mutations needed
overcoming species barrier
H5N1 receptor binding for dummies
Recently several studies came out concerning how H5N1 might bind to human cells and thereby account for its ability to cause human infections. Revere did a good summary under (scroll down) ‘The papers in Science and Nature’.
An even shorter (simpler) version :-) goes like this:
So what we have here is a very simplified model to explain what has been observed, namely that it is relatively rare for humans to be infected by avian viruses, and quite hard for the virus to transmit from one person to another, in the natural state of affairs. These studies do not predict what H5N1 might do in the future nor even attempt to discern how H5N1 specifically achieves its ability to overcome this natural barrier.
What has happened in the media, however, has been some atrociously poor reporting, the worst culprit being Nicholas Wade in NY Times titled “Studies Suggest Avian Flu Pandemic Isn’t Imminent”
Interestingly the same article appears in the International Herald Tribune as “Researchers Find New Details on Transmission of Avian Flu” and in the Scotman as “Avian flu may not be next pandemic”
What does that tell us about journalists fashioning their reporting according to market?
I’m not too ‘smart’ about these things, but is it anyone’s feeling that this may give us more time, if in fact H2H is on the way??
Next I move on to a rather more complicated topic: What needs to happen for H5N1 to change its affinity from avian receptors to human ones?
A recent paper published by Taubenberger (technically this should read Stevens et al as the lead author but I am using a more recognizable name for ease of discussion. Apologies to Stevens if he ever reads this.) “Structure and Receptor Specificity of the Hemagglutinin from an H5N1 Influenza Virus” in Science attempts to narrow down the molecular conditions under which this might happen.
Using the virus isolated from a 10 year old boy who died (A/Vietnam/1203/2004 (Viet04), “Viet04 HA0 was cleaved during protein production into its activated form (HA1/HA2), was crystallized at pH 6.55 (12) and its structure was determined by molecular replacement (MR) to 2.95 Å resolution. In addition, we have investigated the potential of this H5 HA to acquire human receptor specificity by introducing mutations known to effect such a specificity switch on H1 and H3 frameworks.”
I shall <boldly :-)> attempt to summarize some of their findings:
<This issue of binding to the biantennary form of the receptor is intriguing in that even different strains of the same virus may act differently towards it. For example, “the humanized avian H1 (Dk76) double mutant (Glu190Asp/Gly225Asp), and the human H3 HA (A/Moscow/10/1999) did not bind α2–6 biantennary glycans, in contrast to 1918 South Carolina H1 HA and human H1, A/Texas/36/1991,” which do.>
Their conclusion? “Knowledge of genetic changes in circulating viral isolates by themselves obviously cannot predict the impact on receptor specificity let alone predict the effect of future mutations… The mutations that cause a shift from the 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 α2–6 specificity in H3 HAs (Gln226Leu & Gly228Ser) do in fact reduce avidity to α2–3 sialosides, and increases specificity for α2–6 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. Thus, such mutations provide one possible route by which H5 viruses could gain a foothold into the human population, although it is possible that other, as yet unidentified mutations may allow the H5N1 virus to effect a switch in receptor specificity.”
anon_22: Now we are back to the obvious question that arose on the evolution thread: is there a selective pressure that would favor the development of a preference for the “human” receptor (alpha 2,6)? If I recall Racter’s answer to this question correctly, he thought not. Instead, he believed that there were chance mutations in H5N1 that occasionally favored human infection, but that unless these managed to evolve while in a particular human to full adaptation, there would be no pandemic strain. The virus would have to start over with each infected human. He referred to this as meandering evolution, a term I quite like.
Although I agree with Racter’s logic, I think there may be something wrong with his asssumptions. H5N1 does seem to be evolving towards a pandemic strain, to me. Yet, a virus that is found primarily in birds cannot be under selection for adaptation to humans, by definition. How to reconncile these two ideas? Perhaps there are factors that favor selection in birds towards a strain that, incidentally, happens to favor 2,6 receptors. I’m not sure what these would be, but posit their existence.
The general problem reminds me of the explanation of the evolution of flight in birds. Simply put, evolution of the morphological adaptations that resulted in flight required a multistep process. None of the intermediate steps allowed any flight whatsoever. So, how could they be selected for? Darwinists struggled with this for a long time before coming up with the idea of emmergent properties. Each intermediate stage was not a selection for flight, but rather, was a selection for some trait completely irrelevant for flight, but nonetheless beneficial to proto-birds. Flight itself was an emergent, and obviously unintended bonus. Selection for flight did not truly begin until birds could actually start to fly, which they probably initially did quite poorly.
By analogy, I would argue that pandemics may arise as a result of selection of intermediate phases of viral evolution that, only incidentally, result in the evolution of a strain capable of binding to 2,6 receptors. Only after a flu virus gains a “foothold” in humans does selection for a human adapted virus begin.
My 2 cents, with a generous dollop of speculation.
Anon 22- Thank you for the report that is just what I have been hoping for, not subscribing to Nature and Science. I find it interesting, even though the receptor switch is more complicated than just moving HA1 and HA2 around from different sources. There must be a sequence package deal for each virus, but a little more is gained for scientists, even in the process of more questions for each answer. The press releases think the big news is that H5N1 doesn’t bind to human receptors higher in the lung. I knew the reports had to be about something else that the reporters couldn’t get a handle on. I think the jig saw puzzle analogy could be changed to clear strips of code letters, for reassembling the 1918 H1N1 RNA. With repeating strips from four other samples besides the complete tundra extraction, the different fragments can be laid down to match on top, three to four deep and overlapping, matching letter to letter. That would give a redundant pattern for confirmation. Please keep taking the time to digest and pass on the information, for the rest of the inquiring minds.
I feel so dumb….I just don’t get it at all. :S Could you all “dumb it down” for me, including your thoughts on it? Thanks!
anon_22 – at 16:52 What has happened in the media, however, has been some atrociously poor reporting, the worst culprit being Nicholas Wade in NY Times titled “Studies Suggest Avian Flu Pandemic Isn’t Imminent”
thanks for clearing that up. I posted that article hear at FW in news of the day forum with little to no response. What does that tell us about journalists fashioning their reporting according to market? Not sure, I know NY was hit hard during Spanish flu, expecially the poor immigrant population. I wonder how people turned thier thoughts away from the possiblity of a pandemic? NY Times circulation over 1 million.
Cassie – at 19:00
We have a wide variety of Influenza subtypes by on the Hemagglutinin (HA or H as in H5N1). We also know that a certain number of positions on the gene segment that is responsible for the Hemagglutinin determine the capability of the virus to bind to certain types of cells (Human, Avian, Porcine, etc.). These positions are frequently referenced as the receptor domain.
The information posted previously mentions that on certain subtypes (H1) that a change in a certain position in the receptor domain causes a higher probability of human infection. The scientists seem surprised to find that the same position change did not create the same effect in all of the tested subtypes. Sometimes a change at 225 created a large change and sometimes it didn’t in another subtype. We study all the possibilities and look for a pattern. No pattern is truly emergent at this time.
NS1,
“I think the jig saw puzzle analogy could be changed to clear strips of code letters, for reassembling the 1918 H1N1 RNA.
I’m going to respond first to the easiest part for me to respond. The analogy of puzzle (for the H5N1 evolution thread) was intended only for the purpose that you are describing here: as an explanation of how you would lay out many strips of code, figure out the overlaps and the front and back ends, and voila, you have the sequence. :-) It may have been an unfortunate choice as there are no parallels beyond this.
Monotreme,
“Now we are back to the obvious question that arose on the evolution thread: is there a selective pressure that would favor the development of a preference for the “human” receptor (alpha 2,6)?”
Here’s how I solve the problem. I prefer to not use the word ‘select’ as that implies some intentionality which is not proven. Any intentionality in evolution, IMHO, exists only in the mind of the perceiver who has a need to ascribe intentionality or meaning to everything. I am a declared agnostic on that.:-)
“Although I agree with Racter’s logic, I think there may be something wrong with his asssumptions. H5N1 does seem to be evolving towards a pandemic strain, to me.”
I think the critical phrase in your statement is the last “to me”. H5N1 is probably going in many different directions at the same time, eg increasing host range, increasing geographic spread, while there may be quite a lot of dead-end mutations which (since they were dead ends) we never know about. To the extent that it is only (or mostly) of interest to you in the context of a pandemic, you would see the process of it evolving towards a pandemic strain. Since past performance is not a guarantee of future behavior :-), you really have no way of knowing whether it is going to or it intends to end up as a pandemic strain.
That, of course, is not science. It is only personal philosophy.
Cassie,
No, you are not dumb. This is difficult science, even for professionals (except for specialists like virologists which I am not).
Let me see if I can make it even simpler without losing the essence of the dilemmas:
As H5N1 is a virus adapted to infecting birds, for it to infect humans repeatedly one would intuitively hypothesize that there must be some distinctive conditions that arose that made it possible, and, more importantly, that these distinctive conditions might be unique such that if and when they are present repeatedly and consistently, human infection becomes a normal occurrence.
What one would like to do (and I assume that is true in your case as well) is to figure out what these conditions are so that we can have a better idea of whether and when it will become easy to infect humans, or even whether there is anything we can do about it.
So what do we know from the above data concerning receptors? The usual seasonal flu prefers to attack cells in the nasal and upper respiratory tract; the avian flu viruses (in their natural state) prefer to attack certain cells found deep in the lungs only. This appear to (again intuitively) explain why it is harder for avian viruses in general to infect humans because it needs to go deep into the lungs, having survived all the defence mechanisms that a normal nasal and bronchial passage would have. At the same time, because it is not present to such a large degree in the upper airways, it is harder to transmit it by coughing or sneezing.
That is, these conditions make human infections by any avian flu virus a rare occurrence.
This takes care of the results of the 2 papers cited in my first post - the one-line conclusion being that H5N1 should, if it was like any other avian virus find it quite hard to infect humans or transmit from human to human.
But since we know that H5N1 has already infected close to 200 people and killing more than half of them, thus demonstrating the ability to do what other avian viruses find hard to do, there must be conditions that allow it to overcome these natural limitations (or barriers) to its ability.
The paper that I cited at 18:02 attempted to discover what some of these might be, by comparing how different types of flu viruses that infect humans behave:
By studying the conditions necessary for the first 2 categories, Taubenberger’s team were making some educated guesses (and testing them out) that H5N1 might have similar structures or be using similar mechanisms as these.
The answers that they found included a lot of ‘yes’s and ‘no’s.
So have they figured out what H5N1 needs to go pandemic? The short answer is no, not yet. But they have some partial answers which are extremely useful for the next stage of research to build on.
My thoughts? The more we know about this virus, the more we find that we don’t know. I know it’s a bit of a cliche but it still describes our current dilemma. Almost every time someone solves an exciting piece of the problem, a fresh one crops up that we didn’t even know was possible before.
There is nothing that tells us that a pandemic is imminent; there is also nothing that tells us that it is not.
I’m afraid I can’t offer anything more useful than that.
All I know is that there are 6 billion-plus humans occupying the planet at the moment. That is a tremendous resource waiting to be exploited by some organism, non-living virus or not…
Clusters may be one element of evolutionary pressure. When a close human group repeats a H5N1 infection through close personal contact from index case to case #1, #2, #3, etc., then if the virus in the index case may have had some “more successful” human interaction and before we can intervene, it gets to take this experiment and gets to repeat it again from this starting sequence. Then if these experiments continue the adaptation in case #2, #3, etc. We have a mechanism for it to experiment with human hosts - not just an individual and not starting over. It may be transmitted in the meantime by fomite, close contact with fluids, etc. but may end up with the ability to infect the upper lungs. In this sense it could be seen as evolving toward human hosts just from the availability of next of kin to play in their bodies. It may be that case #3 can give the virus back to birds to carry it to another location. Just my late night thoughts after reading the above.
anon_22:
Something which often seems not to get much emphasis is that the concept: natural selection is a metaphor.
Every word we use — and the thought behind it — is the product of an intuitive, goal-driven, human mind. It is not surprising then that as a result, our language is absolutely filthy with intuitive and teleological assumptions. But if abstinence is the solution, it’s a drastic one; what that amounts to is virtually a vow of silence. Equally unrealistic is to attempt a thorough unpacking of each potentially problematic term as it is invoked (this solution is guaranteed to have the audience wishing you’d chosen the vow of silence).
But it isn’t necessarily a problem. The field on which we will do battle with this virus is inside our own minds as much as anywhere. No matter how diligently we may strive for objectivity in assessing this threat, the decisions governing our responses will be made subjectively. Shamelessly so. All we need to know is what to do, and philosophers can struggle with teleological assumptions. From a practical standpoint, the idea that this virus possesses a cruel and purposeful intelligence may be an adequate approximation of the truth. It doesn’t matter if you believe that a bad water hole is under the influence of malevolent spirits, or if you understand that the water is contaminated with toxic minerals — as far as drinking the water goes, they are functionally equivalent.
Selection really refers to a statistical bias in a distribution of traits in a population of organisms. It can be expressed non-metaphorically and mathematically — but that quickly gets cumbersome (unless you happen to be one of the rare individuals like Guenter who actually seem to prefer things that way). As a matter of convenience, biologists often use terms in a sort of “as if” sense, and while they are not immune to being led astray by hidden teleological assumptions, they are surely less prone to it than are news reporters (and, of course, the average reader).
Selection is only one of the two main components of an evolutionary process; the other is mutation. Selection may not be “driving the virus toward humans”, but mutation is (though it’s also driving it toward cats, martens, and who knows what, so it’s not like we’re being singled out). We definitely represent a tremendous resource for the virus, but the virus can’t know that — just like the ancestors of birds (their genes, actually) couldn’t know that flight was further down the design path they were on. To persist, it has to work now; every incremental step toward whatever has to be an improvement.
I think the only ‘pressure’ that might exist would happen after one strain of the virus has acquired affinity to bind exclusively or overwhelmingly to á2,6 rather than á2,3 receptors. If and when that happens, especially if it does not lose the ability to replicate in such an explosive rate as is currently observed in the lungs of infected subjects, then the huge quantity of viral particles produced in the upper airways with the increased affinity to human infection would result in very efficient h2h and a very high R0, with infections in increasingly large numbers of human subjects to the exclusion for practical purposes of any other strain in the habitat. Crowding out other less ‘successful’ non-pandemic strains would then be the evolutionary pressure.
Anon22-
The clear strip idea came from a post by NJ. preppie – at 18:55.
Racter,
I prefer the word ‘favor’ rather than ‘select’ as being more neutral in intentionality: there are conditions that favor the evolution towards some direction over others. The problem that I see quite frequently is in most people who are less linguistically-aware, that certain words trigger a whole gestalt of meaning beyond what can actually be described in science. Otherwise, I agree with you in essence.
“The clear strip idea came from a post by NJ. preppie – at 18:55.”
Oh, OK. Sorry, too many similar names… :-)
Anon22-
Did you see that Dr. Taubenberger visited to answer your question on H5N1 Evolving Towards Pandemic Strain 2 Continued?
NS1,
Yes, kind of him.
It’s both scary and comforting to know that if one makes a big mistake, it will not get passed on but will be corrected soon enough.
:-)
A wiki is an error-correcting system when everyone contributes.
:-)
Gather and Solve.
Anon 22 - Thank you for taking the time at 00:00, to explain the research report, minus the unfamiliar-to-laymen science terminology. I can not believe the likes of JKT reading the arguments here! Guess everyone needs a laugh sometime. :)
anon_22 and racter: I agree with both of you regarding the problems of language when discussing evolution. I think the word “selection” was chosen by Darwin because he was powerfully influenced by what was observed in the production of different breeds of domesticated animals, such as dogs. Dogs were intentionally selected for different traits through controlled breeding programs. This was recognized as “artificial selection”. I think the term “natural selection” was coined by analogy to recognize a process shaped, not by man, but by the natural environment. Although I try to avoid teleological language whenever possible, the use of the word selection is recognized short hand for something like: “a set of environmental conditions that, on the whole, result in a statistically detectable increase in the frequency of certain genotypes over others.” In the interest of space, I will continue to use selection, but you see what I mean.
As regards to seeing a pattern only because I am looking for it, this is certainly possible. I think it was DemFromCT who referred to some of these papers as a Rorshach test. However, I don’t think this is what I am doing in this case, as I will explain below.
Neither of you have commented on my central proposition, that is, that there may be intermediate steps that occur in the evolution of a pandemic strain. To restate: the evolution of a pandemic strain of flu may be a multistep process. There may be selective pressures that act on each of these steps independently. Thus, although selection for a human adapted strain is not possible until the virus enters humans, other selective pressures may, incidently, favor the evolution of a strain that happens to recognize alpha 2,6 receptors, at least to a limited degree, which then allows the virus to infect and be transmitted among humans. Selection for a human adapted virus would begin only then.
What prompts me to think this may actually be happening with H5N1 is the change in the 3D structure of the HA protein. More recent strains of H5N1 are more similar to the 1918 virus than older H5N1 viruses at the protein shape level despite the fact that at the nucleotide level the H5N1 strains are much more similar. This is clearly due to evolution. What are the selective pressures driving this change? Presumably, whatever they are, they allow the virus to spread more efficiently among birds, since, as we all agree, selection for a human transmissible virus cannot be occuring at this point. My hypothesis is that this process may not be complete. The H5N1 HA may become even more like the 1918 HA, in shape, not necessarily at the nucleotide level, until the HA protein is able to recognize alpha 2,6 receptors. The relevance to our current discussion is that if this is in fact being selected for among birds, then evolution of a pandemic strain is inevitable. Hence, I think study of the evolution of the 1918 virus is potentially very relevant to our understanding of the evolution of H5N1.
So Stevens et.al. were testing some mutations and didn’t yet find a pandemic strain, although a “better” strain than Viet04 by implying G228S.
Now, did they tell us about all their trials ? Maybe they did some more trials and _did_ find a pandemic strain ?? We would probably not have been notified. Maybe Webster knows it, though.
Why didn’t they just implement all mutations in the RBD (receptor binding domain) which make Viet04 into SC1918 ? That’s S136T,S137A,E190D,N224R,G225D,S227A http://www.setbb.com/fluwiki2/viewtopic.php?p=214&mforum=fluwiki2#214
Also, can we assume, that H5N1 already searched enough, and if there were a panflu-strain, it would already have found it ? That is, if Q226L+G228S or E190D+G225D would have done the trick then H5N1 would already have found it. The G228S _would_ be useful to increase H2H transmissability. Why didn’t H5N1 already try it ? Maybe it did, but there were some other problems besides binding which made it not advantageous.
gs,
I have no idea as to whether they tried anything else; I would assume they would and still are trying out and refining various methods to probe more deeply. I am no molecular biologist as you know but I suspect that it is a lot more complicated than just throwing every mutation we can think of at the virus :-)
My first reaction from the data was that H5 is far more complex than even H1. That’s probably why we are seeing all these outbreaks over so many years and yet no pandemic strain has arisen. It could be that the species barrier is indeed high, but since the consequences of a pandemic by this virus is so severe, we need to still stay vigilant until we have a lot more certainty. Also, don’t forget that molecular sequences however precise only give part of the story; they are useful only when viewed in the context of epidemiological data.
A few more interesting points from the Swedish team in Science
“In human LRT, H5N1 virus attached predominantly to type II pneumocytes, alveolar macrophages, and non-ciliated cuboidal epithelial cells in terminal bronchioles. Attachment became progressively rarer towards the trachea… These findings fit with the limited pathology data for H5N1 virus infection in humans, which show diffuse alveolar damage (1) and the presence of H5N1 virus antigenin type II pneumocytes (5). ‘’‘However, they contrast with the idea that avian influenza viruses generally have little affinity for human respiratory tissues’‘’ (2).”
“The predilection of H5N1 virus for type II pneumocytes and alveolar macrophages may contribute to the severity of the pulmonary lesion. Because type II pneumocytes are metabolically active and the most numerous cell type lining the alveoli, targeting of this cell type may lead to abundant virus production. Damage to type II pneumocytes may impair their functions, including re-epithelialization following alveolar damage, ion transport, and surfactant production, and so inhibit tissue repair. Targeting of alveolar macrophages may be important because of their role in limiting viral replication and in the immune response to viral infection.”
H5 needn’t be more complex. Just they didn’t succeed to locate the a2,3→a2,6 necessary mutations yet, so this particular situation could be more special+complicated. When you look here: http://www.setbb.com/fluwiki2/viewtopic.php?t=94&mforum=fluwiki2 it seems that there is still much less variety in H5 than in H1. I wonder, why this G228S didn’t happen already. do we really need these “type II pneumocytes, alveolar macrophages, and non-ciliated cuboidal epithelial cells in terminal bronchioles” or can we remove/modify them surgically or pharmaceutically ? (hard for me to read all the English-medical expressions)
“do we really need these “type II pneumocytes, alveolar macrophages, and non-ciliated cuboidal epithelial cells in terminal bronchioles” or can we remove/modify them surgically or pharmaceutically ?”
No, they are an integral part of the epithelium (membrane) and also serve important functions such as surfactant production and repair etc.
Monotreme,
I absolutely think that the evolution of the virus is a multi-step process and that there are intermediate steps. However, I do still think the way we unconsciously use the words ‘selection’ and even ‘evolution’ can be problematic, especially in this instance because it can so easily lead us into traps in our thinking.
An example is in your post “More recent strains of H5N1 are more similar to the 1918 virus than older H5N1 viruses at the protein shape level despite the fact that at the nucleotide level the H5N1 strains are much more similar.” Your conclusion that “this is clearly due to evolution.” is only valid if you already accept evolution as a linear and directional process which is capable of CAUSING something to happen, otherwise you would not and cannot use the phrase ‘due to’.
I would suggest an alternate view, that the virus probably changes its shape and nucleotide sequence in infinite ways at very short intervals, and that our ability to capture and record those changes are extremely limited and heavily skewed by the detection of ‘cases’ (both human and avian), such that if a pandemic strain does eventually appear, and one were to go back in time and examine the ‘intermediate’ strains that we have recorded, one could recognize some pattern suggestive of the sequential nature of the changes, and so we decide to use the word ‘evolution’ to describe this observation of sequential-ness.
So far so good. But there is no basis to make the logical leap that the end point (pandemic) was CAUSED BY such sequential-ness.
The English philosopher Alan Watts had a very good metaphor to describe this problem. Suppose you are an alien from outer space, and you have landed on this earth. Suppose that you have never seen a cat before. Now if I were to put a screen in front of you with a narrow slit for you to see through, and put a cat on the other side, such that at any moment you cannot see the whole cat but only parts of it. As the cat walks across the room, you will see a certain set of features which, you discovered, us humans label as ‘head’. After a brief interval, you see a different set of features which is labeled as ‘tail’. As the cat walks back and forth, you will repeatedly see occurrences of ‘head’ which are INVARIABLY followed by the occurrence of ‘tail’. In fact, assuming cats do not walk backwards, you will notice that ‘tail’ NEVER happens without prior occurrence of ‘head’. Now you might erroneously conclude from your observation that somehow ‘head’ is the CAUSE of ‘tail’, not knowing that at a different level of reality (without the screen) the head and tail were both part of a bigger object ‘cat’, and neither of them are the cause or the effect of the other.
Going back to the virus, to think that certain things are happening BECAUSE OF evolution is the same thing as thinking that ‘the head causes the tail’ in the cat analogy. The problem is that if you believe the latter to be the case, then as a scientist you would be tempted to try and elucidate the factors driving this ‘head cause tail’ phenomenon, as shown by the question that you asked next “What are the selective pressures driving this change?” Now, one can have many interesting philosophical and esoteric musings about the origin of ‘head causing tail’, but if you are a scientist interested only in discovering practical usable knowledge, such musings are at best an fun diversion and at worst a complete waste of time and effort.
To put it in another way, we need to be very wary of confusing description with causation. Evolution is not CAUSING the virus to change; evolution is what is OBSERVED when the virus changes.
The reason why this is important is that thinking that we know causation is far more likely to make us believe the outcome preordained and inevitable.
BTW, to solve the problem, Watts suggested we use the phrase ‘goes with’ in our thinking. Rather than thinking ‘head causes tail’ it is more accurate to think ‘head goes with tail. Or, that certain patterns of changes in the nucleotide or protein ‘go with’ being a particular type of influenza virus.
Geeze,
We’ve been up for barely 12 hours and we already have side scroll. Would the authors please go and look at their contributions and solve the problem, please?
I posted the receptor binding areas occurring in database: http://www.flutrackers.com/forum/showthread.php?t=3547 for human H5N1 there were just these: H GLSSA WLI HHPNDAAEQTKLY EIATRPKVNGQSG,1 H GVSSA WLI HHPNDAAEQIKLY EIATRPKVNGQSG,2 H GVSSA WLI HHPNDAAEQTKLY EIATRPKVNGQSG,17 H GVSSA WLI HHPNDAAEQTKLY RIATRSKVNGQSG,12 H GVSSA WLI HHPNDAAEQTRLY EIATRPKVNGQSG,2 H GVSSA WLI HHPNDAAEQTRLY KIATRSKVNGQNG,3 H GVSSA WLI HHPSDAAEQTRLY KIATRSKVNGQSG,1 H GVSSA WLI QHPNDAAEQTKLY EIATRSKVNGQSG,1 H GVSSV WLI HHPNDAAEQTKLY RIATRSKVNGQSG,2 that doesn’t look as if there were so many mutations possible.
now compare with the H5N1-variants for avian sequences RBDs: (receptor binding domains) there are about 80 different strains with 4 main strains, this variety could be reached for human H5N1-RBD-parts after the possible human pandemic. That would mean, we had roughly 5 times the variety in the RBD as we had with 40 published sequences or there were not much room for further untried mutations with 200 sequences, when we compare human H5N1-RBD-variety with Avian variety and assume that avian H5N1 evolution is already somehow exhausted with the published sequences.
anon_22 wrote: I would suggest an alternate view, that the virus probably changes its shape and nucleotide sequence in infinite ways at very short intervals, and that our ability to capture and record those changes are extremely limited and heavily skewed by the detection of ‘cases’ (both human and avian), I can’t see so many different sequences in the RBD and the sequences uniquely determine the shape (usually, I think) Also, there seems to be a limited supply in possibilities, else there would be much more waves in a pandemic or more than one pandemic in H1,H2,H3
Melanie, can you explain the “side-scroll” problem ? When does it occur, how to fix it ? Which browsers are sensitive ? I can detect no problem here. Except that my sequences have no new-lines although I included the double-slashes
anon_22: I don’t disagree with you about the language issue. What I have been trying to suggest is that there may be positive selection in birds for conformational changes in HA that will incidently favor at least a weak ability to bind to alpha 2,6 receptors.
I know you don’t like to use the word “selection” either, but this is now established usage, blame Darwin ;-).
Its certainly true that mutations are (mostly) random. However, outcomes are not. Due to relatively constant environmental conditions and biological constraints, certain outcomes are much more likely than others. Flight has evolved many times, independently. Australia has a whole range of animals that look like placental mammals, but which clearly evolved from a separate lineage. Comparative genomics has revealed that convergent evolution occurs much more often than had been appreciated previously, much to the chagrin of taxonomists who relied on morphology.
What I’m proposing is that there are a finite number of ways that the HA protein can evolve (or change, if you prefer). This is due to physical-chemical contraints on protein stucture. Given a certain set of environmental conditions (positive selection) it may be inevitable that the H5N1 HA evolve (change) to allow a structure that can infect cells with alpha 2,6 receptors. Basically, I’m suggesting that the same selective pressures (environmental conditions) that caused (permitted) H1N1 to evolve (change) in such a way as to permit it to infect alpha 2,6 receptors may also be acting H5N1. The nucleotide sequences that permit this to happen may not necesssarily be the same.
Looking at the protein stucture, rather than the nucleotide sequence, is analogous to looking at morphology. If I see a small rodent-like creature with modified arms and odd skin flaps that kind of look like wings (a bat), I might think this thing could fly, even though at a nucleotide level there would be little similarity to birds. I might further suspect that similar conditions let to the evolution of flight in both bats and birds, ie, access to insects, fruit, etc.
H5N1’s “wings” aren’t done yet, its more like a “flying” squirrel at this point. But the fact that its got some of the necessary “structure”, makes me think it may be just a matter of time before it takes “flight”.
Monotreme,
I don’t disagree with your premises, and the purpose of my posts is not to debate abstract sementics. I just don’t see the practical use of such speculations? And I use the word speculation with no disrespect; it is just that I don’t know that we know enough about the rules at the molecular level to judge with any certainty what might or might not be the path forward for H5N1 evolution. I have a feeling that in this process we are not more than helpless observers, and we will be extremely lucky if our educated guesses or speculations land us more or less in the same field, let alone the same finish line, as the virus.
Unless we can improve our accuracy dramatically, so that for example we can actually tell in which country or under what environmental circumstances a pandemic strain might appear, all we are doing is talk. Talk is good; it helps us clarify our thinking. But that probably is the limit of what we can do with this at the moment.
To put it in another way, IMHO Darwinian concepts of evolution appear to be more useful or user-friendly in explaining current or past phenomena than in predicting the future.
I wish it wasn’t, but what do I know…..:-)
anon_22: I agree with you that its better to have complete data and easier to describe evolution that has occured than to predict future evolution, to say the least. However, to me, the protein data is a strong signal that H5N1 is evolving along the same path that H1N1 did. There are other clues as well, young patients, cytokine storms, etc. I really don’t want to use telological language, but due to biological and chemical constraints, I think there are a limited number of paths that evolution can take. There are “paths” towards flying, burrowing and swimming that have been taken many times by animals in different classes. Recognizing intermediate steps can be difficult. But, I think its safe to say that if all flying animals were wiped out today, it is inevitable that some animal would evolve with the capacity for flight, because the niche exists and empty niches are always filled. After the dinosaurs were wiped out, the many empty niches they left behind were filled by mammals. It may not have been inevitable that mammals fill them, but it was inevitable that they would be filled by something.
The fact that the HA protein structure of H5N1 changed to resemble the 1918 strain suggests to me that whatever niche existed in the early 1900′s that led to evolution of a pandemic strain may exist again. If this is true, then it is inevitable that H5N1 also evolve into a pandemic strain. I agree with your post about needing more data because we are only looking at a snapshot. My only point is that collecting data on the structure of the HA protein is very useful. I would dearly like to see what the structure of the HA protein that is causing the large clusters in Middle East looks like.
You know alot, more than I do on most things, and I have enjoyed debating this with you.
I’m not sure about this 1918-comparison. They are not comparing the viruses but somehow one of their specific properties. And there the 1918-virus gave the best fit. That needn’t mean, that Viet04 is getting close to 1918-H1N1. In fact, it’s still H5N1 and adapting to H1N1-properties too much might cause other instabilities.
Monotreme,
If I was to pick the most interesting or most rewarding person to debate with on this forum, you would lead the field by a long stretch :-)
But to come back to protein structures, can I ask your opinion on whether our current state of knowledge allows us in any way to judge what host or environmental factors could facilitate the evolution of a pandemic strain (specifically in relation to H5N1)? Is there any way even theoretically of guessing these and not just what the virus needs to change (not that this latter is not important but since it is already the subject of frequent debate, I’d like to look at additional angles)?
gs,
“I’m not sure about this 1918-comparison. They are not comparing the viruses but somehow one of their specific properties. And there the 1918-virus gave the best fit. That needn’t mean, that Viet04 is getting close to 1918-H1N1. In fact, it’s still H5N1 and adapting to H1N1-properties too much might cause other instabilities.”
I agree that we ought to be careful not to bind ourselves too firmly into this notion of similarity to 1918. After all, the same mutations needed (Glu190Asp/Asp225Gly) for H1N1 to bind to human receptors do not work for H5N1 at all. I think the differences with the 1918 virus are emerging and may become far more important in our considerations in the near future.
For example, what does it tell us that H5N1 needs the same mutations as H3 (Gln226Leu/Gly228Ser) and not H1 to affect some change in receptor affinity, but that this is not a sufficient condition? Could it be that the barrier for H5 is indeed higher? Or could the issue of bivalency of receptor configuration which the above study suggests might be important if not essential be used in any way pharmacologically? Is there any anti-viral research in the pipeline that exploits this aspect?
On the other hand, does the fact that H5 has tissue tropisms (i.e. enzymes present in multiple organs as opposed to just lungs can cause cleavage of the HA components and trigger viral replication) account for its very high CFR which increasingly appears to be distinctly different from 1918?
I’m afraid that 226,228 mutations plus some others could be enough and they wrote, they are examining these things now - maybe they found something, and that’s why Webster is so alarmed ? Suppose, they would find something, would they tell us , thus risking a panic ? For the CFR, that’s not mainly HA which is responsable AFAIK. PB2,PB1,PA play a big role.
BTW. when looking at the H1,H2,H3,H5,H7 recently , I found that the best match was H5 and H2. And H5 first appeared 1959 in Scotland, could it be that it emerged/reassorted/recombined from 1957 panflu H2N2 ? I never heard about this.
anon_22, thanks.
Your question as to “…whether our current state of knowledge allows us in any way to judge what host or environmental factors could facilitate the evolution of a pandemic strain (specifically in relation to H5N1)? Is there any way even theoretically of guessing these and not just what the virus needs to change…”
is right on target.
My answer is maybe. I am using Flu Wiki as a crude database to try to assemble the relevant data to address this question. What we need to do is link all of the available sequence data to human and animal cases and include geopgraphic, temporal, ecological, experimental and pathological information. I’m still assembling the data and creating links between the various pages. pm wiki is not the ideal way to do this, but the results are public, which is a big plus. Of course, we do not have access to the most important data, which I rale against on other threads.
I think Taubenberger and colleagues are trying to collect similar information from pre-1918 strains to reconstruct the evolution of that strain. If he is successful in figuring out how the 1918 strain evolved, then in theory, if you had enough information, you might be able to get a better sense of how likely H5N1 will evolve into a pandemic strains. There are many rules and biological constraints that govern evolution. We don’t know all of them, that’s for sure, but much has been learned with the past few years as a result of the genomics revolution, and I am optimistic that we will eventually be able to predict evolutionary outcomes with better precision.
we are linking H5N1 to 1918 because it’s somehow similar (I don’t know exactly why) and because it’s so virulent. But when we just consider transmissability and the needed mutations in the RBD, can’t we compare it with 1957,1968 as well ? I mean, virulence (CFR) seams to be just a random attribute of a pandemic and not related to the RBD in HA.
gs,
The similarity is not just in virulence but in the distinct clinical picture and the propensity to cause more severe illness in young and fit individuals. These were not found in 1957 and 1968.
This was posted in another thread about species barrier but I am including it here to maintain coherence of discussion.
The recent collection of papers in Science contains quite a few gems. Here is a synopsis of portions of Host Species Barriers to Influenza Virus Infections relevant to this discussion.
For H5N1, there are several mutations that show consistent species preference and may therefore be species barriers:
If multiple mutations are required before the virus can establish itself in a new species, where those mutations occur is also important.
2 considerations:
Progressive Adaptation: If a large no of mutations are required to overcome the species barrier, each mutation that happens in the recipient species would require successful transmission within that species (ie h2h) for the mutation to be retained. Since this is a new host species, with no efficient transmission yet, this process is harder, more gradual and haphazard for the virus.
Chance transmission of multiple advantageous mutations: Mutations happening in the donor species, however, require only that the virus be spread to the next host in the donor species (ie b2b) for the mutation to be retained, which is obviously a lot easier since it is already transmitting efficiently b2b. Therefore, if multiple mutations required for causing a human pandemic were to occur within the donor species (birds) and become stabilized before jumping the species barrier, like E627K in wild birds in Qinghai, there is a higher chance of a sudden appearance of a pandemic strain.
Annon_22, Montreme and others
Firstly many thanks for your time spent here enlightening others like me, who have some limited understanding of the issues.
However, reading this thread I have a question. As has been raised elsewhere in other threads, Quail have 2,3 and 2,6 sialic acid receptors and we have had H5N1 outbreaks in Quail in China, recently. I do not understand the technicalities, but logically, the quail virus would have favoured development / evolution of a virus with additional specificity towards 2,6 and 2, 3 receptors and therefore theoretically should have increased infectivity towards humans and moved the virus closer to a pandemic strain. Has there been a gene sequence for these released to genbank for you experts to analyse?
To me, the fact that this Quail H5N1 didn’t produce a pandemic strain as yet must logically mean that there is some other additional factor required for for a pandemic to occur. My question would be, what is this likely to be?
Selection
The fact that it hasn’t produced a pandemic strain is not indicative of anything other than it hasn’t.
I’m not being flippant, just that you might think something theoretically, AND may even very possibly be right, it does not mean that it HAS TO happen, or has to happen NOW.
This is the same as Dem’s famous line: No data means no data.
No mutation means no mutation. It may not (or it may) mean there is any additional factor.
anon_22 at 20:44
>The fact that it has not produced a pandemic strain is not >indicative of anything other than it has not.
it is also indicative of e.g. why Tamiflu prices didn’t rise a lot,etc.
>I am not being flippant, >just that you might think something theoretically, >AND may even very possibly be right, it does not mean >that it HAS TO happen, or has to happen NOW.
it just makes it for me more likely to happen
>This is the same as Dems famous line: No data means no data.
you should hang it over your bed alongside with the quote from another great philosopher who said: it is, so it is. (A==>A)
>No mutation means no mutation. >It may not (or it may) mean there is any additional factor.
this may or maynot be true.
No mutation for 1000 days somehow makes it unlikely that there might be one on day 1001.
Clearly there are lots of other factors, not just this alpha 2,3 vs.2,6 When the current H5N1 works well in birds, including quails, then there is not so much reason to mutate towards 2,6 in quail. If humans would contact quail as frequently as chickens, that could be a problem however, since e.g. S227N should be more likely in quail than in checkens. (ignoring other factors)
gs oops! I mean anonymous, what is your opinion of all required mutations as a group occuring in one event at one time?
If this were just pure math, then Anonymous @21:24 when you say “No mutation for 1000 days somehow makes it unlikely that there might be one on day 1001.” is not correct. If we know that an event can happen, then given all the monkeys in the world and an infinite amount of time and access to a word processor, you get any result you can imagine them writing. NO result is more or less likely. Now, if you introduce very large numbers, to a virus mutation you do increase the chances for it to happen. It happened in 1916. We just can’t predict anything with any certainty. We need to know exactly what result we are looking for and we can’t. We need to know the total number of rolls of the dice and we don’t but it is getting larger all the time. We also need to have this mutation have a chance to be passed on. It may or it may not. My point is that is indeed within probability that on any day of this virus it may do everything it needs to go H-H. Not enough knowledge exists, not enough samples exist, not enough surveillance exits, etc. for us to say much more than it intuitively looks very bad.
In fact, flumonitor is right in that quail is one of the species in which a reassortment event leading to sudden emergence of a fully formed pandemic strain is a concern. However, we know far less about the determinants of transmission than about the determinants of virulence to be able to determine the significance of the fact that it hasn’t happened yet. For example, a change in receptor binding affinity is probably important, but is it SUFFICIENT to cause a pandemic? That we don’t know.
There’s a lot that we don’t know about H5N1 to narrow down predictions further than current attempts by various virologists, and that’s also why we are likely to see wide variations in predictions for some time.
Anon_22-
I’m with you on the RBD issue . . . we don’t know enough to even claim that a complete RBD sequence change would create the pandemic strain.
Until the pandemic strain emerges, I believe that we are holding at about 5% of the knowledge that we need to make predictions on this virus. Once the strain(s) emerges, then we can observe and form interpretations toward predictions for regions and subsequent waves.
I predict that the frequency of predictions will increase and those predictions in the end will have an inverse veracity plot until the pandemic strain(s) emerges. At that time, the veracity area will enlarge slowly as more feedback and more directed analysis allows predictive refinement.
Then we’ll have about 20% of the knowledge that we need to make predictions.
Ok, NS1, all you need is to give me more numbers and percentages and sentences that are actual mathematical equations and I’m done for the day - and it’s only just after breakfast here.
LOL..
Anon_22-
Thought you’d get a giggle from my prediction.
I’m still but a lad, though I can see the importance of perspective and especially retrospective in these matters.
Are you post-jet-lag yet from your duties at the conference?
NS1 at 04:34
how can you make such a detailed prediction but simultaneously claim
that current predictions are useless ?
Explain “inverse veracity plot” !
There is no magical limit of knowledge, since when you can make
predictions. It is continuous.
Current predictions are very useful because they teach us that we KNOW ‘very little about the causal translations of these sequences and even less about the genetic acquisition process, especially the drivers or modifiers.
Truth is data that has been proposed, theorized, tested, measured and found accurate and salient.
The inverse veracity plot mentioned is my determination of the post-scriptive measure of the accuracy of the current group of predictions - less than accurate on the whole due to less than complete observations and very high bias among the theorisors.
I also forthcomingly predict quite openly that my satirical prognostications will continue to be limited in scope, to be sparse in supporting data, to carry a CI 95% and to be completely validated only by proctors of my selection after a rather comprehensive review procedure.
we can also measure the deviation of the predictions of the experts. Are you making a statement about this ? Do we already observe that this deviation becomes smaller ? Also, we see new data coming in, but rarely one expert seems to change his prediction. E.g. Osterholm had always been one of the greatest pessimists, but his arguments do change. That makes me wonder… I mean, when he doesn’t change his predictions then his old arguments should be sufficient and there were no need to include newer developements. Also, I rarely saw him mentioning some positives. It’s difficlult to find someone who mentions positives _and_ negatives. So, are they biased ?!? Did they fix their pre-positions and then comment on the data so to confirm the position ?
An expert only knows what he / she knows at the moment. We comment based on our personal knowledge bases and most certainly pre-position our ideas on our personal foundations. Then we try to confirm our ideas.
This problem has poorly defined causality and multi-variate correlation, so we’ll see predictions all over the map.
All and none of them are useful.
All and none of them are useful
you are hiding your opinion behind pseudophiliosophical language.
Is it just to avoid being clear and fear of being quoted
with a prediction later, when we know whether it became true ?
If you take a radioactive Plutonium-239 atom and ask experts exactly when it will fission (split), they will not be able to tell exactly. But they will be able to tell you that Pu-239 has a halflife of 24,110 year, and let you guess for yourself if that exact atom will undergo fission or not. In the large scale view it doesn’t really matter.
This obsession about data where data is inexact goes nowhere. You cannot predict on this level. What you are asking for is for the experts to predict evolution. As far as I know that is not possible on the micro-level. What the experts can say, working from knowledge about the rate of mutations, is that within a given time-period the exact mutation you are looking for, might come about. We know the conditions are there, we know it could happen, we know that individual these mutations have been seen by themselves, we have not yet seen the all-in-one package. You work it out.
presumable all experts will give the same probability for 239-PU to decay. Again: of course you can predict, you can always predict. It’s just only a (subjective) prediction. I really don’t understand, why you and others still aren’t getting this. Why experts still say this “we can’t predict , no one knows” - nonsense, at least in public interviews.
It doesn’t make sense and is just unlogical. You can’t vote about logics, no matter how many of you repeat this.
The lack of expert estimates is one of the reasons that people are so badly informed and we are so badly prepared. We have no directive from the experts and silly politicians have to come up with their own estimates. And they estimate what serves their purpose, not their scientific understanding.
Can we trust someone who tells us to prepare but then says : “no one can predict how likely this will happen” ?
anonymous – at 09:50 “I really don’t understand, why you and others still aren’t getting this. Why experts still say this “we can’t predict , no one knows” - nonsense, at least in public interviews.” No , my friend, ‘til you who do not get it. This discussion has gone on on several blogs/boards and the result is the same. This is not Burger King, and in this instance you cannot have it your way. Kelly
anonymous,
If you find yourself asking the same or very similar question(s) or repeatedly over many months and finding almost NO ONE agreeing with your approach, do you believe that everyone else is wrong? Or…what???
anonymous…okay if that’s what you want me to call you. You bring a lot to the table and although you do get a little off track once in a while, I enjoy reading and learn from your comments. There is a lot more in this than numbers and I would appreciate your comments on all the other aspects of the situation we have put ourselves in.
By the way, I would like to know your take on the numbers. If and when it is going to happen…how bad (mortality, CFR, collateral damage)
What are your conclusions?
again: this is decided by logics and not by majority vote. I know, that almost all the females are against this for some reason. I never saw some reasonable argument, though. At some point they stop replying, without addressing my points. I really thought, some of you should be convinced by now, being refuted again and again. Refusing to give probability estimates and expectation values is indifferent for the nation’s panflu-preparing and thus dangerous for the world’s health. When you think, that nations are underprepared, then give a clear estimate and let them compare with other expert’s estimates - then they have little argument to not prepare. When experts say: “no one can predict how likely this is” - then why should they do anything ? Sorry, but this is a scandal. IMO even more than the withholding of the data or the delaying of papers.
Okay. I believe you are an expert and I would like your opinion. This is not a debating point…I really would like your opinions after your at two month search for accurate predictions…and I agree with you that the situation hasn’t been helped by experts who are hedging their bets and retracting for some reason and then changing their minds a month later, again without scientific explantation for the reversal…doesn’t make sense to me either.
There is nothing wrong with being wrong about a clearly stated honest opinion without the parachute.
TomDVM, first you should specify which fluwikians you meant who think panflu within 12 months is likely. And why you think this is likely. You didn’t yet answer this. I didn’t find any expert saying this.
anonymous. I can’t find the exact quote that you mention on this thread although I know I made it.
I have spent so much time reading throught the lines when it comes to governments and regulators (WHO etc.) that I so it automatically.
If I made a comment to the effect that I knew the opinions of others on flu wiki, then I should and will retract them right here.
I believe, based on as much information as I can personally gather, that a pandemic is inevitable and imminent: will occur within twelve months…that is my honest opinion…if I turn out to be wrong then I will ethically acknowledge the fact.
I would still be interested in your honest opinion at this point in time, given your specific areas of interest. thanks.
TomDVM, you might have misunderstood, what the experts meant,
because they usually are not clear with their predictions
and transmit sentiments rather than numbers.
Please reread the recent expert-statements and think again.See e.g.:
http://tinyurl.com/nv9sv
my estimate 15% likelyhood per year for a pandemic, 20million
expectation value of deaths per year.
Anonymous.
1) does that mean 15% likelyhood of a pandemic occurring next year and 90% that it will happen within 6 years.
2) Are you saying that the loss will be 20 million in total or 20 million for how many years?
1) it goes down after some years, when it didn’t succeed by then, it becomes less likely. Also we have better vaccine, better antivirals, better knowledge. 50% in total, that there is a H5N1 pandemic 2) sum over all scenarios of their likelyhood and the number of deaths
sorry, I mean : 2) sum over all scenarios of product of their likelyhood and the number of deaths
anonymous.
Okay, If I get it right then you are saying that there is a 50/50 chance of a pandemic in 5 years although you would put the probability at 15% in the next year.
Your maximum estimate of losses (sum over all scenarios) is twenty million deaths.
TomDVM
Are we discussing these estimates and probabilities with someone from our circle who is posting as anonymous or an impersonator?
NSI. I’m pretty sure………….that I wouldn’t want to speculate.
Tom DVM, I think you have said on numerous occasions that this virus (H5N1) is making liars out of all of the experts. I believe Robert Webster said that in all of his years, he has never seen a nastier flu virus. I believe it was Osterholm who said out of all of his experience and research, covering such topics as ebola and bioterrorism, it is H5N1 that keeps him up at night. Taking all of these comments together, it would seem that your nickname for this virus (a frankenstein virus, I believe you called it?) is appropriate. And I also imagine you’ve seen quite a few nasty viruses in your line of work as well. Comments such as these have to make one stop and think that we are looking at a very novel situation, in deed. Such a situation, IMHO, could probably turn in a blink of an eye. Such unpredictability and potential for catastrophe is truly amazing.
De jure. I couldn’t agree with you more. I think part of my problem in this, is the unique position farm animal veterinarians find themselves in. All other types of veterinarians and physicians treat individual animals. Farm vets treat large isolated groups of animals on individual farms. Localized epidemics are their stock and trade. Diseases must be diagnosed and treated with little in the way of diagnostic testing, under a situation that the battle is won or lost before any testing comes back…it’s like playing Russian Roulette…the odds are eventually going to get you.
Human nature is a funny thing. I think it becomes a self-fullfilling prophecy in the sense that any evidence against a pandemic is seized upon and emphasized out of porportion to the other evidence.
All I can say is when I look at the evidence, I see nothing but flashing lights.
If we could put twenty country vets together, you might be surprised at the conclusions reached and the proposed actions taken.
Tom DVM, What is the reaction of other DVM friends or coleges? Do they feal the same. All I know is that I agree with you. gina
Hurricane Alley RN. I’m sure that they are busy behind the scenes doing research on animals…most animals used for experimentation in human settings have a veterinarian on staff.
I don’t think veterinarians are or have time to be effective activists…but believe me, given the climate of denial at the moment, I wish they would come out in mass and comment to get this thing back on track while there is still time…because in the end it is all about saving millions and millions of lives and particularly millions of children’s lives.
Tom DVM:
If we could put twenty country vets together, you might be surprised at the conclusions reached and the proposed actions taken.
So, what are you hearing at your professional meetings, Tom?
Melanie. I must be honest…I haven’t gone to one in a while. That is not unusual for farm vets.
Tom DVM, I wish they would too. However, like many others they probably already have their plate full. Unlike people, animals can’t lie. If you watch them, they can tell you more than you want to here. At his point I would take the word of a vet. over any other doctor. gina
Thanks Gina but I wouldn’t go quite that far. I am absolutely convinced…beyond a shadow of a doubt…that we, the human race, are in very big trouble at the moment…but we are too stupid to see it… human nature being what it is.
But the thing is…I could be completely, 100% wrong.
Tom, You could also be 100% correct. At least I don’t think I’m crazy. I feel to certain. Without a doubt, humanity will not disappoint me. What are we the people not being told. Do the ones in charge not understand they are driving the death rate up. Prep will be to late and for many impossible. I hated the thought of having a gun in the house. I now own one. If backed into a corner, I won’t be afraid to use it. Thanks for being you. There are several people on this site I have gained a great respect for. gina
TOM DVM - Lex in Colborne wd like to discuss BF with you - he thinks you were in his class at Guelph?? I told him about you!
Perhaps the 2 of you cd start a Vet rap locally???
perhaps the 2 of you can start a vet thread?
Why not try to look at the probability of a pandemic from a slightly different perspective. If you are driving a car at 50 mph on a state highway there is some probability of an accident. I don’t know what the probability is but I am sure that someone somewhere knows.
If you are driving on the same highway at 65miles an hour there is a higher probability of an accident. And of course at 130 mph the odds are pretty high that there will be an accident on that same highway.
Bird Flu (or flu in general) must need some number of opportunities to evolve (however that is done) into a deadly virus. I am suggesting that the number of opportunities is in some way akin to the speed of an automobile. With the recent indications of the bird Flu’s presence in India and Africa it seems to make sense that the virus has many more opportunities to evolve. There are 1+ billion people in these areas and plenty of birds.
I am not going to put a probability estimate on this likelihood of a pandemic because I do not have access to the information needed to arrive at an estimate. However,, I find it amazing that someone in the field of epidemiology has not made these calculations. I think it safe to conclude that we are “going very fast” on this highway and it is time to be concerned for our safety.
From this reasoning, I also conclude that someone, somewhere knows a lot more about how to estimate these types of events and they are not talking in public for some good reason. I do note that those whom these knowledgeable people do talk to (politicians and policy makers) seem to be getting the message that we all need to be prepared for a serious event that could easily get out of control. If policy makers are now starting to go out on a limb there must be something eminent going on.
While I have not read every prior post in this thread I get the idea about mixed messages. As a management issue, this is “good policy” if one’s intent is to gradually get the public ready. Numbers might do more harm than good when you think about the overall population. Management of this potential disaster is needed. It is not about the ability of some portion of the population to deal with the truth it is about getting everyone in the population ready.
TomDVM
I’ve posed a private email to our German colleague to determine an answer on the probability questions. No reply at this time.
NS1 - Your German colleague hasn’t been around much lately and I might add, neither have you. Some of us don’t have as much to add and do better as readers and you are one poster we look for, so don’t be too scarce.
AQWF-
I miss Guenter as well. He’s likely been as engaged as I these past weeks.
I’m still tracking the sequences and building supports, but I haven’t had time to make cogent responses lately.
Has anyone done a full review of Niman’s patent application?
TomDVM
GS will be watching the forum closely as he shares a similar interest.
Guenter’s new handle seems quite transparent to some of us. Not sure why he’s doing that. I’m still trying to get free of some commitments I made during the recent outage, and have barely been able to spare an eye for the discussions here. Amazing how well you’ve all been getting along without me.
Racter-
We played no dirge in your absence; its just that we missed the razor wit and keen solution development that always follows your discussions.
Welcome back . . . now get to work!
close for length part 2 here