includes some reposting of the subscriber-only material.

Montanan: Thanks for your kind words. You’re right about us being behind the curve as to how close we are to a pandemic, at least the general public (and most scientists!). When Leavitt says he doesn’t have inside information, can that really be true? Doesn’t he, or whomever advises him, have access to the secret WHO database? If not, we are in deep, deep trouble.

DemFromCT: Its true that mutations in multiple genes are necessary for a pandemic. However, H5N1 has already demonstrated an ability to infect, replicate in and cause severe pathology in humans. The mutations necessary for it do all of these things, and there were probably many, have already been acquired. The only thing it lacks now is the ability to be transmitted efficiently, human to human. I think once it gets into respiratory droplets, that’s the ballgame. The question is: how many mutations does it need to do that? My hunch, not many.

Dem, Do you personally share Monotreme’s feeling that the risk of pandemic just went up in her mind. Do you share her feeling personally that it now seems inevitable? As a public health professional I respect your “feelings” and “intuition” as I also repect the personal opinions of Dr. Robert Webster. Thanks!

BTW, I have created an Opinion page called Blocking Sequence Data is Harmful to Our Health derived from a thread I started on Feb 26.

Thank you, Momotreme, as I didn’t have the report, just press releases to read. So,(H3) happened to be what worked for them in the lab, but H5 could make a drift to different receptors and still be called H5? Now, the argument- is this more likely through random mutations, transmutation, or smaller “Niman” recomination? Can this happen inside the human body, without looking for the pieces in other hosts? I was reading this report, (a few snips below) which Taubenbourg was a part of, saying the 1918 pandemic virus wasn’t a straight jump from bird to man. I had mistakenly heard wrong before about that. Yet, it doesn’t look like they know how the H1N1 got made. Is there anymore explanation that you can provide?

http://tinyurl.com/r7s8z

Journal of Virology, August 2002 Armed Forces Institute of Pathology,

Thomas G. Fanning,1* Richar d D. Slemons,2 Ann H. Reid,1 Thomas A. Janczewski,1 James Dean,3 and Jeffery K. Taubenberger1 - “1917 Avian Influenza Virus Sequences Suggest that the 1918 Pandemic Virus Did Not Acquire Its Hemagglutinin Directly from Birds.”

[….Phylogenetic analyses, however, placed the 1918 HA gene within the mammalian clade, suggesting that the 1918 HA had acquired many changes that distinguished it from avian sequences ….. Phylogenetic analyses of the partial 1917 goose HA sequence demonstrate that it falls within the avian branch of the tree (Fig. 1), while the 1918 pandemic viral sequences are clearly mammalian,…….. The 1918 pandemic viral HA sequences had more changes from a typical avian sequence than was true for the 1957 and 1968 HA genes. Whether these changes accumulated during an indefinite amount of time undetected in another mammalian host cannot be determined from the present data. However, the 1917 avian HA sequence strongly supports the hypothesis that the 1918 influenza virus strain did not acquire its HA segment from a bird immediately before the pandemic.]

Monotreme: what is your background? I find your comments interesting and wonder in what discipline you were trained?

InterestedReader – at 10:43

He’s a rock star with an H5N1 hobby ;-)

Worried in the city – at 10:33

I would neither characterize myself as a public health professional (that’s the reveres) nor Montotreme as a ‘she’, though that’s not clear from the picture. But the issue is whether Taubenberger is more worried, not me or ‘treme. A Science article doesn’t say. I think it’s a mistake to look at 1918 and follow the H5N1 virus looking only for parallels. They’re very important clues to understand what’s happening (then and now!), but it may be that H5N1 is unique enough to make its own way.

NJ. Preppie – at 10:38

What Taubenberger said is that 1918 was an avian flu, but we don’t know which species it was from. He looked at known 1917 avian virues and can’t find the exact bird it came from. Again, it highlights what we don’t know about 1918.

And that it might not have jumped directly to humans, or we can’t show that it did.

NJ. Preppie: Your welcome. Not sure I can answer all your questions, but I’ll give it a shot. H5N1 can remain H5N1 even after it shifts to a “human” virus. There was an avian H3 before there was a human H3. All influenza viruses come from birds. How viruses change is very controversial, at least on bird flu fora ;-). The party line is that most changes occur through random mutation of nucleotides due to a sloppy polymerase. Viruses can also swap genes through reassortment. In some cases, viruses swap parts of genes through recombination. Most scientists think mutation is the source of most changes. Dr. Niman is a contrarian in that he believes recombination is the major driver of viral evolution. I think its safe to say that all three mechanisms occur and that it would be helpful to have more sequence information to determine the frequency. If/when H5N1 goes pandemic, how will it acquire the necessary changes? I don’t know, but monitoring sequences in real time may give us a head’s up. Too bad we’re being blocked from doing this.

Previously, I read too, that 1918 was more like an avian virus than the 1957, and 1968 pandemics, which had milder swine/human assortments. I thought the 1918 was more of an avain type virus. This quote says the opposite, does it not-

“The 1918 pandemic viral HA sequences had more changes from a typical avian sequence than was true for the 1957 and 1968 HA genes.”

I’m not assuming a repeat of the process, but understanding an important past example, helps to understand where the differences lie with the stage of this virus.

Something I’ve been wondering about, and was itching to ask Dr. Niman about during the conference call (but didn’t out of concern for time constraints) was this:

To what extent does all the focus on receptor binding specificities have to do with the fact that this is one area of the genome we have a decent grip on, as far as what the changes actually do? I mean, we know that receptor binding is important for pathogenicity and transmissibility, but we don’t know that they are all-important, do we? This is something we can test; is our focus on it therefore like the guy looking under the streetlamp for his lost car keys because the light is better?

Montanan – at 10:12

Your comment “P.S. Your interpretation of the article was much more helpful than the one posted yesterday” is interesting as is implies you agree with Monotreme’s conclusion. However when you read an interview in which one of the scientist from the article in question inferred that the virus was NOT easily converted to H2H it is disputed. Since 1997 there is not one shred of evidence that the virus is any closer to H2H. In fact the study in question indicates there may be a barrier to H2H. It killed people in 1997 and it kills people today. Nine years later still no pandemic. This board is tiresome as it is overwhelmingly clear most folks will not look at any viewpoint other than there is pandemic around the corner.

BP – at 13:01

As to tiresome I can’t say, but as to different points of view, not so! Check out Tram and the vietnam thread, for instance.

I, for one, much appreciate your posts. Taubenberger, btw, has been a bit skeptical of H5N1 being the Big One, but like most of the H5N1 skeptics, he believes it’s good to prepare and to continue our monitoring.

BP: I really don’t understand your point of view. Paper after paper has shown that H5N1 is evolving into a more dangerous virus. You and Tram simply ignore them. The post that started this thread states:

“…highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA”

The HA protein from an H5N1 virus from a patient in Vietnam in 2004 has a 3D structure more similar to the 1918 virus than the 1997 H5N1 virus isolated from a duck. I really can’t make this any more clear without insulting readers’ intelligence.

DemFromCT: Please check out this thread again: Dr Taubenberger Speaks. He speaks for himself on 17 February 2006 quite clearly. Why did he change his mind and become more of a pessimist? The discoveries outlined in the paper I cite in my first post are the reason why, IMO.

I appreciate your efforts in moderating the extremes, but BP, Tram, Marc Siegel, Wendy Orent and the others who say H5N1 has not become more dangerous and I and the others who think H5N1 is getting more dangerous can’t both be right. Nor is the truth somewhere in the middle. Either the virus has gotten more dangerous since 1997 or it hasn’t. I say it has.

I, as surely many, find it extremely difficult to follow the information and analyses of Monotreme, Dem, NJ, Racter. In truth, I have had to read and reread to at all follow detail, though the main weight and direction are fairly evident.

BP at 13:01, however, is far less cogent, far more emotional. Sweeping conclusion with inadequate basis? Admittedly, the post is brief, may need development—the which I await and probably not all alone, either….

Nikolai---Sydney, please read this article: 1918 Spanish Flu Holds Clues to Future Pandemics

It seems pretty clear to me, but if its not, let me know.

One thing neither I nor many others will have to puzzle over is BP—at 13:01 when he says “…it is overwhelmingly clear most folks will not look at any viewpoint other than there is a pandemic around the corner.”

Firstly, it seems indisputable, evidential, that the general bent is to seek all possible support that H5N1 is NOT hell- bent on becoming pandemic.

Secondly, the thought effortlessly occurs that ‘some folks will not look at any viewpoint other than there is NO panflu just around the corner—indeed there is no nearby corner’.

Although there are issues that remain on how H5N1 evolves 9and I am doing a few commentaries which should put the “random mutations” pillar in the garbage where it belongs, the fact that H5N1 is becoming more dangerous is pretty easy to see based on almost every applicable metric.

More recent H5N1 isolates from Asia more frequently can grow in mice (a mammal). More infected mammals are being report (domest and wild cats as well as dogs , civet cats, and a stone martin.

However the spread of H5N1 has been dramatic after it moved into long rane migratory birds in the spring of 2005. It is clear to anyone paying attention that it will soon be present worldwide.

Conformed cases in humans by country also shows the growth: 1997 Hong Kong 2003 Hong Kong (Fujian province) 2004 Vietnam, Thailand 2005 Cambodia, Indonesia, China 2006 Turkey, Iraq, Azerbaijan, Egypt

Monotreme—at 13:50:

I just read the VoA citation, 17 Feb 06 by Bertel, and then three times more. Puzzled. Not at all what I expected, as a fairly long-time student on this site.

It is very elementary—but effective and convincingly good for the casual layperson. I take it your request for feedback is intention to distribute it for public awareness?

Need I fear you think I need further grounding at that level?

<grin>

Re: niman—at 14:09:

As mammals, do Spoll’s play any part in the development of this threat? Or do I misunderstand utterly?

‘’‘“…highly pathogenic Vietnamese H5N1 influenza virus, is more related to the 1918 and other human H1 HAs than to a 1997 duck H5 HA”

The HA protein from an H5N1 virus from a patient in Vietnam in 2004 has a 3D structure more similar to the 1918 virus than the 1997 H5N1 virus isolated from a duck. I really can’t make this any more clear without insulting readers’ intelligence. ‘’‘


I don’t know, which duck he means here, but Vietnamese H5N1 is not much related to 1918 H1. Even if he found some duck which is even less related, there are lots of differences in H5 and H1.

While the experts may quarrel over probabilities, I for one believe that the fact that there is such debate indicates the danger in and of itself. It is obvious that no one can prove H5N1 is incapable of becoming easily transmissible from person to person. Do that and I’ll start living off off the tuna and dried milk under my bed (Yech). Until that point discuss until you are red in the face but be sure and post your definitive argument to this forum with proof so we can all stand down.

H5N1 can evole into a virus more geographically spread (it’s happened and will happen -birds or smugglers, either way) and it can be more widely spread within different species (cats, dogs and stone martens, and maybe a few others - it’s happened and likely will happen). It’s already a dangerous situation, and Taubenberger describes it as “worrisome”. Now, that is a description I’ve used a thousand times.

It still, however, is very diificult for humans to catch. When they do, they become very ill. The implicit message of this thread and the Taubenberger article is that H5N1 can take steps to make it more 1918-like. And therefore, more pandemic-like.

Whether it’s an inevitable path, that’s something I would dispute. Not because I know it won’t, but because I don’t know it will. No proof either way. So a prudent person would prep and plan for the worst, but not assume the worst.

Dem, I would agree - prepare for the worst and don’t “hope” for the best - expect it.

I just wanted to discuss the meaning of the Taubengerger reports as is, without a prediction argument. Understanding virology evolution, like the rest of “evolution” is based on studying the past, - because you can’t study the future. Evolution is still challenged to be proved in some iron clad way, by those who don’t accept the volume of hindsight. I’m interested in how the receptors can eventually come up with the key to pick our lock. This is an unfolding mystery novel, where we try pick from a cast of suspects, red herrings, and clues; but I don’t believe that all the hindsight will give us any certain foresight. We will keep learning as we go.

Racter – at 13:01

We do focus on the items of interest where we have the most knowledge and that is a limiting factor. Basic research like gs is doing and Niman is interpreting is much more important than ONLY pursuing human receptor affinity studies. the permutations required to go PF51 are unknown and may be one change or 17 across 8 gene segments.

GS-

The HA indicated in the study refers to the expression of the genetic sequence, the folding of the protein (shape), not necessarily to the nucleotidal matching.

yes, I see.And probably only the ctitical binding area. There are some snippets at curevents. The HA’s are still very much different, even if there are some similarities in the 3d-shape. Can we have the whole article please ? Or is there some database with secret articles, where only 15people have access ? ;-)

gs, I’ll send it to you.

Nikolai---Sydney: I referred you to the VOA article because it was clearly written, better than I can do. And I do think its a good article to refer laypeople to. However, I do know that your understanding of H5N1 is much better than most :-)

NS1: Taubenberger and colleagues are doing more than studying HA receptor binding affinity (although this is extremely important work), they have also done work on the polymerase genes. Taubenberger and colleagues also resurrected the 1918 virus.

As regards sequence vs 3D structure, the paper cited discussed both alignments and 3D structure. The latter is actually much more important than sequence. This is due to the protein folding problem. We cannot predict we complete confidence the final shape of a protein based on sequence alone. That’s unfortunate because its the shape of a protein that determines its function, not its sequence, per se. Sequencing nucleotides and doing alignments is extremely easy as compared to protein crystallography, but the latter is much more important than the former. The reason is that two proteins may have very similar sequences but different shapes. Two different proteins may have sequences that differ quite a bit, but which have very similar shapes. Because shape determines function for proteins, this means that simple sequence alignments can be misleading with reference to function. Or, to put it another way, there is more than one way to skin a cat.

gs: I would gladly type in the entire Science article and upload the alignments from the online material, but Melanie would have to agree to jail time for copyright infringments first ;-) Or you could subscribe to Science. Which is the lesser of two evils?

BP – at 13:01 “However when you read an interview in which one of the scientist from the article in question inferred that the virus was NOT easily converted to H2H it is disputed.” I don’t dispute this, but don’t think that a 2004 virus will accurately tell us what a 2006 virus looks like and until the scientists have the sequences and access to the data, I think it is “old” news and not applicable to the virus as it exists today.

Do I agree with Monotreme? sometimes, do I think H5N1 WILL be the pandemic flu of tomorrow - don’t know. Do I think a pandemic will come sometime in my lifetime? Absolutely. Whatever, protocols on data sharing that are forged today may save our lives tomorrow.

The commentary on H1 PB2 sequneces in Candaian swine show why acces to the H5N1 sequences in the WHO sequestered database is critical. The swine paper has sequences that destroy the concept of H5N1 evolution by random mutation. This concept is fataly flawed and refuted absolutely by real sequnece data. Although the data shows VERY clear recombination in all 7 PB2 and PA sequences, the authors (on the dirty thrity list) only talk about reassortment in the peer reviewed publication

http://www.recombinomics.com/News/03180602/H1_Recombination_Swine_PB2_More.html

The really don’t know how to analyze the sequences they gemnerate, and this is true for virtually all of the WHO consultants who have access to the database.

It is literally the blind leading the blind, who insist the earth really is flat as judged by their peers in the flat earth society.

Monotreme-

Just notating a specific mention by gs on the isolates’ similarity / differences morphologically (expression) v. mathematically (blueprinting / sequencing).

Been following J.Tau and company since late 1990′s.

I’d like to certify that they did NOT exactly resurrect the 1918 virus. Via some fantastic collaboration, J.Tau and Co. DID locate specimens, tease sequences out of the limited specimen material and CREATE in the lab a handmade, piece-by-piece, Frankenstein version of our best guess on the 1918 virus. Their creation DOES approximate all of the expected characteristics of the 1918 virus, but is NOT the original or even a clone, if I understand correctly?

Please respond with clarification if you have additional info.

Thanks for the straightforward example on protein crystallography for the readers.

For illustration purposes, would you consider supplying a few examples on the science page with:

• Sequences similar and Proteins different
• Sequences different and Proteins similar
• Proteins with identical primary structure conformation and Functions different
  • P_RP^C v. P_RP^Sc

Would you mind also discussing the non-binary nature of RNA expressions, so that the readers may understand the complexity of the outcomes and the magnetism of certain shapes to the surrounding protein expressions?

NS1: I second your motion that Monotreme give a tutorial on the given topics.

Monotreme at 18:31: Your explanation above was excellent and illuminating.

Henry-

Great commentary. Bread and butter science. Will this open their eyes?

I especially appreciate your forthrightly discounting their most certain argument of your work, differential evolution!

Yes, they used differential evolution to expalin away the recombination in HA of the 1918 strain. Their argument was simply hand waving, but was bought by most influenza or in the words of one of most published “no one believes the recombination”.

The latest swine sequences destroys the differential evolution argument or species adaptation nonsense because in most of the islates most of the recombined portion from the 1977 was eliminated. However, in two of the isolates, the “dispensible” region is copied with absolute fidelity for 26 years!

The commentary on the PA sequences will again be a dagger in the heart because for PA six of the seven have the 1997 Tennessee gene, but each is a different size and again the sequence is EXACT. Four of the sequences have over 1000 BP each of IDENTITY.

Remarkably, the seventh gene has signifiant identity with a 1931 swine isolate, so those regions have been conserved for over 70 YEARS!

Over a long time period random mutations have an evolutionary role. but in the year to year chnages, it is almost all HOMOLOGOUS RECOMBINATION.

NS1: You are correct that Tabenberger et al re-created the 1918 virus by painstakingly obtaining the sequence (most of it anyways) and then using this information to re-create it in the lab.

I’ll add your suggested tutorials to my list of things to do, but I’m afraid I’m already behind in my other “chores”: Cluster page, Sequences of viruses isolated from humans page, Animals shown to be infected by H5N1 page, Country pages, etc.

Also, I’m afraid I didn’t understand your last paragraph at 21:36. I’m a dull molecular biologist who understands only prose. Your haiku-like poetry is sometimes over my head. Were you asking me to explain homologous recombination, or something else?

Medical Maven: Thanks!

I’ll take this opportunity to once again acknowledge how much I have learned from your posts and those of many others here. No-one knows everything about preparing for a pandemic. We all contribute what we can.

Look folks I don’t know a protein structure on a virus from a buckyball, however it sometimes APPEARS to me some here are not looking at the big picture. I am not going to go into my arguments again. I will say I have prepared and have done so for more than a year. It is the only prudent thing to do. However, recently I have read the following comments from experts: “virus has been stable for awhile now”, “the virus would have gone pandemic by now if it were going to” and “there may be a barrier that prevents it from going efficiently H2H”. I like these comments, as they are good news (maybe). Let’s hope H5N1 is marching to oblivion. I would like to apologize for my earlier somewhat strident comments.

A map of H5N1 infections makes it abundantly clear that H5N1 is NOT marching toward oblivion. H5N1 will be worldwide within 12 months, at the outside.

There are lots of fairy tales out there.

The H5N1 spread is quite clear and there are no signs of “oblivion” (at least not for H5n1) any time soon.

Question for Niman and others…

Which upcoming events do you think will pose a critical moment in the potential restructuring of the H5N1 genome to be able to go easily to humans or H2H and why?

i.e. H5N1 through wild birds or poultry coming into contact with North American swine, European swine, Asian swine, or other mammals and recombinations occurring with endemic H3N2 or H1N1 strains… or person X in (name country of concern) has another virus that helps H5N1 morph into ability to go H2H…

-and based on these possibilities, the timeline of windows of possibility of the event occurring…

i.e. H5N1 could be transformed this spring in Europe, this fall in North America, winter/spring 07 in South America or Australia, etc.

BP: No-one can say for sure whether H5N1 will become a pandemic strain or how bad it will be. All we can do is look at the available evidence and give our opinions. Nothing wrong with you disagreeing with me or anyone else. People can read the debates here and make up their own minds.

I’m glad you’re not against prepping. That’s the most important issue, really.

btw, I am desperately hoping to be wrong. I want someone to point out the flaws in my logic. But each scientific paper I read and each report of new clusters of people who have gotten infected makes me more pessimistic. Nonetheless, I am still rooting for you and Tram to be right.

BP – at 22:37

Folks like you keep us from groupthink. Thanks for sticking around. So let’s take the arguments:

“virus has been stable for awhile now” was true from 1997 to 2004. But between October 2005 and March 2006 it managed to spread all over the world (literally) while everyone was watching for it and trying to prevent it from happening. Go figure. So what happens next?

The trouble with the “virus would have gone pandemic by now if it were going to” idea is that it is only proven in retrospect. The H5N1 virus otoh, was not ‘expected’ to infect cats, dogs and stone martens until it did. And the “would have gone inter-species by now if it were going to” argument (had it also been made) would have been true… until it did.

As to “there may be a barrier that prevents it from going efficiently H2H”, there most certainly is. But barriers can be overcome. And the discussion today revolves around how it might happen.

The good news is that it is currently very difficult to catch this virus if you’re a human. The bad news may be in the future, or it may not. But past performance is no guarantee of future earnings, as they say on Wall Street.

BP-

Conventional wisdom has always said all of the comments that you’ve mentioned.

Now that the facts are showing potential pandemic, some of the conventional crowd are noting that there is a possibility, but they are mostly standing in the camp of abject dishonestyy saying that H5N1 is not H2H at this time. The bimodal distribution of dozens of clusters (familial and occupational) clearly indicated H2H at this time, perhaps not sustained, efficient H2H. As you may recall, the WHO continues to re-define the communication parameters of H2H.

If we follow the sequence changes, then it is clear that Niman’s concept of recombination occurs and is a potent description of viral genetic acquisition behaviour. We are missing most of the important sequences. Why they are being withheld is apparently an issue too sober to be answered?

Emerging pathogens are ‘jumping’ the so-called species barriers on a grand scale. If we were to graph a count of emerging pathogens in the last ten years, I’d venture a guess that more than 50% would have originated in animals that are were NOT considered to be incubators of human-infective diseases. We all need to expand our RADAR to encompass some new foundational concepts. Recombination is at the forefront of my present concerns.

TIG-

All of the above.

I know that’s a silly answer with low specificity. Dr. Niman will, in time, provide more detail as he’s allowed more data. You’ve hit the nail on the head with your scenarios. Your ordering is similar to the way I would order the potentials. We could have a number of independent wildfires and then one large wave or one large wave and then wildfires of recombinants for 2–3 years.

Please keep studying and tell us where you see any failures in our logic.

NS1…thankyou :)

Monotreme-

If your blade is dull, what could we call the rest of us, flat?

Thank you for your tireless aggregation of these lengthly threads into digestible portions.

I only asked about those particular examples because I thought that you might have some specific sequences in mind when you began mentioning sequence v. shape v. function. I felt that it would be instructive if we showed examples bounding the characteristics you were mentioning.

• 2 similar sequences with different protein shapes
• 2 different sequences with similar protein shapes
• 2 matching protein shapes with completely different functions
  • Prusiner’s Prion theory

I also thought that a primer on the sheer number of shapes that may be expressed from an RNA sequence might be in order. I got the feeling that you might be the guy to instruct us.

Do you teach as well as search?

Dar-

Good to see you on this thread. What did I do now? Monotreme is burning all the neuronutrients on this one.

NS1: I’m not a protein biochemist, so my “teaching” on protein conformations would be inexpert at best.

I’ll take on your first tutorial tonight, but then I need to go to bed.

• 2 similar sequences with different protein shapes

The basic idea is that relatively small sequence changes can alter protein conformation very significantly. Many genetic diseases result from mutations that affect one or just a few amino acids. These changes can result in shape changes of the protein that reduce or eliminate its function. For example, here’s a paper that describes the affects of mutations in the FXIIIA gene which causes deficient function of the protein.

The molecular consequences of these mutations appear to be an abnormality in protein conformation or folding and/or a reduced production of messenger RNA transcripts of varying length that likely result in a nonfunctional, unstable FXIII protein.

Here’s a nice tutorial that explains the protein folding problem.

Monotreme-

You are very kind to stretch to explain these issues.

Would Sickle Cell Anemia be useful as a tool to explain these ideas? Or can you think of another genetic disease that would be recognizable and fall into one of these categories?

Racter – at 13:01

Webster is studying something important here concerning cytokinic dysregulation and virulence. Segment 8 B92E / Asp92Glu

Niman, how could the viruses be _exactly_ the same over so many years ? Doesn’t that indicate some error in the lab. or the database or such ?


Dem, the Qinghai-strain had been pretty stable recently. The cats and stone marten were maybe only found because they did more testing in Germany ?

can we have a table here with the 64 possible nucleotide-3-combinations, the corresponding amino-acids in full,3-letter-abbrev.,1letter-abbrev in computer-readable form (text-file) ?

NS1: Actually, to get the thread back to flu, the paper I cited at the beginning is a good example of how overall sequence similarity does not necessarily predict protein folding. The strain of H5N1 isolated from VietNam has an HA gene that, based sequence alone, is much more similar to the HA gene of the strain of H5N1 isolated from a bird in 1997. Yet, at the 3D protein level, the Viet Nam strain has a HA protein with a shape more similar to the 1918 H1 virus than to the 1997 bird H5N1 HA protein. This similarity in protein shape would have been difficult to impossible to predict by looking at sequence alone.

but what is more important for the viruses’ virulence or transmissability, the amino-acid sequences or the 3d-structure ?

gs: 3D structure trumps sequence every day of the week. Sequence data can be useful for tracing evolution of a virus and is helpful for predicting the shape of the protein, but it is the shape of a protein that determines its function, not the sequence, per se.

no idea what 3D structure trumps sequence every day of the week means. So, there is no mRNA like thing of forming proteins by copying parts or such. And the immune system also recognizes the 3d-structure ?

“what is more important for the viruses’ virulence or transmissability, the amino-acid sequences or the 3d-structure?”

That’s like asking whether the words are the most important elements in a story, or the letters of which they are comprised. The two are really only separable conceptually; the nucleotide sequences in the viral genome determine the amino-acid sequences, and the amino acid sequences determine the shapes of the proteins — so where a change to those sequences is important, it is important because it results in changes to the shapes of the proteins, and hence to the way they interact with the host cell.

but when the virus replicates, it must somehow unfold, or not ? Or it must transmit its code to the nucleus or such, but I assume, it must somehow be read in 2d.
Racter, the difference with yoour analogy is, that virulence or contagiousness can be measured while story-importance can’t.

gs: Viral RNA sequence indirectly determines protein shape. RNA is translated into protein. We don’t know the rules that determine how a given amino acid sequence folds into a complete 3D protein. I can’t tell from your posts, but I assume you know that RNA is made of nucleotides and that proteins are made of amino acids. Nucleotides carry the genetic information, but the actual work of a virus or cell is done by proteins.

“but when the virus replicates, it must somehow unfold, or not?”

Not. Viral replication is not achieved by reverse-engineering from protein.

“the difference with yoour analogy is, that virulence or contagiousness can be measured while story-importance can’t.”

I must disagree. Just as the elements of a story are not inherently “important” or “meaningful” — but only as the result of their effects on the mind of a reader — “virulence” and “transmissibility” are not exclusive properties of the virus itself, but of the complex interaction between virus and host.

All good discussion, but do not let Monotreme’s main point get lost: You can discuss point mutation, deletion, insertion, reassortment, recombination, etc. as critical to tracking changes over time and how this is important in predicting viral activity, but it is DEMONSTRABLE FUNCTIONAL CHANGE which matters. Breaching the species barrier is the critical issue for initiation of a pandemic, and changes have been found in the Vietnamese strain cited in the article which have increased its ability to bind to human receptors. That we do not understand fully how to predict conformational changes based on sequence data is to our peril at this point, but we cannot let the critical point be lost in the details: whether we can adequately predict it or not, H5N1 is showing itself as an increasing threat.

While it is vital to know how they would penetrate the castle’s fortifcations if we are to prevent an attack, it is of greater moment to the general populace to know just how close to the gate the Barbarians really are.

Thanks for bringing us back on task, Many Cats.

I assume the only work of the virus is : enter a cell, force it to produce copies of the virus and leave those to attack other cells. Does the virus also produce some proteins ? Anyway, when it tells the cell how to make other viruses, it must somehow transmit (only) the 2d-data not the 3d-structure. So it must unfold - how else could it work ? And that’s where the single nucleotides are accessed and the point-mutations may occur. So, I assume both are needed, the 3d-structure is important for entering and leaving the cell and defending against the immune system, while (only) the 2d-sequence-data is needed to transmit the information for replication.

“Does the virus also produce some proteins? ”

Yes. (Though not directly, of course — it relies on the host’s cellular machinery to accomplish all its tasks).

“Anyway, when it tells the cell how to make other viruses, it must somehow transmit (only) the 2d-data not the 3d-structure.”

Right.

“So it must unfold - how else could it work? ”

The protein coating fuses with the vesicle (the cellular structure which conducts the virus into the host cell) to release the viral RNA into the cell; this is referred to as “uncoating” — in this context, to refer to it as “unfolding” would be misleading; it is not the reverse of the “protein folding” process that occurs when amino acids are assembled in a polypeptide chain.

“So, I assume both are needed, the 3d-structure is important for entering and leaving the cell and defending against the immune system, while (only) the 2d-sequence-data is needed to transmit the information for replication.”

That’s essentially correct, though it’s a little more complicated than that; check out the function of the “ribonucleoprotein”, or RNP complex; for viral replication to move forward (and hence to produce illness in the host), a lot of stuff has to work; getting inside the cell is just the beginning. If the whole thing doesn’t work, it doesn’t matter how specific receptor binding is, because there’s nothing to transmit anyway.

I agree with Many Cats that it is demonstrable functional change which matters (another way of putting it is that functional change is the means by which it is demonstrated whether changes at the genome “matter”). I also agree that breaching the species barrier is a critical issue for initiation of a pandemic; whether it is the critical issue remains something of an open question. It isn’t enough for the barbarians to penetrate the castle’s fortifications; if they’re going to do any damage, they must also be equipped with weapons.

Receptor binding does tend to be the main “track” of these discussions; and as far as transmissibility goes, that absolutely makes sense — but as far as high pathogenicity goes, it can’t be the whole story. After all, there are many viruses whose high transmissibility indicates highly specific receptor binding, yet which do not produce life-threatening disease in humans. As I mentioned above, since receptor binding is something we can test for (using glycan microarray), it is something that recieves a lot of focus; it is entirely possible, however, that something is taking place elsewhere on the viral genome which is of equal, or even greater import, and which we presently have no means to test. The global human population will be the ultimate laboratory.

OK, thanks Racter. Now, would we expect, that when this Viet04-HA makes the mutations which lets it bind to alpha2–6 that it would also work similar as 1918 H1N1, although the 2d-sequence is quite different ?
Or would we expect that it remains functional just as Viet04 was but infects humans much more efficiently ? And then, how does it transmit ? Has it already learned to cause the human host to hustle and spread virus with it ? (as I think, the 1918-virus did) Is it sufficient that H5N1 is so new to our immune system to cause a pandemic ? Would a normal flu-virus infect 30% of the world’s population if only it were new to our immune system ? Was the 1918-virus more contageous than normal flu or only newer to the immune system ?

Racter – at 13:01 and at 17:24

Webster is studying something important here concerning cytokinic dysregulation and virulence. Segment 8 B92E / Asp92Glu

Are you following this one?

Yes, NS1. Sorry I didn’t acknowledge that earlier; that’s just the sort of thing I’m talking about. Unfortunately, this sort of work moves forward rather gradually, due in part to a lack of live human test subjects. (I guess this is one area where we might hope that the results are flawed due to unappreciated differences between human and porcine lung tissue). Since the virus is not encumbered by this obstacle, it has the capability of moving forward rather suddenly.

And Guenter, the questions you are asking now are just the sort I had in mind when I said that the global human population will be the ultimate laboratory. If we’re lucky, we may have better answers once those results are in (and if we’re even luckier, we’ll be among the ones who will stand to benefit), but there will probably still be more guesswork involved than makes you comfortable.

Racter: Agreed that the Barbarians must be armed, but when you look at the number of mammalian species which have been infected, including Homo sapiens, and the mortality rates in each case, I am more than a little concerned that the Barbarians already have a faily good armamentarium. I hope I am incorrect in that assumption.

Sorry about the color, didn’t mean to give it that much emphasis…

Many Cats —

The highlighting looks good on my screen. The part that scared me was “armamentarium.”

This thread represents the best our modern technology has to offer those who seek to solve problems.

Dear Many Cats, just be careful where you point that vocabulary. A few of us are easily blown away by intellects as powerful as yours… along with those of the other remarkable minds here.

:-)

Keep up the great work, people. Thank you.

gs at 18:23:

I get my best laughs from your posts! You are a king of Spolls! And both obviously intelligent and extremely well informed! Interesting personality.

But just in the 18:23 post, you pose seven (7) questions in just eight (8) sentences! I must snip this as a ‘model’ in argumentation! Are you an entry in the Guinness Book of Records?

Keep posting, gs! (As IF you’ll ever stop!) This whole pf51 business needs occasional lightening…in addition to your frequent positive contributions!

Cheers!

King of Ockers!

NS 1 — 00:35

Ha-ha! And don’t YOU be an ‘Ocker-knocker’ mate! <grin>

Racter, that sounds as if you were already resignating without hope, that some research might save us _before_ the final big experiment. I’d like to investigate the questions now - when it’s started I’m no longer interested….
Nicolai,NS1: I’m beyond the point already where I might bother people laughing about me. I’m trying to focus on logics and reasonability more than on what is commonly considered good behaviour, sympathy, tradition. We are in a new situation with H5N1 and it’s time to abstract from social behaviour and stop seeking for social acceptance rather than strict logical thinking. I see it daily here, that people are in some collateral ignorance about the pandemic and it’s just considered impolite to talk about it - so the subject is spared and consequently most people thing that if there were a real threat, then there were more in the media.
I don’t know what Spolls and Ockers are, could be some subspecies of the great familie of what Niman considers trolls ;.) I was always best in math, but worst in German, so excuse my wording. Sometimes when I read my own posts, I myself don’t know what I had meant. And no, I’m no expert about viruses. Just what I learned in forums and papers here since december.

gs:

Laughter is sometimes elicited by stress. This whole thing is nearly beyond my bearing—and I am 77 y o with no young dependents or anything!

You can afford to be teased a little—you are highly respected, as I hope you gathered from my post. Just Aussie idea of rough humour. Shrug it off.

‘Consider the source’ mate, and laugh back!

OK, I posted this idea at curevents, just as a theoretical thought but people were incensed, called me Mengele and refused the idea.


There is one other possibility to test whether H5N1 is evolving towards pandemic strain : infect many isolated people and watch how H5N1 evolves through many hosts in chain. OK, infecting people is unethical even if it might prevent the pandemic and maybe in some countries it’s being done already. (“volunteers” for vaccine-testing).
Maybe it also works with pigs, I don’t know. So let’s take pigs. Some charantained island with some thousand pigs and they are infected with H5N1. Keep them close together so that P2P is frequent. Sort of Racter’s big experiment but restricted to a small island. If H5N1 has the ability to go efficiently P2P then it might do so in that experiment before it does it in the real big worls and we can make a vaccine.

Nikolai, do you think old people are safe in a pandemic, because most H5N1-victims were young ? The old would still suffer from social/economical disruption. They might die from normal flu because they get no care or they die because they can’t get their usual daily medication.


I’m not a good poet, but I once posted a fun story about the whale in London to the humor thread :-) So, where are you when I want you to laugh ? ;-)


5 sentences,2 questions.

“Racter, that sounds as if you were already resignating without hope, that some research might save us _before_ the final big experiment. I’d like to investigate the questions now - when it’s started I’m no longer interested.”

You have my complete support. I won’t deny that I find it hard to be optimistic about science saving our butts us on this one, but personally, I’d remain fascinated even if the threat vanished tomorrow. I find that the more I learn, the more I want to learn (and the less I feel that I really know). It’s rather more of an obsession than an interest, I’m afraid. This debilitating affliction robs me of precious time, isolates me from friends and family, and generally wreaks havoc on attempts at a responsible lifestyle. Worst of all, driven by some inexplicable need, I often find myself attemping (with little success) to “infect” others with this obsession. You’re a prospect, you see. As chilling as the threat of a pandemic is, there is a genuine elegance in the details, and you strike me as a potential candidate for coming to appreciate that, despite your claim to be a pragmatist. Your patience and dedication to numbers and sequences is remarkable and inspiring; but the details you’re wrestling with are but window into a world that all of us put together may never master.

gs-

You have a lot of ideas.

I can see that you are trying to solve the problem and trying with great fervor.

I also was pretty good with math, but not so great with German. In fact, I was terrible with German. I don’t know Danke from Danka, but thanks all the same.

Racter-

Come back to us.

The information that you’ve shared with folks here has already helped many to master their fears and to garner hope in the face of such difficulty.

We are going to seek answers until we know that they are no longer needed.

Your continued enthusiastic work is essential.

gs: If you run the virus through a few generations of any species, you will most assuredly find rapid adaptation.

Mortality in all age groups was increased in 1918 due to H1N1; however, it was disproportionately increased in the young.

You might benefit from reading John Barry’s book “The Great Influenza” if you haven’t yet done so. Very highly recommended. Also, his lecture at Johns Hopkins last year: http://www.jhsph.edu/publichealthnews/articles/2005/great_influenza.html

Just a couple of thoughts, Flu Wikians,

We are going to need to keep our senses of humor close at hand. I’m a professional risk communicator and when you are staring the beast square in the face for long periods, if you don’t have jokes you are going to blink.

Next up: to maximize the way this site is used by everybody, take the five minutes you need to learn how to post links. Please. This is so easy that I could learn to do it, and I’m the least techy of the mods. Pogge designed a clear set of instructions which are listed at the bottom of every page. This isn’t hard and it means that the mods don’t have to chase down sidescroll a dozen times a day and can actually pay attention to the content on the site. Wouldn’t that be wonderful!

NS1:

I appreciate that, but I am painfully aware of how ineffectual my efforts seem to have been when directed toward those who have no fear in need of mastering, and whose hope derives from the imagined predictability of their lives. Comfort the disturbed and disturb the comfortable would be my goal, and here I am disturbing the disturbed after… boring the comfortable, I guess. Won’t be getting a job as a “professional risk communicator” anytime soon, doesn’t look like. I’ll keep working on it, though.

“We are going to seek answers until we know that they are no longer needed.”

Perhaps it would be better if we would seek answers always, whether we think they are needed or not.

Melanie-

On my last forum creation, H 5 N 1 Recombination 2 continued, I posted a request on the first entry to use link formatting, but I was wondering if it would be possible to automatically format a header message that requests link formatting at the beginning of each forum?

Racter-

Those who exhibit no fear now are sometimes those with the greatest suppressed fear. If we are able to architect the structure, gather the information, solve for some optimalities early, when or if PF51 occurs, those who are comfortable now will have a place to land then.

I’m just a cupbearer to a King in this odd land of very comfortable people. And since, sometimes, answers are hard to find I’ll keep looking for a place to store them when we do find a good one.

Don’t let the deaf ears discourage you now; you’ve made a difference and you’re creating a refuge for many who are listening.

You must excuse me, I have really only been at this a little more than a week and am slowly coming up to speed (it has been a long time since I looked at these kinds of things).

Anyway, am I correct in that the H5N1 attacks the birds primarily via their digestive track? The mutations/recombination that would take it to a H2H would require attachment via the respiratory system - right? Does that mean the gene changes that we need to be concerned with are mainly in the two or three areas in the “H” part that govern protein sequence and structure and thus attachment?

Do I have that about right?

Oh yes, If I have that right, is the intestine vs. lung attachment the reason it is B2B in droppings and B2H by direct contact and not yet H2H?

Thanks - I am a little slow catching up, but give me time and I will do my homework. Now that I have most of my preps ready, I can turn my attention to the cellular machinery.

Racter - “This debilitating affliction robs me of precious time, isolates me from friends and family, and generally wreaks havoc on attempts at a responsible lifestyle.”

In spite of all that, I think you are brilliant (way over myhead much of the time) and I hope you keep applying your mind to this threat we all face (“we” including those you are boring).

we also need a plan B, how to survive all the laughter, when panflu doesn’t come ;-)
DennisC, see also the Racter’s link above to CE - they have some more info

chuckles.. yes but he ridicule if the event doesn’t happen will be worth it

gs

“….plan B, how to survive all the laughter”

I plan on having a candle lite post prep party with lots of rice, beans, vienna sausage and gatoraid and invite all my neighbors.

“Montanan – at 10:12

Your comment “P.S. Your interpretation of the article was much more helpful than the one posted yesterday” is interesting as is implies you agree with Monotreme’s conclusion. However when you read an interview in which one of the scientist from the article in question inferred that the virus was NOT easily converted to H2H it is disputed. Since 1997 there is not one shred of evidence that the virus is any closer to H2H. In fact the study in question indicates there may be a barrier to H2H. It killed people in 1997 and it kills people today. Nine years later still no pandemic. This board is tiresome as it is overwhelmingly clear most folks will not look at any viewpoint other than there is pandemic around the corner.” - BP

You are right. There is no proof that we are any closer to an H5N1 pandemic than we were 9 years ago. There are many opinions and those differ depending on the “expert”, however, no one with certainty can tell you what a pandemic strain would look like or whether we are marching towards it, just like no one can state with 100% certaintly that it won’t happen.

Some statements that you refered to regarding the study that seem to have been ignored:

“In order for the virus to jump from birds to humans, the protein on the virus has to change so that it can bind itself to human cells and find a new home.

Scripps Research Institute researcher Ian Wilson and colleagues wondered: If they put two mutations onto the H5N1 virus similar to the 1918 version, could it enter humans? It could not.

Wilson and colleagues then imposed the mutations that likely happened to the 1968, Hong Kong flu strain onto the current avian flu virus.

“We got some binding to the human lung cell, but it wasn’t dramatic,” Wilson told LiveScience.

This suggests a possible route for the virus to enter human cells. But scientists advise that the news is not all that grim.

“If it happens, it’s something to be concerned about. But, there has not been any changes like it yet, and hasn’t been for several years,” Wilson said.”

http://www.livescience.com/humanbiology/060316_flu_morph.html

Another statement regarding the same study:

“The authors of the Science paper were able to change the H5N1 hemagglutinin enough for it to latch more easily onto sugars found on the exterior of cells lining human lungs. Encouragingly, Stevens said, the mutations’ attachment to the cells was weak - suggesting the existing virus cannot easily cross the species barrier outside a lab. “It’s surprising that it wasn’t easy to convert,” Stevens said. “There may be other factors that prevent it. That’s not to say that Mother Nature won’t come along and throw us a curve ball.”“

http://www.curevents.com/vb/showthread.php?p=353267#post353267

BP, here is another (recent) expert opinion that questions whether H5N1 is evolving or not towards a pandemic strain:

“Frederick Leung, dean of science at the Hong Kong University microbiology labs that have played a pivotal role in unravelling the secrets of the virus, agreed.

“We are no closer to a pandemic at the 100-death stage than we were at the first death,” said Leung.

“This is a milestone in headlines only — 100 deaths since the disease was first discovered eight years ago is statistically inconsequential,” he added.”

http://www.physorg.com/news11717.html

tram, could it be that you just picked the positive statements and left out the negative ones ?

Tram – at 13:32

I think we are on the same page. I am not however willing to stand out on a limb though and still plan to add to my current preps.

“tram, could it be that you just picked the positive statements and left out the negative ones ?”

If you have paid attention to the context of my reply you already know the answer. Think of my reply to BP as an effort to add balance to the thread.

BTW - Being from Germany (I seem to remember you are) are you familiar with the German virologist Stefan Lanka? He has some radical but very interesting ideas in regards to viruses and their interactions with the human body.

Tram: How would you interpret this paper:

Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals

Also, do you endorse Stefan Lanka’s “ideas”?

Tram at 15:24

Stefan Lanka now that is an interesting idea. Viruses do not make you sick. H5N1 cannot be carried by migratory birds they would surely die before the could fly… Oh yes HIV does not make you sick it is the Medication that they give you the ATZ. Aids come from too much LSD. What is truly, truly scary is that one of the local free newspapers printed his comments on Bird Flu as though the were the voice of Mainstream Virologists and not an extremist from way way out there somewhere.

Monotreme – at 16:39

I have questions about the paper. Isn’t simply stating the virus kills some mammals very well (or perhaps more accurately,the virus is virulent in some mammals). Is there a component of the paper in which it infers pandemic probability? Again I don’t want to beat a dead horse here, but we knew in 1997 it was virulent as it killed people then.

I went to a birthday party on Friday and made the circuit of the room talking about avian flu until everyone’s eyes were glazed over. Thank you, Racter et al. I know I bordered on being a bore, but all these friends have kids whom I’d like to see survive. It helps to know I am not alone in my little neurosis. I like the idea of a post-non-pandemic party starring Spam and Pedialyte. MMM, vienna sausages on crackers! Y’all come!

BP: The paper shows that the 2004 H5N1 virus is more lethal to mammals than the 1997 H5N1 virus. This is what you would expect from a virus that was adapting to mammals and is consistent with the first paper I cited in this thread. We have now have multiple lines of evidence indicating that H5N1 became more dangerous to mammals from 1997 to 1994:

• Sequence data from polymerase genes
• Sequence data from the HA gene
• 3D structure of the HA gene
• experimental infections of animals
• vastly expanded geographical range
• pathology similar to the 1918 virus
• demographics similar to the 1918 virus
• increasing cluster size (in Turkey, probably)

One can always find a different interpretation for a given result. This is why scientists insist on more than one type of data before coming to a conclusion. To me, the aggregate data is overwhelming: H5N1 causes severe pathology and is more dangerous now than it was in 1997. This doesn’t mean that it will go pandemic tomorrow, but it does suggest that the risk is increasing.

DennisCra – at 11:10

Speculation on function vs. sequence is just that; however, many compelling studies have occured to demonstrate that:

• Bird intestines / swine intestines are typical reservoirs
• Bird lungs and other organs are now being infected leading to death
• The virus has acquired the ability to grow in lower temperatures
  • Presumably due to PB2 E627K polymorphism
• These lower temperatures may allow growth in the human UPPER respiratory tract
• Binding receptors for the upper respiratory tract in humans are somewhat similar to those for birds and are postulated to be a mid-step in the change of the virus that is on the way to efficient LOWER respiratory sytem binding.
• The receptor binding domain is generally considered to reside on HA - Hemmagglutinin with involvement at residue 190, 225–228 and perhaps others.
• Strains of H5N1 have been sequenced with Niman’s predicted S227N human receptor polymorphism
• Virulence factors also have been indicated on gene segment 8 (the only nonstructural protein) that are felt by Webster to contribute to rapid replication (may be a factor in ease of transmissibility indirectly due to load factor)

If you have other questions on the specifics, visit Niman’s commentaries and comments on these forums (H5N1 titles, et al), review Webster’s studies and the excellent posts by our resident contributors on the science page.

Postulate ideas and ask the unanswered questions here. Someone will likely have a ready response or be a worthwhile sounding board.

Monotreme: As BP has suggested, what the hell does that paper (from April 05) have anything to do with the study that was referenced, or with H5N1’s supossed progression to becoming panflu?

The fact is that you misrepresented the study, as it does not show that H5N1 is becoming more H2H like. It simply shows what changes it could make to gain a potential foothold in humans. Even when those changes were made, as the study shows, they seen some binding to the human lungs, that “was not dramatic”. Furthermore, “there has not been any changes like it yet, and hasn’t been for several years”. Additionally, the study showed that virus “cannot easily cross the species barrier” and that there “may be other factors that prevent it”. Finally, when the researchers tried to make “two mutations” (remember all the two mutation talk?) to the virus to make it 1918-like, they determined that the result was a dud.

Tram: My suggestion is that you read the paper and my posts carefully. Here is a direct quote from the study from my first post on the subject:

“…mutations that can convert avian H2 and H3 HAs to human receptor specificity, when inserted onto the Viet04 H5 HA framework, permitted binding to a natural human alpha2–6 glycan that suggests a path for this H5N1 virus to gain a foothold in the human population.”

See also my post at 17:31.

You didn’t answer my question regarding Stefan Lanka. Dr. Lanka doesn’t believe HIV causes AIDs. Do you share his opinion?

NS1

Thank you very much.

“The paper shows that the 2004 H5N1 virus is more lethal to mammals than the 1997 H5N1 virus. This is what you would expect from a virus that was adapting to mammals and is consistent with the first paper I cited in this thread.” - Monotreme

This is completely news to me. As a virus becomes more adapted to humans it increases in virulence? Is that what you are suggesting? Do we have epidemilogical studies that prove this assertion?

I have no opinion on Dr. Lanka’s work as he is much more qualified than I to make proclaimations on the interactions of viruses and humans. While many of his theories seem a bit “out there”, some of his points should be considered in regards to H5N1 (ie methods of viral isolation, lack of viral load data in human deaths, etc.).

Monotreme – at 17:31

Does lethality level indicate pandemic probability? Isn’t the most important variable the way the virus transmits? Weren’t the mammals infected from either huge viral loads like cats eating dead birds or in laboratory settings? Which mammals efficiently transmit the virus to like species in nature? To me “vastly expanded geographical range” doesn’t seem like an indication of a probable pandemic. It is a bird virus, birds fly and migrate it is becoming real efficient at infecting birds. My concern would be the condition of dense populations of birds and people living in the same location. We have had this condition for a number of years and still no pandemic. I haven’t seen any compelling evidence of any cluster anywhere. I know Dr. Niman believes there is such evidence however to me it has to be verified by others. I cannot discuss the 3d structure of the HA gene as I have no clue what that is. My analysis comes from reading as much as I can (time permitting) from experts in the field who have been studying influenza for years. I am a skeptic, however I believe it is prudent to prepare for the worst.

A virus that is not adapted in any way to mammals cannot cause any disease in mammals. Obviously, to cause a disease, a virus must be at least partially adapted to that species. It is very common for a disease that crosses species barriers to cause more severe disease in its unnatural host than the host it normally infects. Here’s a review. Normally, foreign viruses do not become completely adapted to the new host. Ebola would be an example of this. However, influenza is famous for crossing species barriers. The H3N2 influenza virus that is currently causing flu epidemics in the northern hemisphere did this, it used to be an avian virus.

Do you believe HIV causes AIDS?

BP: I’m glad you believe in preparing for the worst.

Here is a partial list of the H5N1 clusters?. The more the virus spreads in birds, the more opportunity it has to infect people. The more people it infects, the more likely it is to adapt to humans.

Also, please see my post at 18:15 which addresses some of your other points.

BP. As you, I am not a virus or a bird flu expert but the large majority of experts are completely convinced that it is ‘when’ and their estimates on virulence are huge. Maybe the way to answer your question is to add up all experts and check the numbers on one side or another. These should be experts that are willing to put their names and therefore reputations on the line.

Monotreme you initially stated:

1. “The paper shows that the 2004 H5N1 virus is more lethal to mammals than the 1997 H5N1 virus. This is what you would expect from a virus that was adapting to mammals and is consistent with the first paper I cited in this thread.” - Monotreme

I responded:

2. “This is completely news to me. As a virus becomes more adapted to humans it increases in virulence? Is that what you are suggesting? Do we have epidemilogical studies that prove this assertion?” - Tram

You reponded:

3. “A virus that is not adapted in any way to mammals cannot cause any disease in mammals. Obviously, to cause a disease, a virus must be at least partially adapted to that species.” - Monotreme

Am I missing something or have you completely dodged my questions? Where are the studies that prove your assertion that a virus becomes more lethal as it becomes more adapted to it’s human host? With that logic, are we safe to assume that if H5N1 becomes panflu that the CFR will move closer to 100%? Educate me.

Monotreme – at 18:19

I thought clusters were confirmed H2H cases. If clusters of humans catch BF directly from birds how is that significant? The geographic spread to me seems minor issue in ratio to the density of infected birds and people living together (i.e. asia). I have read several articles which indicated that viral load is important in regard to infection. Also BF was adapted to humans in 1997 as it was fatal then.

Tom DVM – at 18:20

I just haven’t seen the “sides” issue in regard to experts. They seem to all say the same thing, “yes it is a possibility we just don’t if it is a probability. Webster is the first expert who has laid it on the line and I admit it had an impact on me, however I would like to see others fall in line.

BP There have been many others, as in bird flu specialists-virologist who have made essentially the same basic premis as Dr. Webster, it’s just that Dr. Webster is the most senior and most experienced.

Tram: Although I am not a virologist, I once worked with a virus that was harmless (mostly) in its natural host. It was 100% lethal in an unnatural host. When a virus adapts enough to a new host to be transmitted efficiently, it is at its most dangerous. This is because the immune system of the new host has never seen this virus before. Once a virus becomes fully adapted to a new host, one does expect its lethality to decrease. This is because many viruses trade virulence for evasion of the immune response. This is why flu pandemics last about 2 years. It takes this long for enough people to have been infected and hence “educated” their immune systems so that the virus is under selective pressure to evade the immune system. This is when it becomes less virulent. Eventually, I expect H5N1 to become no more dangerous than H3N2, but not until the pandemic has been raging for 2 years.

Tram: I almost forgot to ask, again:

Do you believe HIV causes AIDS? Talk about ducking questions ;-)

BP: If you look at the onset dates of the clusters, you will see a number of clusters that would be consistent with inefficient H2H transmission. Some of this have even been published as “probable” cases. Since H5N1 is now endemic birds in many countries, it is impossible to prove that everyone in a cluster was not infected as a result of exposure to birds. But how likely is it that different family members were infected separately, at different times that just happen to coincide with the incubation period of flu virus? Take whatever this probability is and then multiply it by the number of times this same peculiar patterning occured. I am not a statisitician, but I think you will get a very small number. In any case, even the WHO acknowledges that limited H2H transmission has occured in some of the clusters. I don’t know of any virologist or epidemiologist who doubts this has happened. The only question is how often, and how big were the clusters in Turkey.

“Tram: Although I am not a virologist, I once worked with a virus that was harmless (mostly) in its natural host. It was 100% lethal in an unnatural host. When a virus adapts enough to a new host to be transmitted efficiently, it is at its most dangerous. This is because the immune system of the new host has never seen this virus before. Once a virus becomes fully adapted to a new host, one does expect its lethality to decrease. This is because many viruses trade virulence for evasion of the immune response. This is why flu pandemics last about 2 years. It takes this long for enough people to have been infected and hence “educated” their immune systems so that the virus is under selective pressure to evade the immune system. This is when it becomes less virulent. Eventually, I expect H5N1 to become no more dangerous than H3N2, but not until the pandemic has been raging for 2 years.” - Monotreme

You still have not shown any support for your assertion that a virus becomes more lethal as it becomes more adapted to a human host. I’ll try once again as it is very obvious that you are clearly avoiding your previous assertion. You clearly stated that the increase of lethality of H5N1 supports that it is becoming more adapted to humans. Explain to us how you use the supposed increase in lethality of the 2004 H5N1 virus, compared to the 1997 version, as evidence that it is becoming more adapted to humans.

Monotreme you initially stated:

1. “The paper shows that the 2004 H5N1 virus is more lethal to mammals than the 1997 H5N1 virus. This is what you would expect from a virus that was adapting to mammals and is consistent with the first paper I cited in this thread.” - Monotreme

I responded:

2. “This is completely news to me. As a virus becomes more adapted to humans it increases in virulence? Is that what you are suggesting? Do we have epidemilogical studies that prove this assertion?” - Tram

You reponded:

3. “A virus that is not adapted in any way to mammals cannot cause any disease in mammals. Obviously, to cause a disease, a virus must be at least partially adapted to that species.” - Monotreme

Am I missing something or have you completely dodged my questions? Where are the studies that prove your assertion that a virus becomes more lethal as it becomes more adapted to it’s human host? With that logic, are we safe to assume that if H5N1 becomes panflu that the CFR will move closer to 100%? Educate me.

As far as HIV causing AIDS. I have no idea! I would assume it does, but I’ve never researched it. Furthermore I don’t know why you care about my opinions of a virus that has nothing to do with this message board.

BP. One of the persons the two mutation’s comment was attributed to was Dr. David Nabarro, the UN head for H5N1(separate from the WHO). In my opinion, he is a brave and highly ethical scientist. The comment was based on a conversation that he had with Dr. Osterhaus, a veterinarian who discovered the corona virus as the cause of SARS, and is probably the only virologist of Dr Webster’s status.

The problem was that it appears that this conversation was meant to be off the record. After the fact, Dr. Osterhaus, without being asked, clarified the issue. The thing is that the fully open scientific discussions are being held behind closed doors but we can read between the lines and follow the trend patterns. What we get, other than from the bravest of the scientists, is sigificantly filtered for public consumption and I say this as someone who worked directly with regulatory agencies for many years.

Good evening - I have been reading the posts at this site for some time now and while admittedly not understanding most of the technical aspects of the notations, I still find them extremely fascinating.

Could one of you please do me a favor?

Navigate to a fluwikie topic entitled, “Outdoor Activities That Will Be Safe During an Isolation Period.” Many of the people posting therein are talking of continuing to golf, bike ride, have walks in the park and so on. I added my own thoughts, which could be out in left field somewhere, but would be thankful to “hear” a more experienced voice of reason read and respond to some of the chatter that is ongoing at this link. Thank you.

Tram: I’m not dodging your question, you just don’t seem to like the answer. A virus has to adapt to a host to cause disease. If it doesn’t adapt, it can’t cause disease. A flu virus has to adapt to a host to cause a pandemic. The fact that H5N1 is causing disease in humans proves that it is partially adapted to our species. I don’t know how to put it more simply.

Prior to 1997, H5N1 infected birds, but did not cause disease in humans. To all appearances, it was harmless to humans. In 1997, some change in the virus allowed H5N1 to infect humans. It killed 33% of the ones it infected. This is a partial adaptation. In 2003/2004, an H5N1 virus that infected many more humans emerged. Experimental evidence showed that it was more lethal than the 1997 strain. Further, it was shown to be able to infect cats, a species that is immune to normal flu. Not only that, but in experimental conditions, it was shown to be transmitted cat to cat and cause severe pathology. At the same time clusters of human cases were observed. None of this means that H5N1 *must* go pandemic, only that it is more likely now than prior to 2004. If you remain unconvinced, that is your privilege.

The reason why I ask you about HIV and AIDS is because the virologist you cite as worthy of interest, Stefan Lanka, doesn’t believe HIV causes AIDS. The fact that you find this sort of “expert” credible speaks volumnes.

Tram – at 15:24 to gs:

“BTW - Being from Germany (I seem to remember you are) are you familiar with the German virologist Stefan Lanka? He has some radical but very interesting ideas in regards to viruses and their interactions with the human body.”

Yeah, real interesting ideas. Maybe he’s in communication with the aliens who abducted Elvis and know’s what planet they took him to.

Tom DVM – at 18:48

I just haven’t seen their comments anywhere (not that I doubt your word I just haven’t run across them).

Monotreme – at 19:09

“In any case, even the WHO acknowledges that limited H2H transmission has occured in some of the clusters. I don’t know of any virologist or epidemiologist who doubts this has happened. The only question is how often, and how big were the clusters in Turkey”. Has this been published anywhere by any virologist or epidemiologist?

Monotreme. First, Congratulations. Second, why don’t you write a book. You are really good at describing the intricacies of virology. You could use a pen name…I know…why not Monotreme.

BP Keep your ear to the ground and you will hear them.

Monotreme at 18:19- re: “The more the virus spreads in birds, the more opportunity it has to infect people. The more people it infects, the more likely it is to adapt to humans.”

Yes, yes yes yes!!! I keep hammering this at people who say not to worry- only a bird’s disease. It is now, but keep offering it new hosts/victims and it has more and more opportunities to do what it does best-mutate. recombine. whatever. It all adds up to increased risk. I’m not a numbers expert/virologist/doctor. But common sense counts for something.

Thank You.

BP: I’m not sure which of the statements in my quotes you are referring to. However, here are couple of citations regarding human to human transmission and clusters:

• Probable Person-to-Person Transmission of Avian Influenza A (H5N1)
• Family Clustering of Avian Influenza A (H5N1)

We don’t know what happened in Turkey because the WHO is suppressing the cluster information. Same thing may be happening in Azerbaijan.

Tom DVM: I’m not a virologist, but admit to being fascinated by the evil buggers ever since I saw what one could do to a susceptible host, first hand. Its the reason I don’t have a problem believing H5N1 could have a high CFR. Actually, it wouldn’t be a bad idea for all of us to write books whilst holed up for the pandemic ;-) If/when a severe pandemic occurs, it will be an historic event. If more people had written books about 1918, we wouldn’t be as unprepared as we are.

Grace RN, your welcome. Great minds think alike.

I scan the daily News Reports regularly, filtering out the many reports of two-dead-ducks here and so-many-chickens-culled there BUT

Never have I encountered so many news items of such core importance to all of us as on today’s, March 20, News.

These are CDC origin, on H5N1 clades and the implications for multiple vaccines being required, etc etc. I refer any interested to start at “Dav—at 09:24″ and “Quartzman—at 18:11″ though there are three-four others…

BTW, I am posting here as the material seems relevant to the core arguments here, rising from Monotreme’s initial post.

Nikolai - That’s interesting you mention that because I have been focusing on the reports of new H5N1 cases and plan to come up with some sort of daily summary to keep track of where the new and expanded infections are occuring. I’m glad someone has an “eye” on the other very important reports.

Heather, here is a nice recap of expansion by country and date.

Heather here is a recap of expansion by country, http://tinyurl.com/le48l

DennisC - Great map! Thanks.

“Tram: I’m not dodging your question, you just don’t seem to like the answer. A virus has to adapt to a host to cause disease. If it doesn’t adapt, it can’t cause disease. A flu virus has to adapt to a host to cause a pandemic. The fact that H5N1 is causing disease in humans proves that it is partially adapted to our species. I don’t know how to put it more simply.”

Again you’ve purposly dodged my question and you’re ignoring what you originally said. Show me how an increase in lethality demonstrates that a virus is becoming more adapted to a human. With that logic, the CFR of H5N1 would move closer to 100% as it get closer to and becomes panflu. In fact every virus would increase in lethality as in better adapts (even the common flu). That logic is completely wrong and would mean that evolutionary pressures would prevent viruses from becoming more adapted to anything. Ask any epidemiologist and they’ll agree.

Shall we go back and review our points and counter points? You seem to want to now take this back to a virus not infecting humans (no disease period) to infecting humans (disease and death). That was not your original point. You were clearly stating that the 1997 version (apparent 33% mortality) could be measured as less adapted to humans because it’s less lethal than the 2005 version (apparent +50% mortality) because it’s more lethal. Let’s review:

1. “The paper shows that the 2004 H5N1 virus is more lethal to mammals than the 1997 H5N1 virus. This is what you would expect from a virus that was adapting to mammals and is consistent with the first paper I cited in this thread.” - Monotreme

I responded:

2. “This is completely news to me. As a virus becomes more adapted to humans it increases in virulence? Is that what you are suggesting? Do we have epidemilogical studies that prove this assertion?” - Tram

You reponded:

3. “A virus that is not adapted in any way to mammals cannot cause any disease in mammals. Obviously, to cause a disease, a virus must be at least partially adapted to that species.” - Monotreme

Maybe DemFromCT can interpret what you were trying to say, because your answer now does not explain your earlier point that as a virus becomes from adapted to a mammal is becomes more lethal. In no way shape or form does that make sense.

Tram: From Barry’s book, “The Great Influenza”, p 176–177:

“In 1872 the French scientist C.J. Davaine was examining a specimen of blood swarming with anthrax. To determine the lethal dose he measured out various amounts of this blood and injected it into rabbits. He found it required ten drops to kill a rabbit within forty hours. He drew blood from this rabbit and infected a second rabbit, which also died. He repeated the process, infecting a third rabbit with blood from the second, and so on, passing the infection through five rabbits.

Each time he determined the minimum amount of blood necessary to kill. He discovered that the bacteria increased in virulence each time, and after going through five rabbits a lethal dose fell from 10 drops of blood to 1/100 of a drop. At the fifteenth passage, the lethal dose fell to 1/40,000 of a drop of blood. After twenty-five passages, the bacteria in the blood had become so virulent that less than 1/1,000,000 of a drop killed.

This virulence disappeared when the culture was stored. It was also specific to a species. Rats and birds survived large doses of the same blood that killed rabbits in infinitesimal amounts.

Davaine’s series of experiments marked the first demonstration of a phenomenon that became known as “passage”. This phenomenon reflects an organism’s ability to adapt to its environment. When an organism of weak pathogenicity passes from living animal to living animal, it reproduces more proficiently, growing and spreading more efficiently. this often increases virulence.

In other words, it becomes a better and more efficient killer.”

It is highly recommended that you read this book. Are you one of those persons resistant to the concept of evolution?

BP There have been many others, as in bird flu specialists-virologist who have made essentially the same basic premis as Dr. Webster, it’s just that Dr. Webster is the most senior and most experienced.


who are they ? Is there anyone who remotely supports what Webster said in the latest ABC-interview that 50% of the world population could die ?

Tram, yes this Lanka-nonsense is all over the German “boards”. He must have some disciples who are trying to spread his words. I should say that German birdflu boards’ traffic amounts to only some dozend posts daily in total and most of these are not about the pandemic threat.

Monotreme – at 21:04

The two links you are using as your support are referencing one case of child to mother transmission. While I do find this disturbing it isn’t much of a cluster.

Tom DVM – at 20:28 I am keeping my ear to the ground (it is getting a little sore) however I still haven’t seen ANY expert quoted to support the assertions being made here.

gs..23:42:

Yes, but I hesitate to say, since anti-Russian sentiment is so rife. A chap in Russia (hiss, boo!) who’s probably not educated beyond highschool. Surname: Lvov.

Subject of much ridicule about 2–3 weeks ago, was it? Someone will recall a better reference.

Should give you a good laugh, Guenter! <sneer>

Timber at 23:42 on 3/19: You are too kind. My mother is a linguist, and taught us well, so I can use a sesquipedalian vocabulary when I feel the need (sesquipedalian, from the Latin root meaning “a foot and a half,” refering to the length of the word, or other words of like kind). It is merely a pretense to intimidate the big guns on this thread into thinking that I may actually know something. I rather suspect they have seen through the facade and choose to ignore me, which is just as well since it is dangerous to attempt to swim with the sharks.

Even so, Monotreme is right in saying that viruses are most dangerous when they are sufficiently adapted to enter into a new host environment. They have not evolved in a symbiotic relationship with the host and have no evolutionary imperative (no pre-existing mechanisms to reduce pathogenicity) to maintain the new host species for sustained transmission. That is not to say an individual host will survive in a “successful” relationship: AIDS patients will die as a consequence of HIV infection without medical intervention, but not before the HIV virus has disseminated itself well enough to survive for decades in the population as a whole, and this is a relative late-comer in terms of human viral diseases. Any changes in H5N1 which make it more likely to infect and transmit H2H are extremely worrisome because they represent the earliest stages of interaction between H5N1 and humans, with no assurance of survival for new hosts while the relationship evolves.

Tram: I suspect that Monotreme may have meant an increase in pathogenicity as a result of more deaths due to greater initial infectivity. That is to say, greater ability to infect a host on the way to establishing a new relationship but not far enough along to adapt to the point of decreased pathogenicity as you point out.

There is no indication that the virus has to “lose” pathogenicity to “gain” transmissibility.

Humans and other mammals have succumbed to infection resulting from intimate contact with the virus in birds.

That H2H clusters have been small to date only indicates abortive attempts at achieving transmissibility. This represents neither a failure nor a complete success for cross-species infection. There is no conclusive evidence yet as to the ability or inability of the virus to ultimately “make the jump”.

Despite these observations, a lack of reduction in pathogenicity, coupled with new evidence that the virus can acquire the ability to bind to human receptors means we must be vigilant and prepare as if the worst will occur, for there may not be enough time to humor misplaced optimism in high places.

yes, I remember the Lvov article. Also some others from Russia. We are used here to be sceptical about anything that comes from Russia… No anti Russian sentiment, I had lots of nice correspondence chess contacts to Russia but the “news” from Russia are often unilateral and biased.

P.S. Don’t you guys ever SLEEP, let alone work?????

Tram:

With so much focus on receptor binding specificities, one might easily be forgiven for the error you seem to be making, which is to assume that if higher lethality means better transmissibility, then better transmissibility therefore means higher lethality. The virus can be transmissible without being highly lethal; lots of viruses are that. But it can’t be lethal without being transmissible; if you can’t catch it, you can’t die from it. I think this is mainly what Monotreme was trying to help you to see. In its present form, the virus is already highly pathogenic; it doesn’t need to become highly transmissible to be that. To produce a pandemic, it needs to become more transmissible — but it doesn’t have to remain anywhere near as lethal as it is (assumed to be) now; at a tenth of the current CFR, with an attack rate similar to what was seen in previous pandemics, it would be the mother of them all.

If you’re looking at entire populations, further opportunities for confusion present themselves. For example, a virus which was highly contagious yet produced milder infection could still result in more deaths than a poorly contagious yet highly lethal one — in this sense, the former would be more “lethal” simply by virtue of being more transmissible. See what I mean?

In this article which NS1 linked above, you’ll see an example of a property of the virus being studied which (if verified experimentally in “the big lab”) may equip the virus with the ability to thwart the immune system’s first line of defense — and therefore increase lethality — yet, one which does not directly involve receptor binding.

Racter-

I have a deep concern about this H5N1 ability to antagonize NF-kappaB, a transcription factor to Interferon alpha and beta - our first line of defense against viral infection.

I believe that it is this early failure to act by our our immune systems, a masking of infection, that causes the system to make the last ditch effort later when viral load is high.

Think of this last ditch effort as a person trying to drive to the hospital after a gunshot wound. They don’t know how to staunch the bleeding with a tourniquet (first line of defense). It’s already too late, but they must try to get trauma attention. Their vision is weak, coordination is low, and blood loss is dramatic so they drive 100 mph arriving at the highway exit for the hospital only minutes before bleeding to death. On taking the highway exit, they are too weakened and uncoordinated to brake properly at the main road and they crash into an embankment destroying the car and driver.

Just like Cytokinic Dysregulation brought on by interferon failure.

Tram: If you read my post at 18:58, you’ll recall that I said: “Eventually, I expect H5N1 to become no more dangerous than H3N2, but not until the pandemic has been raging for 2 years.”

The dangerous time is after a virus has adapted enough to a new host, us, to be readily transmissible but before our immune systems have been “educated”. Although Many Cats is quite correct that the human immune system never learned how to deal with HIV and, without medical intervention, it is still highly lethal in our species even after 20 years. This is a great example of a virus that came from another species, likely monkeys, where it caused little disease, but became highly lethal when it crossed species barriers and started to infect humans. Of course, if you’re a follower of Lanka…

Thanks to eyeswideopen, Many Cats and Racter for explaining my point in alternative, and more eloquent language. I agree with all of them.

“If you’re looking at entire populations, further opportunities for confusion present themselves. For example, a virus which was highly contagious yet produced milder infection could still result in more deaths than a poorly contagious yet highly lethal one — in this sense, the former would be more “lethal” simply by virtue of being more transmissible. See what I mean?”

Racter, I appreciate you efforts to explain what you thought Monotreme meant. Unfortunately he was quite specific in comparing the CFR of the 2004 virus to the 1997 virus (not pathogenicity) and using the apparently higher CFR as evidence that the virus is adapting to humans.

“The paper shows that the 2004 H5N1 virus is more lethal to mammals than the 1997 H5N1 virus. This is what you would expect from a virus that was adapting to mammals and is consistent with the first paper I cited in this thread.” - Monotreme

The paper was comparing virulence, not pathogenicity. An increase in pathogenicity would be expected as a virus adapts, I completely agree (which could end up killing more people due to increased spread) and this is what ManyCats assumes he meant, as what he said makes no sense. I’m sure he appreciates it when you or ManyCats try to explain what he said by saying what he didn’t say, as it allows him some distance between what makes sense and what he said. Using his logic, the CFR for any virus will head towards 100% as it becomes more adapted to it’s host.

Tram, I consider your role as skeptic here to be a vital one; if you’re seeing something the rest of us are not, I hope you’ll be able to be patient with us as we struggle to grasp what you’re saying. So far, it looks like what we have here is mostly a failure to communicate. I’m glad that the distinction between “virulence” and “pathogenicity” is so clear for you; I often see the terms used interchangeably. Considering that not everyone uses these in exactly the same way, it might help if you would clarify exactly what these terms mean to you. My take is that the article addressed neither directly, and that your tacit assumption that it did is a result of your continuing to equate virulence (or is it pathogenicity?) with better receptor binding — but maybe we’ll make more progress here if we try not to assume so much about what the other is assuming.

To anyone:

1. Which mammals transmit the virus to like species (or unlike species) in nature? 2.Why do we keeps seeing the term “clusters” since there has only been one “family cluster” in which virus has been confirmed to have gone H2H (infant daughter to mother). All clusters cited so far have been families in which chickens seemed to have infected the victims directly. 3. Please tell us why the following statement is incorrect: There is little or no evidence the virus is any closer to pandemic virus than in 1997. Please don’t use geographic spread of the virus as an answer unless it is accepted in any scientific discipline as part of the test for possible pandemic. Please cite any experts to support your argument. If you cite Webster please cite any expert which agrees with his analysis.

Racter – at 10:54

I think Tram’s points are very clear. What science exists to back up some of assertions being made in this thread. So far in my reading there has been little if any support for the premise we are closer to pandemic than we were years ago. In fact recent research supports the idea the virus is difficult to be made to go H2H even in the lab. Of course as the same researchers stated “of course nature could throw us a curve ball”.

…..closer to pandemic than we were years ago……

It is a pandemic if you are a bird - it wasn’t before.

DennisC – at 11:18

Tell that to the chickens in HK 97.

Yes, chickens in 97 died. But the meaning of a pandemic is not a few deaths in a limited region.. The definition of a pandemic is: “Epidemic over a wide geographic area and affecting a large proportion of the population”

It was not widely spread in 97 and did not affect a large proportion of the bird population. It does qualify now as a pandemic in birds.

It is now a pandemic in birds. Before it was not - even by your strange view, how many died in 96?

DennisC – at 11:29

Lets stay on task. No one has stated BF is not pandemic in BIRDS. We are talking about people and whether we are any closer today for pandemic in HUMANS.

“I’m glad that the distinction between “virulence” and “pathogenicity” is so clear for you; I often see the terms used interchangeably. Considering that not everyone uses these in exactly the same way, it might help if you would clarify exactly what these terms mean to you. My take is that the article addressed neither directly” - Racter

If your take is “that the article (published in the Journal of Virology) addressed neither (virulence and pathogenicity) directly” then I guess you should probably re-read it, starting with the title: Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals.

BP, Words mean things. If you mean pandemic in humans then you should say that. You indicating that it was a pandemic in birds in 87 is just wrong.

H5N1 HAS developed into a pandemic strain in birds and it has developed in to a more virulent strain in many mammals. Even if it changes to an H2H form it will not be a human pandemic until it is in many geographic regions and in a large proportion of the human population. The term pandemic is related to the numbers and area of a disease and not it virulence or pathogenicity (even though they contribute to its spread). I think that is exactly on task here.

Tram, the problem with debating you is that you don’t take the time to actually read the articles you discuss. It gets tiresome arguing past you when you just read the title and nothing further and then just make up your own story as to what the paper says. For example, the paper you keep citing in bold says nothing about CFR. H5N1 viruses isolated from humans and birds from 1997 and 2004 were experimentally introduced into mice and ferrets. The 2004 isolates were able to replicate to higher levels, and therefore cause more significant disease than the 1997 isolates.

Here is a direct quote from the paper:

“The apparent increase in virulence and expanded host range underscore a heightened risk to human health posed by recent H5N1 viruses.”

For anyone following this debate, the entire paper is open access. If you’re interested, you can read the whole thing and come to your conclusions.

Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals

“Tram, the problem with debating you is that you don’t take the time to actually read the articles you discuss. It gets tiresome arguing past you when you just read the title and nothing further and then just make up your own story as to what the paper says. ‘For example, the paper you keep citing in bold says nothing about CFR.” - Monotreme

From the paper: “Although the true numbers of human infections during the H5N1 outbreaks remain unknown, the 62% mortality rate among humans with documented H5N1 disease in 2004 and 2005 was markedly higher (WHO [http://www.who.int/en/]) than the 33% fatality rate among documented human H5N1 cases in 1997.”

Tram:

Like I said, what we have here is failure to communicate. We aren’t even talking about the same article. I was referring to the very first article linked in this thread.

Some new info from the CDC Conference on Emerging Infectious Diesease (no links yet) from anon_22:

Cambodia: March 05 After HPAI outbreak in one village, they interviewed all heads of households and questioned them about poultry death. Village 93 households, participants (serology) 351, 95% raised chicken, average size flock 20. 66% of households had poultry die-off

Then one person in that village got infected. June, 05. Repeat interview + blood tests of all people in village. Total 13 close contacts, 351 participants. Seroprevalence= 0%. Of these 68% touched live poultry, 51% collected dead poultry, 41% cleaned faeces,, 57% touched poultry organs

They also tested the blood of hcw who were completely unprotected (number unknown) and that was all negative as well.

Indonesia:

Reporting on 4 clusters involving 12 patients, total number of contacts 446, of whom only 2 tested positive.

Vietnam:

The presentation was on the h2h case, but when asked, the presenter said they had about 2% seropositive in contacts of their cases.

Also, the Indonesian study was on 12 cases with a clade 2 virus of cases in clusters with a CFR 58%.

Cambodia – 4 cases of clade 1 virus with CFR 100%. But since July 05, Cambodia did not have any more HPAI.

Bottom line: these are 2 distinctive strains but both have low seroconversion.

let’s try to depersonalize this a bit.

Um, Tram, the link you provide was not to the paper I cited. Although it does make one of my points very effectively. Thanks.

anon_22 and DemFromCT, thanks for the info from the CDC conference. Informative, but not reassuring. How many heads will this hydra have? I wonder.

“Um, Tram, the link you provide was not to the paper I cited. Although it does make one of my points very effectively. Thanks.” - Monotreme

Are you just pretending to be dense? The link was in the paper you cited @ 12:52. This is where you suggest that I “don’t take the time to actually read the articles you discuss….For example, the paper you keep citing in bold says nothing about CFR.” Well I would suggest that based on your comments that you don’t take the time to read the articles you reference!

Let me help you. Go to the article you linked @ 12:52. Then go to the “Introduction” section and scroll down to the 4th paragraph. You will find this:

“Although the true numbers of human infections during the H5N1 outbreaks remain unknown, the 62% mortality rate among humans with documented H5N1 disease in 2004 and 2005 was markedly higher (WHO [http://www.who.int/en/]) than the 33% fatality rate among documented human H5N1 cases in 1997.”

Again, don’t be confused. The link in the quote is contained in the paper you posted a link for at 12:52. You know, the one that you said says “nothing about CFR”.

It is more data, along with the news stories today, that post-1997 Hong Kong the seroprevalence data does not support widespread infection. That’s both good and bad, of course. H5N1 - hard to get it, but when you get it, it’s nasty.

WQell, I’m glad we depersonalized this discussion. Look, it’s not Tram vs Monotreme. It’s “what does the data say?”, and reasonable people can disagree in dsata interpretation.

Kapiche?

Dem, how might these stats be affected by the high rate of false negatives that we saw in places like Turkey, which actually turned out to be positive when re-tested (and then some of which turned out negative when re-tested at Weybridge).

Tram, Mono, Racter, BP et al — this may be a critical discussion, although the technical details are way over my head. If the *will* was there on all sides, it should at least be possible for you to agree on what is known/not known, clear/unclear at this point. That would be enormously helpful to the rest of us though it’s not going to happen unless egos and competitive animosities can be set aside (and I’m not even going to hazard an opinion on whose ego(s) is/are getting in the way and who sincerely seems to be seeking common ground).

I have absolutely no expertise in this area, but my common sense tells me that what happened in Turkey and now nearby Azerbaijan suggest some cause for worry. Even if there was no H2H, these unusually large recent clusters suggest the possibility of a version of the virus that can more easily go B2H. The ability of this avian virus to infect so many mammalian species, the now-widespread distribution in birds and the lethality (I’d also like clarification on the difference between virulence and pathogenicity) also warrant some warning flags, IMHO. None of this conclusively points to the virus evolving towards a pandemic strain, but it seems to me it also suggests that we can’t rule that out. So it’s unclear. But worrying nonetheless.

Maybe it’s also a futile discussion. Isn’t it impossible to conclusively demonstrate that a virus is or is not evolving towards a human pandemic (at least, until this actually happens), if we have no previous experience and well-documented evidence of the exact same thing happening in the past?

but it’s still the same virus. Very few mutations recently in this Qinghai strain. It’s stabilized and I think, that’s good news. I wished, the same were true with the Indonesian,Chinese strains.

and what strain is in Nigeria?

Name, it’s a very different test. serology (blood tests) take a lot longer to come back, but shouldn’t have the same false negative problem as PCR testing from the nose and throat we saw in turkey. They’re not perfect (they have a different problem… whether the test reflects the presence of even older infection, and whether false positives are present), but false positives are likely a bigger issue than false negatives. However, we don’t know the exact sensitivity and specificity of the tests.

And Name, the difference between ‘suggests the possibility’ and ‘conclusively demonstates’ is the main reason for the disagrteement. Very little of this is conclusively demonstrated. But worry sometimes makes us see things before they are proven.

“Isn’t it impossible to conclusively demonstrate that a virus is or is not evolving towards a human pandemic”

Yes. It is possible to establish that the virus is developing an increased affinity for human receptors (which I think we are seeing) and it is possible to establish that it is becoming more widespread in bird populations (which nobody questions at this point). In that sense, it may be said that the likelihood of a pandemic is increasing — if nothing else, by the simplest of logic, the more little genetic experiments being conducted by the virus the greater the probability of some given arrangement being stumbled upon.

But, I also think the objections raised by Tram and BP are valid, despite the unnecessary vitriol coloring their presentation. The observed instances of human infection command our attention for obvious reasons, but I agree with Tram that they are not “statistically significant”. Because we see the immunologically naive global human population as a vast opportunity for the virus, we may be rather hasty to anthroporphize this as a “goal” for the virus, and to measure everything we see happening against that.

One objection mostly hinted at is that some fundamental obstacle may prevent the virus from becoming easily transmissible between humans. I haven’t seen anyone actually attempt to present evidence that would support such a position, but I have seen some arms waving around in the air as if to suggest that doing so is all that is required to make the objection a valid one. In the absence of any such evidence, the only prudent course I see is to proceed on the assumption that the virus is a threat, that it became a threat as soon as it demonstrated an ability to infect humans at all, and that in attempting to predict its behavior, the best thing we’ve got right now is extrapolation from the behavior of other influenza viruses. We have seen the avian/human barrier crossed many times before.

Racter - well said, indeed.

DennisC:Nigeria was also the Qinghai/Europe strain. Almost identical to Kurgan,Russia. http://tinyurl.com/rv96r

“One objection mostly hinted at is that some fundamental obstacle may prevent the virus from becoming easily transmissible between humans.”

People only hint at it because they don’t know. In the recent Science paper, there was hinting as well. The fact is that they had a “difficult” time getting the virus to cross the species barrier and when they did they got some binding that “wasn’t dramatic”. The results only “suggest a possible route for the virus to enter human cells”. Increased pathogenicity is not conclusive, even when they we’re able to force it across the species barrier.

IMHO, the study confirms my past characterization that a final pandemic version is an invisible target. If we don’t know what it looks like, we can’t proclaim that we are getting closer to it.

Tram – at 17:03 - “IMHO, the study confirms my past characterization that a final pandemic version is an invisible target. If we don’t know what it looks like, we can’t proclaim that we are getting closer to it.” I would say you have a very good point. Would you agree though that with the wide spread of AI, that the “odds” for it to develop into a strain that may go H2H have risen?

Name – at 15:07

I will post again. You made a good point with your statement “None of this conclusively points to the virus evolving towards a pandemic strain, but it seems to me it also suggests that we can’t rule that out. So it’s unclear. But worrying nonetheless” I would only alter the first part by inserting: “very little of this points to the virus evolving towards”….

Cache Cow – at 17:07

Just because the physical area the virus now covers is larger I don’t see the increased danger. My fear has always been super high population density in the same area as high rates of infected birds (i.e. asia). In all the years the virus has been in asia still there has been no H2H. You can have super high permuatiotions in a dense area without going it going widespread area wise.

Bottom line, we don’t know. We have no relevent data. We are basing a lot of our assumptions on 1918, but we have no way of knowing if that is the only pattern an influenza pandemic would follow.

Virulence factors typically describe the level of pathogenicity; however, the terms virulence and pathogenicity are frequently interchanged in their reference to the general loss in fitness of a host due to an endogenous virus.

The rapid rate of repliction of H5N1 makes it highly ‘virulent’, resulting in a dramatic loss of fitness leading to a higher than average Case Fatality Rate.

Others, please clarify if you feel there is a marked distinction in the two terms?

• Virulence
• Pathogenicity

Tram, there is a difference between a citation in an introduction and the work that is reported on in a paper. In a scientific paper, the Introduction reviews other people’s work, the Results section reports the author’s work.

Ad hominem attacks aside, you have made my points for me.

Name: Not the ultimate authority, but the one on hand: from Bailliere’s Comprehensive Veterinary Dictionary: Pathogenicity: The quality of producing or the ability to produce pathological changes or disease…See also virulence. Virulence:The degree of pathogenicity of a microorganism as indicated by the case fatality rates and/or its ability to invade the tissue of the host…

Thus many things can contribute to the production of disease, but with reference to viruses, infectivity (and in the case of a pandemic, transmissibility) are integral requirements for a virus to be able to produce disease.

The paper discusses BOTH virulence AND pathogenicity as is stated in the results section:

“…of 34 ferrets infected with H5N1 viruses isolated in 1997, 35% did not recover from infection. In general, these ferrets developed neurological symptoms 7 to 13 days post-infection, necessitating euthanasia…In contrast, most ferrets infected with a comparable dose of the 2004 highly virulent H5N1 viruses died acutely without signs of neurological dysfunction… Thus, the 2004 highly virulent H5N1 viruses isolated from humans identified in this study were significantly more lethal for ferrets than the …1997 H5N1 viruses, HK483 and HK486 (P < 0.01).”--exerpted and condensed from the article cited by Monotreme at 12:52

The above describes the increased pathogenicity of the 2004 virus as comparable to the 1997 virus since the CFR increased when a “comparable” dose of virus was given in each experiment. The paper also discusses infectivity in terms of LD50 values, given in Table 2.--see article cited by Monotreme at 12:52

I hope this provides some clarification. Big guns fire away as you see fit…

Aside from knowing very little about this virus, the proponents of the theory that this virus won’t or can’t mutate into a pandemic strain are treating the 1918 occurence as an anomaly, or a fluke of nature. However, it seems that very little is known about the origins of the H1N1 strain, even though it was reconstructed in the lab. And even though there is no explanation of why there seems to be an average of 3 pandemic strains per century, there is no way to predict exactly when the next pandemic will occur. In fact, there is no data to prove that another pandemic will ever occur. However, it would show a lack of good judgment to bet on no future pandemic, even though it can’t be proven, owing to the history of the flu virus. Likewise, it would show a lack of good judgment to discount the possibility that the H5N1 strain might mutate into a pandemic strain, even though its ability to do so cannot be scientifically proven.

Flukes of Nature, like lightning do strike (more than) twice. And fires can smoulder in peat bogs or coal seams for years before starting wildfires above ground.

It isn’t just Nigeria - so many African nations have absolutely no way to track what is going on with H5N1 in humans or other animals now. Even more chances for the virus to mutate, including all the HIV+ (or immunocompromised for whatever reason) people in Africa, Asia, and Europe. There is nothing stop it going pandemic if that is what happens, so, better to be preparing.

As an aside to this rather scholarly discussion - has it occured to anyone else that 6% of all human deaths from H5N1 have been reported in the last 48 hours?

“Tram, there is a difference between a citation in an introduction and the work that is reported on in a paper.”

The fact is that you were wrong. You clearly stated that “the paper you keep citing in bold says nothing about CFR”…which I proved it did. You attacked me for not taking “the time to actually read the articles you (I) discuss”. Complete hypocrisy is what you just displayed. To top it off, you didn’t even recognize that the quote was from the paper you referenced.

This debate is ultimately going nowhere and I think everyone here is tiring of it. I will close by saying that you need to look squarly in the mirror when you speak of “Ad hominem” attacks, however. By your tone, it appears you’ve taken the suggestion of you “writing a book” a little too seriously and it’s gone straight to your head.

ManyCats, good post!

A six percent rate in 48 hours would seem nonlinear to me…

pathogenicity

the property of being able to cause disease.

virulence

aggressiveness, ability to cause disease. (adjective virulent)

From http://www.aegis.com/ni/topics/glossary/

Thanks, Tram!

Despite the contentiousness of this thread, you, Monotreme, NS1 and Racter, et al. are true giants in the wiki community and everyone benefits from your input.

Please, Big Guns, consider what I was told is a French saying: Civility is like air in the bicycle tires—it may not be essential for getting from point A to pint B, but is makes the ride much more pleasant.

Our real concern remains H5N1 and what it will or will not do. We need to remain united in effort, if divided in opinion.

Tram: I have no interest in word games. Nor in gotcha quote wars. Nor will I respond to your personal attacks (after this). There was a guy at the old Agonist Disease Outbreak board who ignited flame wars with Dr. Niman and contributed to its destruction with those tactics.

On one thing we agree on, I also liked ManyCats’ post.

Also, I want to make it clear that I don’t think I’m infallible or that I am certain that I am always right. I’m happy to discuss ideas but have no interest in discussing personalities.

Wow, 2 for 2! Love you guys! :)

Tram- without passing judgement on the whole Tram/’treme sparring session, I feel the need to make an observation that has little to do with the merits of the debate, but much to do with how it is viewed.

You’re an ass.

Perhaps an intelligent one, but an ass none the less.

That opinion is not based on whether I agree with you or not, it’s just based on your general demeanor throughout this and other threads.

I’m not saying “shut-up” or “go away” or “you’re stupid”-just that you come across as an ass, and if you’re entering into debate in these threads for the purpose of enlightening the rest of us , or giving some offsetting perspective-we’re not able to hear your logic through your seeming contempt.

Thanks for the explanations and contributions, all. It feels extraordinarily frustrating that with all this science and the immensely important questions at stake, that we cannot produce any satisfactory answers, though it’s a credit to all of you that you keep trying.

Three things I read today add to my unease:

1) The recent deaths, as noted above, including confirmation of another large cluster.

2) A report that intensive testing of birds somewhere in Northern Europe or Russia failed to show any evidence of H5N1 and then despite this, it popped up in the midst of winter when no birds were migrating and they could find no way to explain its sudden arrival.

3) Dem’s ominous stats about the CFR.

Something is clearly going on, we understand very little about it, and one potential outcome of it is extremely scary.

ManyCats: Your next task, bring peace to the Middle East.

Name: Agree completely.

Tram:

Precisely my point. It’s a strong claim; it essentially posits that the design-space available to this virus does not include any configuration which would result in efficient H2H. To hear that some mysterious unknown barrier exists (and again, I haven’t actually seen anyone do this) — would be about as compelling for me as hearing that invisible fairies prevent it.

Yes, I can agree with that, although it could probably be qualified somewhat: we do know at least a little about some of the components a pandemic strain would require, and it does seem reasonable to infer — not only from the increased numbers of human infections in recent months, but from the results of studies such as those presented here, and work being done by Niman and others — that recent changes in the virus represent progress along at least one possible pathway which may lead to its aquiring the whole package. I don’t think we know that we’re getting closer, but I do think we know that we may be getting closer (“whatever that’s worth”, you might say; and again, I’d have to agree).

BP:

What matters most is the total number of viral replications taking place. The odds against being dealt a royal flush in a single hand of poker are vanishingly small; the chances of it happening to any player in an all-night poker game are better, but not much; but turn the whole planet into a casino in which millions of poker games are being played around the clock…

As far as our collective ability to limit the spread of a pandemic virus goes, we’ve already placed our bets; by making “just-in-time” our policy for managing everything from large-scale manufacturing to individual household purchasing, we’re betting that nowhere on the planet will a single one of those players get lucky.

Gentlemen, may I suggest a topic for further study.

In 1997, a previously unknown strain of H5N1, with unique infective characteristics, was introduced into the world’s viral landscape.

Since May 2004 at Q. Lake in China, the geographical spread and opportunity has increased significantly.

1) The increasing spread into virgin territory, previously unaffected, has increased the opportunity for direct mutation.

2) H5N1’s potential ability to infect children co-infected with other influenza viruses combined with its unique character, provides ample opportunity for recombination etc (H5N12 selects higher lung temperatures fulfilled by co-infection with other viruses…Katerina et al). The geographical spread will soon produce a mechanism for interaction with all previously known influenza field viruses.

3) The resulting viri may have little resemblance to the original, two primary strains observed to this point in Asia.

4) Is there a potential for multiple pandemics using the same virus for raw materials of previously unseen components.

You’re making a lot of sense to me, Racter!

Racter: I agree with your analysis.

A casual mate at the pub, a Scotsman, knowing only that I have some interest, asked me about Australian government expenditures on H5N1 and also worldwide layouts. He was clearly aghast at the huge figures I could approximate.

“Well, I can only HOPE that thing does turn out (‘oout’) that pandemic strain!” he exclaimed. “Otherwise a mickle lot of wasting of money!”

Jack does hate to see money wasted, so he puts his into beer. I had to admit I hadn’t thought about that problem! So I shouted (‘bought’) the next round.

Maybe Tram should turn to economics and accuse Monotreme, et al, of just wanting to protect their expenditures to date by hoping for a pandemic? He’s tried everything else and he most certainly is not a ‘quitter’ I think all agree!

Come to think of it, that may partly explain my own cheerful pessimism! <grin>

TomDVD—19:23

Re your point 4):

Just what CDC yesterday (2 days ago now?) expressed as a concern in those of the reports that were more complete.

That should quiet Jack a bit, more return for the $$$ in that case….

You don’t expect a bunny to bark. You wouldn’t expect a Rottweiler to meow. But again and again on these discussion threads I see one post-er or another get testy when some one replies in a different manner than in the questioner’s “voice” or style. There seems to be very little patience when someone responds “while flying at a different altitude.” What a prickly bunch! (And sometimes you can leave off the -ly). Less hammer and more effort in decoding, please!

Olymom, perhaps you haven’t been reading these threads for many moons. But these dust ups happen now and again. These are brilliant guys. I don’t understand most of it, but I read it hoping it will eventually make sense to me. It’s all par for the course. It’s late, time to go to bed. Hope everything settles down by morning. Good nite Y’all, I admire you all.

I work with a fellow who is quite smart and capable but has the problem of having his sense of self-worth wrapped up in his ideas. You cannot question his ideas without triggering a HUGE defensive response. He also likes to argue. ALOT. These together are a deadly combination. As a result he has become much less effective in that folks have learned to just steer clear of this person. He is not included in many discussions and has become somewhat marginalized in his capacity and his talents wasted in many regards. When he attempts to engage me in an argument I simply won’t be engaged because it is simply a no-win situation. To some extent end game for him is the conflict itself. If he gets an argument out of me he “wins” apart from the argument itself. So I just don’t participate. In any case I believe that when your ideas are so important to you that your sense of self is threatened when those ideas are questions you might want to think about why that is the case.

OK, re-engage! Any other articles/news/etc. that anyone has come across to indicate whether H5N1 is moving closer to becoming a pandemic threat or not? I still think Monotreme’s initial post is too important to lose in the rancor. There may be no evidence that the Sun exploded 5 seconds ago and we won’t know one way or the other for another 3 seconds or so, but I would sincerely doubt it and I would sincerely doubt that H5N1 is an entity that we can ignore, either. Back on track!

Keep an eye on the cdcieid conference. Anon_22 posts interesting data about Indonesia. it’s not at the molecular level, it’s at the epidemiological level.

Here’s a disturbing thought: what if the bird flu never goes human-to-human, but instead gets really good at going from bird-to-human? Right now, it takes a large viral load to infect a human, but what kind of changes would the virus have to make to easily infect humans (via digestive tract, for example) in a very small viral load? In other words, H5N1 is almost all over the world right now. It wouldn’t matter if it ever went H2H if all you had to do was walk through an area where there had been bird droppings in the last 10 days to get it. Is that kind of scenario possible?

DeJure: Sure, anything is possible at this point. The scenario is basically already happening in alot of places in the world. However, if it remained a B2H problem, it would be a major health issue but would not have all of the ramifications of a pandemic(collapse of such industries as travel, stock markets, public services, etc). It would not bring the world to a grinding halt. Am not minimizing the threat in the least but, like AIDS, would be a health problem for those who got it and something the rest of us would take precautions against acquiring. It would become a part of everyday life as AIDS is.

De Jure at 21:43: Don’t you think that would just be another route to h2h? With that kind of “saturation bombing” I woul think that whatever barrier that previously existed to h2h would be obliterated.

Logically, I might give your idea some credence, if we had not already seen limited h2h.

Medical Maven. I haven’t heard a better or more accurate or more concise statement that describes this point in time.

Medical Maven: I agree that this might be another route, but I’m thinking a two-step process. If S227N is now reserved in one or more of the circulating strains, how many more polymorphisms would be needed to switch the receptor affinity from avian to human to the point where the virus went directly from bird to human? Might not this be an easier approach for the virus instead of reassorting in a dual-infected host? Then from that point I agree: the saturation would almost be complete.

As Many Cats suggests, an article on topic from the Times (UK) discussing increased pandemic risk:

The above adds a few ‘expert opinions’ on the topic of this thread.

Kinda’ like living in London with 2 Jack the Rippers roaming around….

I keep thinking of that little dittie that the children made up back in 1918 to skip rope to: “I had a little bird, it’s name was Enza, I opened the window and in-flew-Enza.” Kind of creepy, isn’t it? And they didn’t even know back then that their “flew” came from the birds…out of the mouth of babes.

De jure

Ring around the rosy was a Black death nursery rhyme. Right down to the ‘all fall down’.

Something else that Garten said that I thought was interesting, that Clade 1 virus sequences showed very little diversity, whereas Clade 2 had a lot more diversity right from the beginning.

This notion that genetic diversity gives more biological advantage reminds me of what we used to teach in coaching: that the system (or person) with the most flexibility of behavior has the highest chance of success.

For example, if you are a parent with a 2-year old who likes to throw temper tantrums on the floor in the grocery store to get his way, and you are easily embarrassed and therefore have great aversion to anything that will escalate the episode, then the 2 year old is very likely to get his way more often than not. Converse, if you stop self-censoring your own behavior and start to choose from a wider range of responses, you are more likely to win. So, if next time the kid does not do what you tell him to do, you throw yourself on the grocery store floor and start screaming and crying and whinging, I assure you that pretty quickly the kid will get so shocked and then embarrassed he will probably not want to try that again. :-)

This virus has no qualms or difficulty about killing people, birds, anything, to get to its endpoint. We do.

For example, we will not and/or cannot cull all wild birds or cats or dogs or pigs.

That’s why we are at such a huge disadvantage biologically……….

Cluster, Familial. observed and reported by WHO with BIMODAL distribution of fatality.

Are we moving toward

• more efficient and sustained reporting?
• more efficient and sustained transmission?

WHO Update 2006-03-21

<SNP>

Six of the cases occurred in Salyan Rayon in the south-eastern part of the country. All six cases resided in the small Daikyand settlement of around 800 homes.

A 17-year-old girl died on 23 February. Her first cousin, a 20-year-old woman, died on 3 March. The 16-year-old brother of this woman died on 10 March. A 17-year-old girl, a close friend of the family, died on 8 March. All four of these cases lived together or near each other. The source of their infection is presently under investigation.

<SNP>

anon_22 :

It depends.

There is always a trade-off between generalization and specialization. The specialist may have a better chance of exploiting resources efficiently, while the generalist stands a better chance of surviving the transition to a new environment. Think of a Swiss army knife; carry one, and you’re ready for anything — but can you imagine, say, giving a decent haircut with the little scissors that are included? So, where resources are plentiful, we’d expect to see a trend toward greater efficiency through specialization, and where new environments are being explored, we’d expect to see the first successful colonies established by generalists. (It’s actually more complicated than that; even within an established range, the greater the numbers of specialists, the greater the advantage in being a generalist, and vice versa).

Currently, we, the global human population, are at the periphery of the virus’s natural range: the global avian population. Those strains best adapted to produce infection in birds (i.e., the most specialized) are busy doing that, and those strains with more flexibility (i.e., the most diversified) are more likely to be the ones producing infection in humans, and the most likely to lead to pandemic strain. It is inevitable (unless Niman is right, and there is significant recycling of old mutations via recombination) that these prospective colonists have paid a price for this flexibility. Considering receptor affinities alone (as usual), they cannot be both well adapted to birds and better adapted to humans — and therefore those strains cannot be expected to persist in avian populations, as they are unlikely to be optimally competitive. This is why I am inclined to go along with those who have voiced objections that — in an important sense — the virus is not “moving toward” more efficient H2H.

Racter-

You are leaving a lot of people hanging here?

Are you saying that H5N1 isolates are diverging and that there may be one set that is capable in birds and yet another set that is fully human-grade?

No.

I’m saying that diversity in the genomes being examined is not surprising — where samples include isolates taken from infected human patients, it’s actually just what we’d expect — and that results of that sort tend to be very pliable in the hands of various interpreters. I really like what you said about more efficient and sustained transmission versus more efficient and sustained reporting; the tricky thing about observer bias is that (pretty much by definition) you can’t be aware of when you are doing it — and no matter how hard you try not to do it, you’re probably still doing it anyway. The very first opportunity occurs before the results are even in; before you’ve looked at anything, you’ve already made some inevitably biased choices about what to look at, and how to measure it.

It’s bad enough when results are being examined directly by a trained scientist; scientists are human, and therefore subject to various human motives and foibles (appreciation of which is sometimes best accomplished by someone other than the person himself, and — as demonstrated above — sometimes not). It’s worse when you’re hearing the results interpreted by someone else, even where that someone else is a trained scientist. When all you’re getting is some reporter’s version of some scientist’s interpretation of the results of some study, it’s probably best to be cautious in reaching conclusions.

it’s probably best to be cautious in reaching conclusions.

LOL. That’s always been very true, including about WHO, CDC, Mill Hill etc. and their reporting of the reporting.

But not to worry. It won’t stop us from reaching conclusions. ;-)

Anyway, I had a chance to review this thread from the beginning. wonderful stuff, here. Thanks all (including the skeptics).

I strongly agree with Racter’s conclusion. I find it interesting the amount of credence placed in news reports versus the statements made by people who work with the problem. Even those who work in the field could be a little more circumspect.

It is useful to hear about how it works, and what is known. Speculation about how it might work is much less useful. The individual is likely to use their own perspective (bias). Which could be somewhat useful if identified.

It is also interesting to note how individuals take organizations to task but are unwilling to identify themselves and their own credentials. One scientist I greatly admired said that if you told him where a person went to school he could tell you what they would think about the problem. Over the years, I have learned there is a great deal of truth to this position.

One must definitely read with care. I have also noted that “great” scientists are modest: They can always point to someone with more expertise than their own and seldom become ego involved because ego is a contaminant.

It would be helpful if there was more realization of these problems here.

Dem

DemFromCT – at 21:41

Well this data from Indonesia seems to strongly indicate H2H in that cluster. Am I wrong in my interpretation?

DemFromCT – at 22:13

That seems to answer my question of the importance of wider geographic distribution. Any more bad news for us today?!

Bad news and goosd news every day ;-)

To me, Indonesia is my biggest worry. Different clade, different issues (no culling), ongoing cases, large population…

“Considering receptor affinities alone (as usual), they cannot be both well adapted to birds and better adapted to humans — and therefore those strains cannot be expected to persist in avian populations, as they are unlikely to be optimally competitive. This is why I am inclined to go along with those who have voiced objections that — in an important sense — the virus is not “moving toward” more efficient H2H.”

Racter, I completely agree. You’ve incorporated a key component into your analysis that is always ignored and that is natural selection. The virus can’t have a greater affinity for bird and humans at the same time. In fact, a strong argument can be made that with the increased spread of the virus via wild birds, we are simply seeing the virus become more “avian”. With increased avian diversity, evolutionary pressures will force the virus, over time, to become less deadly and eventually it will simply become a LPAI. We’ve seen this with every single human influenza pandemic in history. This is not to suggest that it can’t continue to infect mammals B-M, and as long as the virus exists it will retain some capacity to mutate.

Monotreme, one final item that I’d like to answer to regarding your attack on me after I asked gs if we was familiar with the German virologist Stefan Lanka. Your statements below demonstrate your disdain for him due to his theory that HIV does not cause AIDS. As I clearly stated, I have no opinion on it, since I have not studied it. My interest was only in some of his views on the H5N1 virus (especially how it’s been isolated and the lack of proof via viral loads of it’s causation in the deaths of humans). Upon doing a brief bit of research, I’ve found that there a many other qualified experts that share in Dr. Lanka’s skepticism regarding the HIV/AIDS link including Nobel prize winners. The lesson here is that maybe, just maybe, you shouldn’t be so quick to attack those whose opinions might differ from yours or whose ideas might not fit neatly within the framework of conventional wisdom.

“The reason why I ask you about HIV and AIDS is because the virologist you cite as worthy of interest, Stefan Lanka, doesn’t believe HIV causes AIDS. The fact that you find this sort of “expert” credible speaks volumnes.” - Monotreme @ 20:11

…

“Yeah, real interesting ideas. Maybe he’s in communication with the aliens who abducted Elvis and know’s what planet they took him to.” - Monotreme @ 20:11

…

Some other researchers who question the link of HIV & AIDS:

Harvey Bialy, molecular biologist, research editor of Biotechnology.

Peter Duesberg, Professor of Molecular Biology, UC Berkeley.

Kary Mullis, Nobel Prize in Chemistry (1993) for the discovery of the polymerase chain reaction (PCR).

Robert Root-Bernstein, Associate professor of physiology at Michigan State University, E East Lansing; author of Rethinking AIDS: The Tragic Cost of Premature Consensus, New York Free Press, 1993; author of Diversity (Harvard University Press, 1989; former MacArthur Fellow (1981–1986).

Harry Rubin, Professor of Molecular Biology, UC Berkeley.

Richard Strohman, Professor Emeritus of Molecular and Cell Biology, UC Berkeley; former Director of the Health and Medical Sciences Program at UC Berkeley.

Tram:

Well, I’m hardly the first to take natural selection into account; the concept is arguably the most powerful explanatory tool ever placed in the hands of biologists. Perhaps because of this, however, it does seem to me that what can easily be overlooked is that the application of this tool is somewhat error-prone — and I’d actually be inclined to suspect that rather more of the errors result from excess enthusiasm than from under-application. Perhaps the most common error I notice is what is sometimes referred to as the “just-so story”. It can happen when a top-down approach is used (starting from an intuitively compelling idea about how things should work, and looking for examples in the real world) or when a bottom-up approach is used (starting with an observed statistical trend in the distribution of alleles in a genome, and attempting to explain that as the action of selection upon some yet-to-be-identified trait). I’m not saying that either of these approaches is intrinsically flawed; merely that the prcess provides generous opportunities for bias all around. Natural selection is a statement about probabilities; and, as such, it’s really more of a guideline than a rule.

As long as the virus exists, we can expect to continue to see these peripheral isolates defy selection by spilling over into the human population, and that places us at risk. As the frequency of these spillover events increases, the risk that one will find a fortuitous foothold increases accordingly. In that sense — in a probabilistic sense — saying that “the virus is moving toward more efficient H2H” is, if not strictly accurate, close enough to justify our taking strong action.

As for the rest — let it go, dude.

Tram - “With increased avian diversity, evolutionary pressures will force the virus, over time, to become less deadly and eventually it will simply become a LPAI. We’ve seen this with every single human influenza pandemic in history. “

With this you imply two contradictory views (actually, more than that if you count the fact that your second sentence contradicts your sustained opposition to the notion that H5N1 is evolving toward a human pandemic strain).

In one sentence you say H5N1 will be forced by “evolutionary pressures” into a “less deadly” virus. In the next you say “we’ve seen this with every single human influenza pandemic in history.” Should we be comforted then that after a “human influenza pandemic” H5N1 will become less pathogenic?

I must be missing something here.

In the end, the virus will show us what it will do. I base my actions to prep on one simple fact. An avian flu in 1918 made a jump to humans, it did not listen to any of the arguments pro or con for it doing this. It did it. I learned in calculus classes that any event over time and with enough chances will happen. Time and chances and sustained effort. With the number of known and not yet known factors in this discussion, not even an Einstein could create a mathematical model to predict with any range of certainties what will come about. The extended time, more chances, and its sustainability are what have me worried.

“In one sentence you say H5N1 will be forced by “evolutionary pressures” into a “less deadly” virus. In the next you say “we’ve seen this with every single human influenza pandemic in history.” Should we be comforted then that after a “human influenza pandemic” H5N1 will become less pathogenic?” - Scaredy Cat

Scaredy Cat, a human pandemic is not a requirement for natural selection to make H5N1 less deadly.

The news (see new thread 22) is that bird flu type N5 was found in Mexico and they are testing even now. My question is: is it possible for N5H2 to recombine with the H3N2 that we know is in Mexico (in birds, humans and swine) to gain the needed genes for the H2H we all fear? I am sorry I just have not followed the sequence info like most, but I am sure some here will have a ready answer (or two). It was the H3N2 that killed those 11 in Guatemala last week.

Bird flu can’t spread easily in humans: expert

Scientists said on Wednesday they may have uncovered why the H5N1 avian flu that is so lethal in birds has not been able to spread easily among humans.

It is because bird flu viruses attach to receptors, or molecules on cells, in different regions of the respiratory system from human influenza viruses.

Receptors act like doorways that allow the virus to enter the cell, multiply and infect other cells. Humans have receptors for avian viruses, including H5N1, but they are found deep within the lungs.

Cells in the upper airway in humans lack the receptors targeted by avian flu viruses, which limit their ability to spread from person to person.

“For the viruses to be transmitted efficiently, they have to multiply in the upper portion of the respiratory system so that they can be transmitted by coughing and sneezing,” said Dr Yoshihiro Kawaoka, a virologist at the University of Wisconsin-Madison, who led the research team.

See Avian flu: Influenza virus receptors in the human airway

Note the above is a description of ‘what is’, not ‘what will be’.

DennisCra-

If the H5 is in proximity to H3N2, there will likely be some recombination.

Niman could tell us the potentiality of important polymorphisms occcuring between the two in any particular area where sequences have been deposited in GenBank.

NS1

Thanks,I am new to this. I really very unsure about all this, but it looks like a potential problem to me. Let me know if you hear anything.

‘Bird flu can’t spread easily in humans: expert’…yet.

If we held a discussion in 1996 about whether a high pathogenic avian flu could infect humans the predominant attitude would be no.

If we held a discussion in 1998, the conclusion would be that Hong Kong 1997 was an abberation not to be repeated.

If we held a discussion in 2003 about other species of animals that could be infected asymptomatically or infected and killed, the predominant opinion would be not possible.

If we held a discussion in Jan 2005 on the mortality rate in humans increasing instead of decreasing, the opinion would be highly unlikely or impossible.

If we held a discussion in Jan 2005 on H5N1 being around the world in fall 2006, the opinion would be unlikely or impossible.

we are presently having a discussion on whether H5N1 has the potential to become a pandemic. The majority of experts say yes, the majority of politicians say no, and the population largely isn’t interested.

The pertinent question is how many battles in history were lost by underestimating your opponent vs how many battles in history were lost by overestimating your opponent. Our opponent has a bad habit of ignoring the opinions of humans.

The opportunity for a bad outcome is determined by template and time. The whole world is its template and H5N1 has shown us that it is very patient. We have learned today that it can infect pigs and spread between pigs asymptomatically. Pigs are the flu virus’es best friend…it is the mixing vessel.

What would comfort me is evidence that it did not have the characteristic of all flu viruses to mutate ….and rather than having a barrier to infect humans, a barrier preventing it from reassorting, recombining or in any other way to remix with the human virus of its choice.

The virus we are looking at today doesn’t matter. What matters is the opportunities it has to transform itself in the future…and it now has an infinite opportunity to do just that.

Tom-

Excellent introspection. You’ve summarized well.

Dennis-

Start at the beginning if you really want to see the trend. The reveres and others have posted excellent articles here on the science details. Read all of niman’s commentaries at recombinomics in order for a blow-by-blow account.

On msnbc today i saw a reporter say no need to fear bird flu they mentioned this report. my heart sank. what a bunch of mixed messages the media has spread in the last week im sure the public will think another y2k no need to worry. the boy who cried wolf did get eaten by a wolf.

Every poultry farmer in North America is going to try and isolate his flock from wild birds. Incorporated in this, is to have grain storage and feed production facilities also totally isolated from wild birds and their droppings. I hope it works for them as there is a no more honest and hardworking group of people. I fear it is an impossibility.

Secondly, the plan is to isolate domestic birds but no action has been taken with respect to pigs or boars, which are omnivores. What do you think happens to a bird with H5N1 that falls out of the sky into a pig pen?

From DemFromCT – at 17:14

Note the above is a description of ‘what is’, not ‘what will be’.

My thought on it is that could also: what WAS

the following is an except from the top link in your 17:12,

“Scientists do not know how far the H5N1 has mutated…”

I’ve read many posts in other threads stating that only a certain few people in the world currently have access to “that database”, which contains CURRENT strains of H5N1.

I do not doubt that the doctors in those articles are 1000 times more inteligent then I on this subject, but, no where in the article did it mention the “age” of the virus that they analyzed.

Was it from Hong Kong 1997?

Was it from Vietnam 2004?

Doesn’t say… so I’m taking there findings as “probably” old news…

Lunch.

LOL! my previous post was referring to Tom DVM’s post at 18:57

MaMa Right again.

I must be missing something. Headline “Bird flu can’t spread easily in humans: expert” Well DUH!!! I’m not an expert and I could have told em that. Of course there is currently a reason why H5N1 is not highly contagious H2H. That is apparent from its behaviour. Why then does it follow that knowing what that something is should to be of great comfort to us given that what has been identified is subject to mutation?

I don’t think that the public yet gets the notion that the FLU virus survives and prospers thorugh its amazing ability to change its genetic structure through multiple means. THAT’S WHY WE NEED A NEW FLU SHOT EVERY YEAR!

This all seems like grasping at straws to me. There is no indication that the genetic changes necessary to create a more infectious virus is either likely or unlikely. It is a complete unknown. All we know is that should it happen there are about 6.5 BILLION people this critter would like to have for lunch. That’s quit a buffet. Prep on people… prep on.

Tom DVM, I agree it’s important to look at the big picture as we are all going to be forced to live with H5N1 eventually. Just like pet owners will have to adjust their habits, other vulnerable species should be considered as well.

my 2¢

the article is about analysis of human lung tissue, not viral analysis. The fact that the virus can change is very relevant, but not what the article is about. in that sense, there’s no virus age, old or new, or location to discuss. it’s an explanation of current behavior based on location of viral receptors in the lung and not a prediction of future behavior.

NW

Figuring out the ‘why’ of what appears to be obvious is always a plus. It gives insight into “why else” and “what next”. ;-)

TomDVM at 18:31 and NW at 19:17 - I will be reading your posts to skeptics I know. You both said it better than I ever could have. Thanks.

I have spent my life with farmers because there is nobody I would rather be with…and I have spent a lot of time cleaning up messes because they sometimes take statements from supposed experts at face value.

There are a lot of regulators and politicians around the world stating that “keep in mind, this is just a disease of chickens”. If I am a farmer with a pigs to feed and I buy that statement at ‘face value’. Where do you think the dead chickens are going to end up?

NOVA had a science movie on several weeks ago that basically said for the virus to mutate to the human to human virus it would have to go through millions of sequences. Then they said something like “it would be like someone winning the lotto twice” …

They couldn’t say “it would be like someone winning the lotto’ because someone always does. ;-)

lol…someone winning the lotto twice….honest, thats what it said….

Just a couple of notes from the wild. <g>

Lightning strikes twice for Taree Grandfather – double winner is one of three players sharing $500,000

A 70-year-old Taree grandfather who had already won $1 million in Lotto was one of three winners sharing in the game’s First Division prize of $500,000 last night.

— A woman who won $1 million playing a Pennsylvania Lottery scratch-off ticket earlier this year won another million on the same game Thursday.

Donna Goeppert, 55, of Bethlehem said it was “just unbelievable” after filing her claim Friday at lottery headquarters. “What are the odds of that?” she asked.

The odds of winning just once are 1.44 million-to-1, according to the lottery. Lehigh University engineering professor Bob Storer placed the odds of winning twice after buying 100 tickets at 419 million-to-1.

—

Remember, the law of averages basically says : Anything that CAN happen, Will.

: 0….Gulp!!!!!

Fla-Medic,

That gives me chills.

I think I’ll keep prepping….

Fla-Medic, I hope this virus is a very unlucky gambler.

but later in the didease the virus infects almost any organ. So it should spread also by coughing and sneezing then. But maybe the victim is too sick by then to spread the virus efficiently.

Can’t we remove or manipulate these binding cells ? Why do they bind viruses ? That’s not what they were made for. Apparantly other animals have cells which do their work but don’t allow H5N1 to bind.

Some medicine to change this binding behaviour ?

sue – at 19:42

Winning the lottery TWICE does seem about impossible doesn’t it?

A lady in New Jersey has in fact already done that…

From a MoneyCentral article:

“Winning the lottery isn’t always what it’s cracked up to be,” says Evelyn Adams, who won the New Jersey lottery not just once, but twice (1985, 1986),

tamiflu and relenza work by changing binding behavior. From Moscona, 2005, NEJM.

Of course, it’s binding-in-reverse. You want something to prevent the HA binding in the first place.

Bird Flu: “This thing just continues to march”

Will H5N1 be the pandemic strain, and will it occur in the next six to twelve months? The answer is, we don’t know. What is troubling about this virus is that this thing has continued to mutate from its earliest days, in Hong Kong in 1997. And what is very, very troubling to us is that it’s mutating in very similar fashion to the way the 1918 virus did. We went back with the 1918 virus and found all eight genes of that virus in tissue samples—five from soldiers’ pathology slides that had been stored away, three from the recovered corpse in Alaska. They didn’t have any live virus, but they’ve been able to make the virus from those eight genes. And by studying that, they could determine how it actually mutated and jumped directly to humans from birds. It didn’t go through other species as the 1957 and 1968 viruses did, where a bird and a human virus got together, most likely in a pig lot, because pigs happen to be the universal recipients for both [birds and humans].

snip

Then, when you look at the Turkey virus—that thing mutated. This is the case of the young girl in Turkey who died from her infection, and so did her uncle. We definitely have clusters where it’s not just bird contact [spreading the virus]. The uncle’s only exposure to this virus was riding in the ambulance with her from hospital one to hospital two. He became ill three days later and died. Her virus has now been fully sequenced, and there were three mutations that occurred in that virus, between the bird version and hers. One was the substitution of a glutamic acid with lysine at the 223-hemagglutinin position. That is what changes it from a bird-receptor virus to a human-receptor virus. The second thing was two other substitutions that served to make it look more and more like a human virus.

snip

The mortality rate so far for this virus is around 55 percent, so this virus would have to attenuate a lot to get down to that level. And we do have good data. There are not a lot of mild, asymptomatic infections out there [with H5N1]. We’re now aware of six studies involving over 5,000 close contacts of H5N1-infected people, in Indonesia, Vietnam, and Hong Kong, in which less than one person per thousand contacts had evidence of an H5N1 infection that was missed—that is, a mild infection

Sorry for the cross-posting on another thread, but I think this germane to this thread.

‘treme,

Not good news, eh?

“Can’t we remove or manipulate these binding cells?”

Destruction of infected cells is part of what happens during the early stages of the natural immune response. The phrase: “coughing your lungs out” comes to mind.

“Some medicine to change this binding behaviour?”

Good thinking. There are medicines that do this. They’re called vaccines, and though they don’t change the binding behavior directly, they help the immune system get started producing components (called antibodies) that do, among other things. Look for a vaccine specially formulated for H5N1 at a pharmacy near you, like about five years after the start of a pandemic (if you’re somebody important, you might get one as soon as about six months).

Racter – at 21:35

(if you’re somebody important, you might get one as soon as about six months).

Yeah, well, theirs prolly won’t work, if that’s any consolation.

Racter,

Is there a way to “load” the binding sites with something else (competitive inhibition as a chemist would say) so that they would be occupied and the virus would not be able to bind?

Dem,

I suspect that you and I could construct some scenarios:-)

The binding sites have functions other than providing a convenient entry point for virions. Though some antibodies do target infected cells in this way, massively glomming up the binding sites on healthy cells would have adverse consequences. Neutralizing the virions themselves is the favored approach, and this is just what happens. It’s a beautiful system, really; far more elegant than anything we’re likely to come up with anytime soon.

Jared Diamond’s fascinating view of human history “Guns, Germs & Steel” talks about the key role of our western germs in shaping the course of history. Those germs—from measles and smallpox to flu viruses—were themeselves shaped by us, evolving to become human germs when our ancestors abandoned their hunter gatherer ways and settled down in dense communities with domesticated animals.

The point is that while we seem to know very little about how or when or why or even if, the broad idea of H5N1 evolving towards a human pandemic strain would certainly fit a very familiar pattern, even if we still can’t understand the mechanisms whereby that might occur well enough to know whether indeed that is what is happening or not.

It should be expected that in a world with unprecedented population densities, mega-cities, factory farms, intimate human/pet/domestic animal/wild animal contact, globalized production, unprecedented international trade and jet travel, we should be expecting a whole lot more of this, perhaps in more extreme ways than we’ve ever seen before.

Name,

Jared Diamond’s more recent book, “Collapse” may be even more of the moment for this discussion.

The situation unfolding has a military dimension. I’m not simply talking about bioterror. I’m talking about information, virus data, etc. That information will not be released. I encourage all of you to dig as deep as you can. However, we are currently being told to prepare. I would, at this point, take this as an indication of where this situation is heading. I hope there are not folks waiting for you to solve this riddle before they prep. You will never have all the pieces to solve it. Roman

Melanie: Not good news. What I want to know is how did Osterholm hear about the ambulance ride? I never saw this in the news. Did I just miss this somehow?

so it’s partially human to human, what is this about missing data from the clusters in Indonesia? are we waiting to find out if some of those were human to human? How far then do we go until it’s declared? Bird Flu is transferring human to human.

Monotreme,

The event was 8 or so weeks ago. I haven’t found it specifically yet. I would hope that Osterholm would have access to more direct information that just the net.

moeb

It still worries me that we are just learning of the Uncle in the ambulance H2H 8 weeks after the event. I wonder how long it will be before we learn about Indonesia.

Mono, I’m wondering if that Osterholm report confused the Turkey and Iraq cases, or if he was actually referring to Iraq. The index case in Turkey was a boy, not a girl—he was the one who had the unique mutation. Iraq began with a young girl, followed by her uncle and no clear history of contact with birds for either one (the girl’s mother insisted that she hated chickens and avoided being around them and the uncle got sick after caring for her.)

Name,

I like that- it would just about fit the time line right.

As to preparing, I find it interesting that the maker of Tamiflu has announced that ALL of its employees and thier families will get Tamiflu if a pandemic breaks out …which means, I think, that they already have stockiled the neccessary while ramping up to make as much as they can, because they could sell even more. So someone in the private sector is putting thier money on a pandemic, relatively soon.

One thing I got of the interview with Dr. Michael Osterholm in City People was that the expected dumbed-down virus that will cause a mild pandemics is dependent on an intermediate host. If this doesn’t happen, then the virus doesn’t lose any of its virulence.

Published March 23. 2006 6:01AM Studies Suggest Avian Flu Pandemic Isn’t Imminent

…

The avian virus would need to accumulate many mutations in its genetic material before it could become a pandemic strain, said Yoshihiro Kawaoka, a virologist at the University of Tokyo and the University of Wisconsin.

…

Viruses find it difficult to switch hosts, and though they may quite often cause outbreaks in just a few individuals, “viruses that produce a self-sustaining chain of transmission in the new host appear rare,” Dr. Kawaoka writes in the current Annual Review of Microbiology. “Most of these transfers are dead ends,” he said.

…

The H5 virus has been present in the human population since the late 1950′s, said Dr. Offit of Children’s Hospital, but has never acquired the full set of mutations needed to set off a pandemic. Such epidemiological evidence “should make us feel safe that there’s a substantial barrier,” he said, noting the small number of people who have been infected.

…

Dr. Offit (a virologist at the Children’s Hospital of Philadelphia) said it was a good thing to worry about the next flu pandemic, given that about three can be expected every century. “What’s not good is to try to sell the public on their fear of pandemic flu being this particular bird flu, since if it’s not, crying wolf will lose you credibility,” he said.

…

http://tinyurl.com/hr4f5

I would like to know why this report on the Japanese researchers, says they found a sample of H5N1 from a Hong Kong victim, that had adapted to the alpha 2,6 receptors. Does someone have the “Nature” original article?

http://tinyurl.com/qk3a9

[The Japanese researchers, who published their findings in Nature, also tested an H5N1 virus taken from a person who died of bird flu in Hong Kong in 2003. That microbe’s hemagglutinin recognized both the human and bird linkages, and it attached to cells from nose to lung. Most H5N1 samples isolated from people do not generally follow that pattern. The ability to bind to alpha 2,6 human receptors is one of several features that would have to become dominant for the H5N1 virus to become easily transmitted from human to human.]

The studies DON’T suggest that avian flu pandemic isn’t imminent; news reports suggest that the studies suggest that avian flu pandemic isn’t imminent. The studies provide further confirmation of what virologists have been saying for some time: that to produce a pandemic, the virus would need to aquire mutations associated with receptor affinities, and that the virus hasn’t done that yet. Everything that follows is just somebody’s interpretation of the results (and interpretations of those interpretations).

“The H5 virus has been present in the human population since the late 1950′s, [ ] but has never acquired the full set of mutations needed to set off a pandemic. Such epidemiological evidence should make us feel safe that there’s a substantial barrier.”

I find that to be a dangerous and irresponsible statement. If Offit has evidence that such a barrier exists, he should present it. He hasn’t done that; what he’s done instead is attempt to persuade us that the fact that the virus has not aquired efficient H2H transmissibility constitutes “epidemiological evidence” that there is a substantial barrier.

If the bomb squad determines that an explosive device found in a building can’t go off because the wires aren’t connected properly or something, that’s one thing — but to assume that it can’t go off simply because it hasn’t done so yet would be ridiculous.

One thing that bothers me about all these “positive news” reports is that they keep refering to the “old” strains of the virus that a few years old. Since then, we know it has split into at least 2 distinctive branches. -and even that is a few years old news. We are behind this viurs by months if not years and a mutation can occur at anytime. Look at how the regular flu mutates year to year. Are we not expecting this flu to mutate at all in 3 years?

When the info comes out about more modern sequences…that is what we need to pay more attention to. -like the girl and her uncle… that is a little newer. Where are the Azeri sequences? New Indonesian sequences? Chinese ones?

We are looking at photographs of the virus from years ago saying “see, not to worry because this is what it looked like” -the problem is, if we look at a picture TODAY, will we still see the same virus?

(I have pictures of my aunt from 3 years ago. I look at her know and can recognize it is her, but the fact that she lost like 200 lbs. makes her a lot different…not just looking, but the way she acts now too. -I like that analogy of the virus.)

Racter: Like an old World War II bomb degrading for decades, becoming unstable, and then just the right vibration sets it off. Except what we have is worse. We will soon a a world-full of the these degrading/mutating viral bombs in numerous species, including Humans.

Monotreme’s snip at 21:12 mentions mutations in the virus of a Turkey Victim. My snip at 13:23 mentions mutations in a Hong Kong victim. These mutations may have dead-ended with the death of the victim, and did not succeed with the last part needed for transmission: “getting out of the swamp and into another person”. Since new viruses adapt from birds to humans, three times a century, ad infinitum, using the word “barrier” would not fit my definition of the word.

“If Offit has evidence that such a barrier exists, he should present it.”

Racter, the barrier he’s referring to is the species barrier which we already know exists. The fact that he’s referring to it as “substantial” should also come as no surprise as the Scripps paper clearly indicated:

-“Encouragingly, Stevens said, the mutations’ attachment to the cells was weak - suggesting the existing virus cannot easily cross the species barrier outside a lab. “It’s surprising that it wasn’t easy to convert,” Stevens said. “There may be other factors that prevent it. That’s not to say that Mother Nature won’t come along and throw us a curve ball.”“

LOL.

This paper is a Rorschach test. Offit and Palese have been saying this since November (they’re well qualified experts, and they, along with many others believe this, partly because they don’t believe in recombination, and think reassortment is unlikely). For all I know, so has Tram. ;-) So the elegant discussion of why it’s difficult to transmit at this point in time becomes more than that… evidence of why it won’t in the future, or why they should reiterate their views.

But if you read what they’ve said, it’s that the species barrier would be difficult to overcome (we knew that empirically), not that it can’t be or won’t be overcome. Most importantly, Palese and Offit also strongly believe in prepping (in the sense of strengthening the public health infrastructure to hadle the next pandemic whichever virus it’s from - iirc, Palese worries about H9).

It’s an important contribution, not the final word.

Tram at 14:13: And that possible “curve ball” is why both you and I have prepped. (I believe that you did tell me some time back that you have done some prepping). We agree on the possibility, but not on the probability. It really is a fine distinction, if you get down to what people should be doing, regardless of the probability.

“they’re well qualified experts, and they, along with many others believe this, partly because they don’t believe in recombination, and think reassortment is unlikely” - DemFromCT

Other than Niman, can you name other “experts” that do believe in recombination (as the primary driver of flu virus evolution)?

many of the experts believe in reassortment vs. random mutation and/or recombination. Perhaps only niman thinks it’s the primary driver. But there’s a split between those who think it’s possible (and don’t distinguish between random mutation vs recombination) and those who don’t.

The CDC recently redid their FAQ to include other than reassortment as the path to pandemic, and the ECDC said this (I asked the question):

Q Do most virologists accept that recombination is necessary for a pandemic? Does a lack of acceptance affect pandemic likelihood predictions? The CDC FAQ, for example, implies reassortment is necessary for H2H, but the 1918 studies suggest otherwise.

The questioner is right. Though reassortment (two different influenza genes swopping genetic material to produce a novel virus) is one way that a pandemic virus might emerge it could also theoretically happen by genetic drift (the process of spontaneous mutation). Its probably incorrect to say that the 1918–19 pandemic virus emerged by recombination or drift – we simply do not know enough about what happened.

http://tinyurl.com/fnuez : Scientists at The Scripps Research Institute “Our recombinant approach to the structural analysis of the Viet04 virus showed that when we inserted HA mutations that had already been shown to shift receptor preference in H3 HAs to the human respiratory tract, the mutations increased receptor preference of the Viet04 HA towards specific human glycans that could serve as receptors on lung epithelial cells,” Wilson said. “The effect of these mutations on the Viet04 HA increases the likelihood of binding to and infection of susceptible epithelial cells.”

There is something that I fear that I don’t every see said - perhaps because it is too horrible. But just as there are people that love to create computer viruses, there may be some that want to create a human virus. All the random mutation, recombination, reassortment issue aside, it may not take anything more than one evil person, a few syringes, a few dead birds and a few pigs.

Can some of you wizards out there tell me that it would be impossible for someone to direct the “evolution” of H5N1? It sure would help me sleep at night. Perhaps that is why WHO doesn’t want the sequences public. Once known, someone could pick and choose.

I admit that I don’t understand the mechanisms but it sure sounds like it just takes two or so flu bugs in the same host to become something bad. What am I missing?

DennisC, Lets take one issue at a time!

I’m gonna drop dead from overload!

in this previously posted link to the Charlie Rose roundtable discussion of Bird Flu

 http://tinyurl.com/olmwy 

one individual Laurie Garrett, science and health writer, winner of the Pulitzer, Polk, and Peabody Prize, is the author of The Coming Plague and Betrayal of Trust brought up the possibility of BF gaining entry to HIV infected individuals in Africa. It is her concern that the virus would not kill these individuals (as they would in a non HIV infected person), as the suppressed immune systems would not be able to overreact to H5N1.

It would then remain active in these individuals with the capability to change in a viable human host… your thoughts?

this has been a concern of others… I believe Laurie heard this at the CFR summit in September.

QUESTIONER: Laurie Garrett, Council on Foreign Relations.

Dr. Webster, you’re really the godfather of flu research. Among flu scientists you wear the crown. So I had the question for you.

And, Steve, since you are, also — your other hat is HIV research, I’d ask you the same question — does the section of the migratory bird flyway that’s likely to fill in in the next few weeks, is that which heads to Africa. And in Africa we have an unprecedented problem. They have a massive population of people infected with HIV.

Would you please speculate on what you think would happen when an individual who is HIV positive becomes exposed to a bird or in some other way acquires an infection of H5N1?

WEBSTER: Well, thank you for the crown. I’m not sure that I wear it comfortably at the moment — not at all.

My great concern I think I’m sharing with you is that if this virus and when this virus gets into Africa into the HIV-positive people, who are immunosuppressed, what happens in an immunosuppressed person we know with influenza in cancer patients, the virus is shed for an extended period of time, and it gives the virus the chance to accumulate the mutations of adaptation to humans.

And so this — you put your finger on the great worry that we all have for this virus getting into Africa along with HIV.

Thanks DemFromCT, I think we were on slightly different pages as I was only speaking to recombination being the primary driver.

It’s nice to see that some things never change though. Any “positive news” stories seem to be met with rapid skepticism as well as the need for moderator commentary, while many/most “negative” stories are accepted as largely factual, rarely needing further editorializing. :0)

thank you, she seemed to very much want to get that message out

hmmm I thought the vaccine working in mice story was pretty good until a later story indicated that mice were not the best test subject in relation to H5N1 and humans

Tram:

I agree with NJ that the problem seems to be in the way “barrier” is defined. My interpretation is that Offit was making a statement not so much about structure as about probabilities — in the same sense that while there is no fundamental barrier to being dealt a royal flush in a single hand of poker, there is a (substantial) probabilistic one. We already knew that the virus could not easily cross the “species barrier”; it’s trivially obvious from the fact that a pandemic is not sweeping across the globe as we speak. What’s interesting is what happens when we try to take that observation and attempt to use it to estimate whether a pandemic is imminent.

The human brain is superbly crafted by nature to perform a wide range of difficult tasks. Due to the nature of the tasks most often faced by our protohuman ancestors (which tended to favor speed over accuracy) the cognitive equipment we inherited from them often performs surprisingly well when extrapolating from minimial information. But, unfortunately, when applied to the sort of task we’re confronting here, that tends to be as much a liability as an asset, and that the original design specifications did not include an intuitive grasp of probabilities and statistics leads to rather high rates of error (a fact which enables gambling casinos to collect huge profits, and inspires statisticians to refer to lotteries as “the stupidity tax”).

When hands of poker are being dealt continuously, the dealing of a royal flush is never any more (nor any less) imminent at any one time than at any other; the odds against it are the same after the millionth hand as they are on the first. I will continue to maintain that — while I see no sound basis to support any statement one way or another about whether a pandemic is “imminent” — whatever the chances are, they increase along with the geographical expansion of the virus, and the accompanying increase in opportunities for reassortment (and maybe recombination) — it’s like increasing the odds for a royal flush by increasing the number of hands being dealt.

The best way to avoid the influences of biased reporting is to tackle the raw data directly, to the best of one’s ability, and attempt to draw one’s own conclusions. Most folks aren’t going to be willing to do that, so they’ll take whatever they get — if they get any of it (and lots of them apparently haven’t gotten much) — with whatever spin it had on it when they got it. We try to de-spin stuff here, and you’re part of that. But you aren’t the first to notice that one or two of the people involved in these discussions appear to be sort of “in love with bird flu”, and while your generalization is not without some basis, I’d say it’s a bit strong. When Webster blurted out the business about the chances of a pandemic being “about even” — without offerring any support for what I thought was a rather spectacular conclusion — I also thought that was careless and irresponsible, and I think I said as much. That a number of us play a constant game of “whack-a-mole” with various far-out ideas that pop up here makes your charge seem a bit unfair, but if there’s anyone whose viewpoint on all this is absolutely, spot on, just right, I don’t know who it would be. Maybe if we could just deal in facts, all the spin and counter-spin would take care of itself.

“That a number of us play a constant game of “whack-a-mole” with various far-out ideas that pop up here makes your charge seem a bit unfair, but if there’s anyone whose viewpoint on all this is absolutely, spot on, just right, I don’t know who it would be.” - Racter

My comment was not directed at you as you seem more than capable of “reason and clear thought”.

As far as Ofitt’s comment regarding “barrier/species barrier” goes, IMHO it was an observation of the intraspecies (interspecies?) stability of the virus, backed by recent findings in primarily the Scripps study. Many of the recent press headlines have contained the following: “two mutations away”, “one mutation away”, “minor mutation away”, “evolving towards h2h”, “50/50 chance with 50% deaths”, etc. Ofitt’s commentary on the barrier being “substantial” seemed to be directed at those characterizations. Note that he didn’t say it was insurmountable, he simply said the if the virus is to jump the barrier (species) the jump will have to be “substantial”. Thus far, it’s had 47 years to do so and it hasn’t been able to do it. Additionally, there is no indication that structurally it’s getting closer to knocking down the wall (ie imminent).

A quick review of some comments from the Scripps study:

Scripps Research Institute researcher Ian Wilson and colleagues wondered: If they put two mutations onto the H5N1 virus similar to the 1918 version, could it enter humans? It could not.

Wilson and colleagues then imposed the mutations that likely happened to the 1968, Hong Kong flu strain onto the current avian flu virus.

“We got some binding to the human lung cell, but it wasn’t dramatic,” Wilson told LiveScience.

This suggests a possible route for the virus to enter human cells. But scientists advise that the news is not all that grim.

“If it happens, it’s something to be concerned about. But, there has not been any changes like it yet, and hasn’t been for several years,” Wilson said.”

http://www.livescience.com/humanbiology/060316_flu_morph.html

Another statement regarding the same study:

“The authors of the Science paper were able to change the H5N1 hemagglutinin enough for it to latch more easily onto sugars found on the exterior of cells lining human lungs. Encouragingly, Stevens said, the mutations’ attachment to the cells was weak - suggesting the existing virus cannot easily cross the species barrier outside a lab. “It’s surprising that it wasn’t easy to convert,” Stevens said. “There may be other factors that prevent it. That’s not to say that Mother Nature won’t come along and throw us a curve ball.”“

Man has always been smarter than nature….in his own mind.

Isn’t it significant that we have an avian influenza, H5N1, that causes disease in humans at all? The fact that it has now been discovered that it currently has a propensity for cells deeper in the lung rather that higher up seems to be of little comfort. It has the opportunity once it has a host (the fact that humans get sick at all from it) to mutate to receptors in the cells a bit higher up. I’m sure that those cells are in some cases very close to one another an some intermediate point in the lung. What is going to stop that event? I’m sure someone here knows the answer to that question.

Racter-

Your cogent explanations should be grasped by now by Tram. We don’t know, but we are still looking. You’ve provided yet another prodigious explanation of proximity = opportunity = higher probability.

Keep up the good work.

Tram- What are you motives?

DennisC-

BioTerrorism via influenza is a possibility that became more real when we published the sequences of the Taubenberger frankenstein. Transparency is probably much more important now than bioterrorism.

Tram, Racter et al. Your debate here is excellent. I am learning from all of you. Please do keep it up and please do remain civil to each other. You are all valuable to this forum and are all appreciated. Many thanks.

“Tram- What are you motives?”

Truth. Scroll up and look at the title of this thread. The recent studies do not support the headline. I see you, like Racter, agree that any “increased” probabily lies in chance and not known structural changes (ie evolving) in the virus.

What are you motives NS1?

Tram – at 15:54

“Any positive news stories seem to be met with rapid skepticism as well as the need for moderator commentary, while many/most negative stories are accepted as largely factual, rarely needing further editorializing.”

I appreciate your skepticism, links and thoughts but I don’t live on this thread 24 hours a day. I’m actually occupied playing whack-a-mole with real trolls (of which you are not one) and putting down conspiracy theorists and tin foil hat vendors. If someone reports positive H5 in a bird, there’s little need for moderator editorializing. Going to the top of this thread, my comments were placed to add data to stimulate the conversation (my role), not to take the editorial slant that pleases you most. But, like you, I show up on threads I find to be interesting.

You’re trying to “play the refs” and I’m not impressed.

Dem, why do you give Spoll the benefit of the doubt? He has never substantiated his position. He is only good at vitriolic attacks against anyone who posits the belief that there is a POSSIBILITY that H5N1 could cause the next pandemic. If he represents the “other side” to the debate, anyone can see he is throwing the match, so to speak. He has never added anything in the way of scientific evidence that H5N1 CAN’T cause the next pandemic, but he would have everyone believe just that, on his word, I guess, or on his friend “Mike” Osterholm’s private conversation with him during their secret handshake. In fact, someone out there who really can support the proposition that this virus won’t go pandemic should really weigh in on this, because ALL of the proponents for this side of the debate have been woefully deficient on evidence. And no, cutting and pasting quotes from what other bloggers or “experts” don’t count as evidence one way or the other. How about weighing in with some honest to goodness hard-core evidence on why the virus CAN’T go pandemic, if that is what they really think?

Tram supplies valuable perspective, good links,and a POV which I think is widely held. The challenging of ideas and request for documentation is a valuable service that is a needed check on over-speculation. I can say the same thing for BP, too, but BP doesn’t generally get into fights with other posters.

I’d miss them if they weren’t around. I dislike the bickering and name-calling, though.

Dem, I don’t mean to be redundant, but what is backing up the POV? You asked Dr. Butcher to respond. He didn’t. Would he still hold the same belief today that he did a year ago? Who could tell us this? Are Tram and BP the ONLY ones that visit this website that hold this POV? This reminds me of the fairy tale where some mischievous tailors convinced the king that they had made him a splendid outfit (when in fact, the king was wearing nothing). So it is one thing to challenge an idea. Quite another to posit the opposite belief and provide nothing to back it up. OK, I’ll be the one to say it: the king is naked.

NW – at 18:52 What is going to stop that event? I’m sure someone here knows the answer to that question.

Actually the question was bait. Didn’t really expect a bite. I know that no one here knows the answer to that question. No one anywhere else does either. If there is one thing that I have learned in the 6 months of following this event and this forum it is that arguments pro and con for a pandemic are interesting, contentious, sometimes funny but mostly a waste of time except for general information purposes. For whatever reason, some folks feel one way and other feel another. EVEN THE SCIENTISTS WHO ARE EXPERTS DISAGREE! That tells me that the science regarding this issue is incomplete. Although it would seem to me that a clear majority are worried. It would also seem to me that we will not have long to wait for an answer. All argument will be moot at that point.

BTW, back to topic. This Charlie Rose show with palese, fineberg and laurie garrett deals directly with the question at hand. At 27:02 of a 56:42 broadcast, fineberg reviews why we don’t know whether we are 10%, 50% or 99% of the way to a pandemic.

Very good review.

Tram quoted Lanka, that made him/her suspicious for me. Also picking only positive aspects from one article while ignoring negative ones. But the posts were too long, too many. I didn’t read them all. This is going to become a general problem : you can’t follow a discussion because the threads are too long

watch the show, gs. You will be disappointed but enlightened at the discussion of probabilities.

Dem, so they are figuring out now, why they don’t know. I don’t know whether they will succeed with this. It could be that they’ll have to conclude that they don’t know why they don’t know. We don’t know. No data is not necessarily no data, it can also be lots of confusing data and noone knows whether they are relevant or not…

Don’t get into paralysis by analysis, gs.

Do you suggest closing this thread, and opening up a new one because this is too long?

No-one can say with any certainty whether a H5N1 pandemic will occur or how bad it would be if it did occur. As Racter (I think it was Racter) pointed out at some point, speculation is built into our DNA because it has a survival advantage. If we waited for absolute proof before acting, we would not last too long. This is especially true of potentially catastrophic events like a severe pandemic. I submit that there is an advantage to analyzing all of the scientific data, even if we cannot come to any definite conclusions as to the meaning. To me, the fact that the 3D structure of the HA protein of H5N1 now resembles the 1918 virus more than it does the 1997 H5N1 HA protein suggests to me that H5N1 evolving towards (I use the word loosely) a pandemic strain. Others may disagree. In any case, I think there is value in calling attention to work such as this so that people may come to their own conclusions.

Monotreme, I agree and thank you for your EVIDENCE; namely, the fact that the structure of the HA protein has changed more to resemble that of the H1N1 virus. I don’t believe anyone refuted this. Perhaps we could open a new thread, one devoted solely to PROOF or EVIDENCE that the H5N1 CANNOT change into a pandemic strain. Of course, you are good at adding DETAILS to your explanations, for I believe explanations without details are otherwise known as OPINIONS. By the way, if you ever hear of why H5N1 cannot go pandemic, would you please share that with the rest of us? Apparently, nobody else seems to know how to substantiate the other POVs out there. Thanks again for all of your DETAILED analysis.

There is no PROOF or EVIDENCE that it CANNO… hey, why are we shouting? Of course we are going to continue to post whatever data, scientific evidence and testimonials (expert opinion) we can find.

I expect that there will be more emerging from Atlanta from the CDC Emerging Infectious Disease conference. There are a couple of bloggers there (including our own Anon_22) and I look forward to new data.

There are barriers to pandemic.. they are not insurmountable, any more than the levees were in New Orleans.

“Dem, why do you give Spoll the benefit of the doubt? He has never substantiated his position. He is only good at vitriolic attacks against anyone who posits the belief that there is a POSSIBILITY that H5N1 could cause the next pandemic. If he represents the “other side” to the debate, anyone can see he is throwing the match, so to speak. He has never added anything in the way of scientific evidence that H5N1 CAN’T cause the next pandemic, but he would have everyone believe just that, on his word..” - De Jure

First, you’ve provided an excellent example vitriolic attack.

Second, please provide all of us one example where I’ve stated that H5N1 can’t cause a pandemic! You can’t, and what you’ve done is misrepresented my position with a big lie. Now go away as you provide nothing meaningful to the debate. By the way, you seem a little disappointed by the good news I posted. Why is that?

“Tram supplies valuable perspective, good links,and a POV which I think is widely held.” - DemFromCT

Thank you for your kind words. It’s been stated before but you are the gentleman of the board.

Finally, I’d like to apologize to Monotreme if anything I’ve posted to him has in any way offended him. We are each entitled to our opinions and I certainly don’t fault you for yours. Cheers.

DemFromCT. Would you please provide a link to evidence for the basis of your statement…”There are barriers to pandemic..they are not insurmountable, any more than levees were in New Orleans”…could this possibly be an opinion based only on intuition…JUST KIDDING…oh yeah sorry I was yelling.

Tram, I respect your right to have an opinion. You are not the only one who has that opinion.

What irks me is you seem to believe you have a right to flatten every single debate and turn some really interesting, stimulating, multi-dimensional discussions where no consensus is required even, into a single issue discussion where everyone has to address YOUR ONE AND ONLY CONCERN EVER, that is, to prove that there is no proof that there will be a pandemic caused by H5N1 (or something to that effect so don’t nitpick on my wording cos you and everyone else all know exactly what I am talking about).

How about if we all surrender to the wisdom of the mighty Tram, and declare that we accept that there is no proof that there will be a pandemic caused by H5N1? How big and how many times do we have to write this so you will quit and we can have some real sophisticated, educational, enlightening discussions?

Dem, for once I disagree with you. Tram has a right to his POV, but his presence is becoming a thread-killer.

De Jure, you’re welcome.

As to whether there is an insurmountable barrier to H5N1 going pandemic, that would be pretty hard to prove. A more testable hypothesis would be: is it possible to identify the barrier to efficient H2H spread and determine whether it can be surmounted? The answer is yes, at least in part. There are now several papers showing that the reason H5N1 has not gone pandemic yet is because it doesn’t bind to and infect cells in the upper respiratory tract and therefore is not present in respiratory droplets (in any significant amount). Why doesn’t H5N1 infect the upper respiratory tract in humans? The answer is that the cells in this region are “decorated” with a different type of sugar (alpha2–6) than is found in other cells (alpha2–3). The HA protein protein of H5N1 currently prefers the alpha2–3 sugars which are found in bird intestinal cells. (Birds infect each other fecal-oral, one duck’s toilet is another’s soup). In order for a pandemic to start, it is thought that H5N1 will have switch preferences from alpha2–3 to alpha2–6. Most scientists who study flu believe that this one of the key events that turn a bird flu into a human flu. This does not happen very often, be we are only starting to understand why. Recent studies have shown that only a few mutations are necessary to switch an avian H3 virus to a human H3 virus. In the study I cited in the first post, the scientists found that:

“…mutations that can convert avian H2 and H3 HAs to human receptor specificity, when inserted onto the Viet04 H5 HA framework, permitted binding to a natural human alpha2–6 glycan that suggests a path for this H5N1 virus to gain a foothold in the human population.”

This experimental result strongly suggests that the current barrier can be surmounted, perhaps with only a few mutations. Will these ever occur? That’s the million dollar question. IMO, the virus has had relatively few chances to adapt to humans thus far. Soon, thanks to migratory birds, it will have many more chances. Thus, my estimate of risk went up signicantly after reading this paper.

Tram: I accept your apology. I’m also sorry if I have said anything that offended you. As I have said many times, my heart is rooting for you to be right. Just can’t get my brain to agree.

Monotreme, “As I have said many times, my heart is rooting for you to be right. Just can’t get my brain to agree.”

We spend our days looking for people to convince us we are wrong. Alas, to no avail.

I think a lot of folks here will agree with me when I say “Thank God you know the difference between your heart and your head!”

Bless you for keeping up the good work.

a summary of a thread every 10kilobytes or such would be useful


yes, I watched the show. Posts are still better - I nead a dictionary occasinally. And also people could prepare their answers better and needn’t answer spontaneously.\\\\ What was it with 70M dead ? Was it just 1918 or a prediction ? I didn’t understand why AIDS could trigger a H5N1 pandemic. Leavitt said: prepping is always good, so H5N1 requires no more prepping than usual ? If there were no H5N1, he would still advocate prepping ? They avoided to give numbers, so we couldn’t relate the importance of the sub-issues. They didn’t address the real problems : what does it cost, who gets the tamiflu, where should I hide, will the state go bankrupt, what laws will be changed, what’s with Webster’s 50% dead figure, how likely is the pandemic, expectation value of deaths

“Well, I’m hardly the first to take natural selection into account; the concept is arguably the most powerful explanatory tool ever placed in the hands of biologists. Perhaps because of this, however, it does seem to me that what can easily be overlooked is that the application of this tool is somewhat error-prone — and I’d actually be inclined to suspect that rather more of the errors result from excess enthusiasm than from under-application. Perhaps the most common error I notice is what is sometimes referred to as the “just-so story”. It can happen when a top-down approach is used (starting from an intuitively compelling idea about how things should work, and looking for examples in the real world) or when a bottom-up approach is used (starting with an observed statistical trend in the distribution of alleles in a genome, and attempting to explain that as the action of selection upon some yet-to-be-identified.”

So you are not willing to entertain the idea of an species barrier (i.e. an “invisable fairy”) but you are willing to accept that natural selection might be at play based upon some unknown “yet-to-be-identified” trait. What gives? You can’t have it both ways. If you accept that there might be some postive selective pressure pushing the virus towards mammalian adaptation you must accept the—equal—possibility that there is negative selective pressure that prevents a fully mammalian adapted virus.

Howsabout we go with the most likely scenario: that there is neither positive nor negative selection at play. In this case it is absolutely incorrect to say that the virus is “evolving towards a pandemic strain.” That would imply that there was some selective pressure at play. As Koawoka points out the human strains are all evolutionary dead ends. There cannot be selective mammalian adaptation until the virus is passed mammal to mammal.

Here, the virus can pick up “mammalian” aa’s but it is just as likely to revert back to the avian aa’s as it is to pick up additional mammalian aa’s. It’s not evolving so much as meandering.

AIDS could trigger a H5N1 pandemic

That comes out remarks webster made here

 to Laurie Garrett.

QUESTIONER: Laurie Garrett, Council on Foreign Relations.

Dr. Webster, you’re really the godfather of flu research. Among flu scientists you wear the crown. So I had the question for you.

And, Steve, since you are, also — your other hat is HIV research, I’d ask you the same question — does the section of the migratory bird flyway that’s likely to fill in in the next few weeks, is that which heads to Africa. And in Africa we have an unprecedented problem. They have a massive population of people infected with HIV.

Would you please speculate on what you think would happen when an individual who is HIV positive becomes exposed to a bird or in some other way acquires an infection of H5N1?

WEBSTER: Well, thank you for the crown. I’m not sure that I wear it comfortably at the moment — not at all.

My great concern I think I’m sharing with you is that if this virus and when this virus gets into Africa into the HIV-positive people, who are immunosuppressed, what happens in an immunosuppressed person we know with influenza in cancer patients, the virus is shed for an extended period of time, and it gives the virus the chance to accumulate the mutations of adaptation to humans.

And so this — you put your finger on the great worry that we all have for this virus getting into Africa along with HIV.

WOLINSKY: I agree it’s — in one respect, and then give you an alternative.

Certainly it’s been a changed world. We now have, not only in Africa, but HIV infection is worldwide. We have cancer patients that didn’t exist in previous epidemics — solid organ transplant patients, bone marrow transplant patients.

And certainly if we saw a — an influenza problem like we saw in 1957 or 1968, that’s indeed true. We would see prolonged shedding; it’s a definite problem there.

Thanks, anon_22. I’m sure you know I look for and read your posts with great eagnerness. Your analysis is greatly appreciated.

Hi Monotreme, Anon-22, Tom, GS!

Do you have any opinion as to whether the virus may become less deadly, if it did begin to infect humans in the upper respiratory area? I read that part of the reason the virus was so deadly was because it infected the lower respiratory area.

AnonymousAlcoholic – at 22:28

You’re more than welcome to post here. The previous troll threads you were involved in were erased (and not because of your posts), but you (obviously) were not banned. Please keep it civil.

And you raise some good points about where we are at. Mutant swarms don’t always evolve, mostly they devolve. There’s no inevitability to which direction the virus goes. Dead-end paths are not in and of themselves dangerous. But the increased geographic range, which is new and sustained, is quite worrisome.

Tram, anyone who gives credence to an authority who does not believe that HIV causes AIDS is not a scientist. But then again, you’re really not, are you? You’ve managed to fool a few folks with your gibberish, but as they say, you can’t fool them all. Your unsubstantiated opinions are dangerous. They are dangerous because anyone who doesn’t have higher than a fourth-grade level education might begin to believe you, that H5N1 isn’t really a threat. You are most transparent to me, and I’m sure to many others who have had to suffer through reading the most unimaginative and boringly repetitive invectives. Go on believing that H5N1 is not a threat. Just do us all a big favor. Do it somewhere else.

mom11: Good question, but I’m afraid I don’t know the answer. The problem is, we don’t know for sure which other cells H5N1 will be able to infect once (if) it acquires the ability to infect cells in the upper respiratory tract. Its possible that it will loose the ability to cause as severe pathology once it becomes a pandemic strain due to the mechanism you suggest, but I wouldn’t count on it. Still, this is probably our best hope for the virus to become less lethal once it goes pandemic.

When we talk more about talking than we do the subject, we are off task. It is easy to phrase a remark so it is neutral even when it is critical of another’s POV. It is called being a gentleman (lady) in the best sense of the words. I have been taught that it is the best of all worlds to make the person you really disagree with feel very comfortable. When that happens you may just be able to sustain real communication, and your idea might be actually considered by them. In 1918 it has been proved that we had a pandemic bird flu in humans. It was H1N1 (if memory serves) and I know after a year of study what that basically means. My point is that it has been done before by one AF. (If the scientist of that time could have seen that coming, I bet they would have had the same debate we are having now.) So, I think the very general argument leans in favor of those who might speculate that this could happen again with H5N1. This opinion is on the level of analysis that a “species barrier” does not allow evolution to bridge this gap. That argument I am incredulous about given history. Specifics may prove this incorrect (for H5N1), but in the absence of evidence I tend to go with what history has shown.

To add another wrinkle to the debate. There was a time not long ago when the dogma was that avian viruses do not evolve—at all. Webster was huge proponent of this viewpoint although I don’t know if he still holds it.

[AIDS could trigger a H5N1 pandemic]
Webster: the virus is shed for an extended period of time, and it gives the virus the chance to accumulate the mutations of adaptation to humans.


so, HIV-people have H5N1-disease longer than others ? How much longer ? From the virus’ point of view : would it prefer one HIV-infection over two normal ones ?

BTW., that Webster interview, was it after his 50% dead statement ? Did he comment on it ?

Mom, I have no expertise in anatomy. My only argument is historical : H5N1 probably did infect humans or other animals before. If it had succeeded to do severe damage we might have found some traces. And it would not have vanished completely but had left us with “better” respiratory receptors. Some have predicted H5N1 would vanish in 150 years . Maybe to reappear in 1000 years ? But then it would be a strange coincidence that our generation was the one who “founded” H5N1. So, this is some evidence that it existed before and was not so severe to cause a severe pandemic.

Mono, apparantly some species (e.g.birds ?) have cells in the respiratory tract which aren’t infected by H5N1 but still do their respiratory work well. What’s the reason ? Can’t we make use of this ?

Thanks Monotreme and gs!

How about this one….Have all other flus, started infection in the upper respiratory area or have there been some that began elsewhere?

mom11,

I am going to start a different thread with this issue about upper vs lower respiratory receptors. This thread is so long no one will be able to find anything.

Sorry, ‘treme.

gs: Sorry, I can’t answer your question.

Hey, anon_22, no problem. There’s more than enough content in this thread as it is ;-)

Thanks Anno-22!

You have been so much help for me, and everyone else here!

Eh, probably not tonight. My PC is suddenly deciding to do weird stuff…

you shouldn’t let it decide this by itself.Not yet.

AnonymousAlcoholic:

I’d be happy to entertain the idea should it happen to come accompanied by some kind of evidence.

A more careful review of what I said may reveal that I was actually highlighting the risks inherent in such an approach.

I can happily agree with that, since I don’t hold that positive selective pressure is pushing the virus towards mammalian adaptation. There IS a lot of stuff in this thread, so it’s not hard to imagine how you might have overlooked where I said that the “peripheral isolates” we see infecting humans defy selection by doing so.

I pretty much agree with that as well (though I would, perhaps somewhat pedantically, protest that we can safely assume that selection is always at play, whether we correctly identify its mechanisms or not). In a broad sense, to say that selection is driving the currently avian-adapted virus toward human-adaptation flies in the face of the simplest of evolutionary logic; the virus is doing fine in avian populations — but there is an exception, that being the competition that takes place between individual members of a viral “swarm” inside an already-infected human host. A virus which finds itself thusly committed suddenly faces selective pressures as different to those of its natural range as would a polar bear transported to Australia. Apparently, these (thankfully fleeting) selective pressures have been more than any isolate has so far been able to bear. But it only takes one lucky one.

I agree, though I’d phrase it a little differently. There can be selective pressure, but until sustained transmissibility occurs, it doesn’t lead to adaptation — unless reassortment or recombination is a lot more common or a lot more efficient that is currently thought, it is quite correct to say that the virus is “not evolving so much as meandering”.

Monotreme:

Regarding Tram 21:46 on 3/23 and Monotreme 22:09 on 3/23,

Maybe I should apply to the State Department (re: Monotreme 19:11 on 3/21) :)

Medical Mavin on 14:35 on 3/23: Yes, I seem to recall that Tram mentioned he was preparing. Thus, I think we have finally reached the crux of the debate: There are some who state that an H5N1 pandemic is now much more likely and there are some who say it is no more likely than it was years ago. But thoughtful contrarians are still preparing. That should be the big take-home message to all following this thread.

Holy Cats! Leave for a day and you have to wade through War and Peace all over again!!! Everbody---Step Away From the Wiki…at least for 1 hour every 24! :)

OK, so I put an “i” when I should have put an “e” (sorry, MM) and forgot the “y” in everybody. That’s what happens when you have to spend 2 hours reading posts…wiki overdose…

You… you left… for a whole DAY?

Racter: BIG LOL!!! If it makes you feel any better, it was under great duress and I suffered a few nervous ticks which I believe are the cardinal signs of Wiki Withdrawal. :)

“Tram, anyone who gives credence to an authority who does not believe that HIV causes AIDS is not a scientist. But then again, you’re really not, are you? You’ve managed to fool a few folks with your gibberish, but as they say, you can’t fool them all.”

Hey De Jure, have you found anywhere where I said the H5N1 can’t cause a pandemic yet or are you finished now that your lie has been exposed. You are a fraud and the number one perpetrator of vitriolic attacks on this board.

By the way, as I said several times I have no opinion on the HIV-AIDS connection. The list of scientist that seriously question it is significant however, as the partial list below shows:

Charles A. Thomas, Jr. Ph.D. (Mol. Biologist, Pres. Helicon Fnd., San Diego, CA) Harvey Bialy, Ph.D. (Editor Bio/Technology, New York, NY) Harry Rubin, D.V.M. (Prof. Cell Biology, Univ. Cal. Berkeley, CA) Richard C. Strohman, Ph.D. (Prof. Cell Biology, Univ. Cal. Berkeley, CA) Phillip E. Johnson (Prof. Law, Univ. Cal. Berkeley, CA) Gordon J. Edlin, Ph.D. (Prof. Biochem. & Physics, Univ. Hawaii, HI) Beverly E. Griffin, Ph.D. (Dir. Dept. Virology, Royal Postgrad. Med. School, London, UK) Robert S. Root-Bernstein (Prof. Physiology, Michigan State Univ., East Lansing, MI) Gordon Stewart, M.D. (Emeritus Prof. Public Health, Epidemiologist, Isle of Wight, UK) Carlos Sonnenschein, M.D. (Tufts Univ., Medicine, Boston, MA) Richard L. Pitter, Ph.D. (Dessert Research Inst., Univ. Nevada System, Reno NV) Nathaniel S. Lehrman, M.D. (Psychiatrist, Roslyn, NY) William Holub, Ph.D. (Biochemist, Live Sciences Inst. New York, NY) Claudia Holub, Ph.D. (Biochemist, Live Sciences Inst. New York, NY) Frank R. Buianouckas Ph.D. (Prof. Mathematics, Cuny, Bronx, NY) Philip Rosen, Ph.D. (Prof. Physics, Univ. Mass. Amherst, MA) Steven Jonas, M.D. (Prof. Preventive Medicine, Suny Stony Brook, NY) Bernard K. Forscher, Ph.D (Ret. Editor Proc. Nat. Acad. Sci., Santa Fe, NM) Kary B. Mullis, Ph.D. (Biochemist, PCR inventor, Consultant, La Jolla, CA.) Jeffrey A. Fisher, M.D. (Pathologist, Mendham, NJ) Hansueli Albonico, M.D. (General Practitioner, Langnau, Switzerland) Robert Hoffman, Ph.D. (Prof. Dept. Pediatrics Univ. Cal. Med. School, San Diego, CA) Timothy H. Hand, Ph.D. (Dept. Psychology, Oglethorpe Univ. Atlanta, GA) Eleni Eleopulos, M.D. (Royal Perth Hospital, Perth, West Australia) Robert W. Maver, F.S.A., M.A.A. (Dir. Research, Mutual Benefit Life, Kansas City, MO) Ken N. Matsumura, M.D. (Chairman Alin Foundation & Research Inst., Berkeley, CA.) David T. Berner, M.D. (Condon, MT) Theodor Wieland, Ph.D. (Max Planck Institut, Heidelberg, Germany) John Anthony Morris, Ph.D. (Biochemist, Bell of Atari College Park, MD) Sungchul Ji, Ph.D. (Prof. Pharmacology & Toxicology, Rutgers Univ., Piscataway, NJ) Vahagn Agbabian, D.O. (Pontiac, MI) Barry R. Alexavich (Cell Biologist, Bristol, CT) David T. Berner, M.D. (Condon, MT) Shelly B. Blam, Ph.D. (Alameda, CA) Lawrence Bradford, Ph.D. (Benedictine College, Atchison, KS) Melinda Calleira (Pres. Amer. Ass. Science & Public Policy, Los Angeles, CA) Hiram Caton, Ph.D. (Prof. App. Ethics, Griffith Univ., Brisbane, Australia) Dennis Chaney, Ph.D. (Chaney Scientific Inc. Burlingame, CA) Hywel Davies, M.D. (Cardiologist, Pueblo West, CO) Marlowe Dittlebrandt, M.D. (Portland, OR) Peter H. Duesberg, Ph.D. (Prof. Mol. Biology, Univ. Cal. Berkeley, CA) Fabio Franchi, M.D. (Trieste, Italy) Lawrence A. Falk, Jr., Ph.D. (Virologist Abott Labs, Consultant NCI, Chicago, IL) James A. Fimea, Ph.D. (Laguna Beach, CA) William L. Gardner, Ph.D. (Wellesley, MA) Martin Haas, Ph.D. (Dept. Biology Cancer Center, Univ. Cal., San Diego, CA) Alfred Haessig, M.D. (Emeritus Prof. Immunolgy Univ. Bern, Switzerland) Neville Hodgkinson (Science Correspondent The Sunday Times, London, UK) John Holmdahl, Ph.D. (Los Angeles, CA) Heinrich Kremer, M.D. (Mueckenburg, Germany) Hans J. Kugler, Ph.D. (Editor Prev. Med. Update, Redondo Beach, CA) Robert Laarhoven (S.A.A.O., Hilversum, The Netherlands) Paul Lineback, M.S. (Eastern Oregon State College) Henk Loman, Ph.D. (Prof. Biophysics, Free Univ. Amsterdam, The Netherlands) Maurizio Luca-Moretti, Ph.D. (InterAmerican Medical Health Ass., Boca Raton, FL) David Mertz (Dept. Philosophy, Univ. Massachusetts, Amherst) Richard Mitchell, Ph.D. (Assoc. Prof. Sociology, Oregon State Univ, Corvallis, OR) Joseph E. Morrow, Ph.D. (Cal. State Univ. Sacramento, CA) Cindy Orser (Ast. Prof. Bacteriology, Univ. Idaho, Moscow, ID) Hannes G. Pauli, M.D. (Former Director Bern Univ. Med. Faculty, Bern, Switzerland) Paul Rabinow, Ph.D. (Prof. Dept. Anthropology Univ. Cal., Berkeley, CA) Rodney M. Richards, Ph.D. (Amgen Inc., Thousand Oaks, CA) Judith Riesman, Ph.D. (Author, Arlington, VA) Michael Ristow, Ph.D. (Bochum, Germany) Mel T. Roach (Avatar Research, Tuscon, AZ) Frank Rothschild (Project Dir., Berkeley Project on Bioscience & Society, CA) David F. Salehi, Ph.D. (Lake Dallas, TX) Caspar Schmidt, M.D. (Psychiatrist, New York) Frederic I. Scott, Jr. (Editor American Clinical Laboratory, Baltimore, MD) Udo Schuklenk (Dept. Ethics, Monash Univ., Melbourne, Australia) David Shugar, Ph.D. (Prof. Biophysics, Univ. Warsaw, Editor Pharmacol. Therap., Poland) Ernest G. Silver, Ph.D. (Radiation Biologist, Oak Ridge, TN) Frederick Tobin, Ph.D. (Gorke, Australia) La Trombetta (Burzynski Research Inst., Houston, TX) Wai Yeung, M.D. (Orinda, CA)

Waste of good bytes, Tram.

Off topic

Red Herring

Please state your motive for continually engaging in banality and directing these wonderful minds off-track?

There does not seem to be a species barrier- plenty of bird and mammals including human have been able to be infected by H5N1.

Horizontal transmission has happened in mammals; not all the zoo tigers that got sick had eaten the sick chickens, and, the researchers who tested cats by feeding or injecting -the others cats, not deliberately infected, got sick too, from the other cats. The few human-to-human-stop cases, has just meant we were lucky so far, not that it can’t go pandemic.

gs, if people with low/no immune systems don’t die of ARDS, yet can’t clear the virus totally from their systems, they could give it more time to mutate in a human as well as continue to shed it. With the immense populations in Africa that are not part of any effective health/monitoring networks there will be too many chances. Also, the strain in Indonesia (and some of regional “unreporting” nations)is rather alarming.

De jure – at 20:48 March 23

The title of this thread and first post posits the point we are getting closer to a pandemic strain of influenza. I do not speak for anyone else however I believe there have been relevant studies cited for a good questioning of the thread’s pov. Furthermore, what is the harm is questioning your pov. I am willing to learn and change my mind when science comes closer to the answer (in either direction). For example, the Indonesian familial cluster which was published the past few days concerns me. Let’s talk about the science which either backs the thread’s pov or is contrary. Mother Nature has a laboratory in Asia (and currently expanding to other parts of the world) and let’s see what she is experimenting with.

“In a broad sense, to say that selection is driving the currently avian-adapted virus toward human-adaptation flies in the face of the simplest of evolutionary logic” - Racter

I completely agree with you. This has been my core point throughout this thread (no proof the H5N1 is “evolving” towards a pandemic strain). The one thing we don’t know is that if H5N1 is going to get there through “chance”, what are the odds. The only guide we have to this is history. It’s had at least 47 years and hasn’t been able to do it. This would imply, and the Scripps study showed, that the “barrier” is substantial and that the odds are likely long.

There has been some discussion regarding the fact that H5N1 is “looking” more like H1N1. However when the researchers “pushed” it further to become H1N1 like, they found it was a dud. This is important and should not be lost. From the Scripps study:

“Scripps Research Institute researcher Ian Wilson and colleagues wondered: If they put two mutations onto the H5N1 virus similar to the 1918 version, could it enter humans? It could not.”

Translation: “Just to see what would happen, we took our big, clumsy fingers and frobbed some of the fine mechanisms on a mind-bogglyingly complex and delicate piece of biological machinery, and we broke it”.

The development of large software packages typically involves dedicating considerable amounts of time and energy toward assuring that various sub-components will integrate smoothly with one another. As anyone with even a passing familiarity with the end products can attest, these efforts are not always entirely successful. If just casually swapping chunks of code between projects produced programs that didn’t work, how surprising would that be?

“If just casually swapping chunks of code between projects produced programs that didn’t work, how surprising would that be?”

Well I don’t think I would quite put it that way as participants in the study did recreate the 1918 version of H1N1. That likely required a bit more that “big, clumsy fingers” don’t you think?

Maybe. But you get my point nonetheless?

Tram-

They created a frankenstein approximation of the 1918 virus from the best genetic material that they could tease out of aged corpses and our tissue bank.

The did no CREATE or RESURRECT the actual virus. We have no idea what the exact sequence is on that virus.

NS1: they also confirmed each and every base from scratch. It would take a hell of a coincidence for the published sequence to have been incorrect.

“The did no CREATE or RESURRECT the actual virus. We have no idea what the exact sequence is on that virus.”

You’ve made a good point NS1. I’ve even read (some time ago) that the model most resembling H5N1 was “selected” as the H1N1 prototype. Since we really don’t know for sure what the 1918 version of H1N1 looked like would you then agree that any comparisions of H5N1 to the “assumed” re-creation are meaningless?

AA-

Were they able to sequence the material 100% with precision?

I’m sure that they did match the frankenvirus to the sequence that they created. The sequence, the bases, I believe, are not likely a true match to the exact virus?

NS1:

It’s either 100% precision or its a hell of a freaking coincidence. They sequenced the genes, went back and started from RNA and sequenced it again. If the sequences didn’t match they went back and sequenced the genes until a consensus emerged. Coincidenses are possible, but that doesn’t make the flu sequence any different from any of the sequences in GenBank.

The sequence is reliable. Its much more reliable than all of the egg-adapted, amantadine resistent strains in GenBank.

Explain where your quibbles lie with this:

Well, I guess that’s probably about it for this thread then. Way to go.

Sorry. I did not anticipate the jpeg posting in the thread…

Don’t worry about it. You certainly settled the argument.

AA-

Nice picture of an averaged HA.

If you worked on the team, please describe how you teased each and every nucleotide out of only 2 fixed samples and 1 permafrost-preserved necroscopy. Very small sample set.

Did the primer selection and design determine the results of the sequencing?

A few notes from your reference are in order:

• Of 78 possibilities, only 2 from the tissue bank were found useful.
• RNA templates larger than 150 nucleotides could not be amplified in these two cases.
  • A/South Carolina/1/18
  • A/New York/1/18
• RNA templates greater than 120 nucleotides could not be amplified in the single permafrost case
  • A/Brevig Mission/1/18
• Sequence Analysis. The HA gene sequence of A/South Carolina/1/18 (nucleotides 33–1,733), containing 1,701 nucleotides, and a theoretical translation are shown in Fig. 1.
• All avian and swine viruses share four glycosylation sites, whereas human strains from the 1930s have two additional sites, and modern human H1N1 viruses have up to five additional sites (27). The 1918 strains, in contrast, have only the four glycosylation sites shared with avian and swine strains (Fig. 1), suggesting that acquisition of additional glycosylation sites is not required for efficient replication in humans.
  • Are the receptor changes required or not?

My only argument is that we cannot KNOW anything about the 1918 strain without a viable sample to isolate. I laud J. Tau and company for their achievement; however, we need to keep it in context as a reference point and an uncertain reference point at that.

We are breaking new ground and sometimes that takes several passes. As we learn more about H5N1, we will likely continue the research into the PF11 in 1918 with better assumptions and keener eyes.

This forum is being continued to reduce sidescroll.

H5N1 Evolving Towards Pandemic Strain 2 continued

Old thread closed to speed Forum access

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