Forum: What I Learnt from Talking to JKT

OK, I’ve decided that I’ll have a go at writing this up. Be forewarned that this may require some heavy-duty thinking as well as reading. Another caveat is that I am only writing my own understanding of Taubenberger’s ideas, and is not a direct reproduction of his words. The third warning is that this is only a first post, which is about a third of what I want to write about. I’m going to number the paragraphs for ease of discussion only, the numbers may not represent separate items.

So to start, the major thing is there are a lot of ideas or so called ‘accepted wisdom’ on which we base our thinking. We need them, but it is also important to examine them from time to time and see how true they are. Here I attempt to point out a number of things that we think we understand but may not be correct, or that we do not know enough about to be sure that we are correct.

Happy reading!

1. There are 16HA and 9NA subtypes � well these are the ones that we know of, that are currently surviving, in various species. We do not know whether historically there were a lot more than that, or even whether there are other subtypes living in hosts that we haven�t sampled. Both those questions are important.

2. The first problem is the issue of evolutionary bottleneck, and it goes like this: suppose for thousands of years, there used to be many more subtypes of flu viruses, maybe hundreds or thousands of them, and at some point in time say several hundred or thousand years ago, an ecological event or events happened and most of the strains died off, and what we are seeing are mostly descendants of a very small number of survivors. Why is that important? Because we cannot assume what we observe from these 16 subtypes are necessarily the full capabilities of flu viruses. There could be a whole number of things the flu viruses can do that we don�t know about, and suppose one of these days we encounter one particularly unusual strain that actually had very different characteristics from the �normal� ones that we observe, then we have no data on which we can base to build our assumptions.

3. The second problem has to do with the fact that far too little research on flu has been done for decades. We accept as true the supposition that aquatic birds aka ducks are the natural reservoirs of flu viruses, and that in ducks the virus is in evolutionary stasis. Well, again we have to look at these ideas separately.

4. Are aquatic birds �natural reservoirs�? The origin of the phrase came from the fact that you can find all the different subtypes (that we know of) in ducks. But the thing is that there was never major surveillance done on other birds, let alone mammals or other species. JKT told the analogy of a bank robber, after he was arrested, when he was asked why he robbed the bank, he said �cos that�s where the money is�. Similarly, they went and looked for flu viruses in ducks cos that’s where they found them. After the initial discovery, they went around some more and did lots of sampling from ducks, and found lots more, and concluded ducks were natural reservoirs. BUT they didn’t sample other birds or other species. Not enough, anyhow.

5. For example, we don�t even know what flu viruses normally do in chickens, cos no one has studied them, not sufficiently anyhow. How could we possibly understand the significance of the transformation from LP to HP in chickens if we do not know what LP looks like? It�s the same thing as studying one half of a equation and declaring it valid.

6. Let�s look at the issue of �evolutionary stasis�. The idea or hypothesis (which btw was never proven) came from the observation that avian flu virus sequences are often highly conserved, ie they don�t change a lot. But the thing is every in vitro and in vivo observation tells us it is in the nature of flu viruses to mutate constantly. The point is not that they don�t mutate, but that the changes tend to be deleterious or harmful to the virus, so that the mutated strain does not survive. That is, change is actively selected out.

7. This is discussed in the recent paper Avian Influenza Virus Exhibits Rapid Evolutionary Dynamics, Chen and Holmes, Aug 06 Abstract: Influenza A viruses from wild aquatic birds, their natural reservoir species, are thought to have reached a form of stasis, characterized by low rates of evolutionary change. We tested this hypothesis by estimating rates of nucleotide substitution in a diverse array of avian influenza viruses (AIV) and allowing for rate variation among lineages. The rates observed were extremely high, at >10–3 substitutions per site, per year, with little difference among wild and domestic host species or viral subtypes, and were similar to those seen in mammalian influenza A viruses. Influenza A virus therefore exhibits rapid evolutionary dynamics across its host range, consistent with a high background mutation rate and rapid replication. Using the same approach, we also estimated that the common ancestors of the hemagglutinin and neuraminidase sequences of AIV arose within the last 3000 years, with most intra-subtype diversity emerging within the last 100 years, and suggestive of a continual selective turnover.

8. I already wrote about the issue of pigs in an earlier post. Here I want to add the big picture question of whether pigs are mixing vessels where if an avian and a human strain infect the cells at the same time, reassortment can occur resulting in a pandemic virus. Again, much of this hypothesis is based on the discovery that pigs have both types of receptors. But like the duck sampling problem, just because something looks like it may be a mechanism or an answer to a question, it doesn�t necessarily mean that it is. The fact is that we have rather more frequent occurrences of human flu viruses infecting pigs than pig viruses infecting humans. The 1976 swine flu fiasco is just about the only instance where this was documented. JKT tells me that tracing back to historical records, there was no swine flu before 1918, but there were descriptions of �fowl plague� which was exactly the same as the present day HPAI. Before 1918, influenza was thought of as a purely human disease. After 1918, the main virus infecting pigs was H1N1 from humans, until the 70�s when an avian H1N1 got into swine in Europe.. It has been shown that experimentally it is possible to infect pigs with avian flu viruses, but natural infections were otherwise very rare. The emergence of novel swine influenza viruses in North America, Olsen

9. So JKT says �if we study one pandemic, we learn about one pandemic�. Meaning that we do not know enough about pretty much anything to be sure of what we are talking about in predicting what might happen in the next pandemic.

10. significance of receptor binding: In this paper that JKT co-authored Glycan Microarray Analysis of the Hemagglutinins from Modern and Pandemic Influenza Viruses Reveals Different Receptor Specificities, Stevens et al they measured the receptor binding affinity of 2 different strains of the 1918 virus, one from South Carolina (18SC) and one from New York (18NY). What they found was that 18NY had one mutation from 18SC. Whereas 18SC showed strong affinity to alpha2,6 (human) and no affinity for alpha2,3 (avian) receptors, 18NY showed significant reduction in binding to alpha2,6 and a gain in affinity to alpha2,3 receptors. And yet, there was no difference in clinical presentation, pathogenesis, mortality, transmissibility between the 2 strains. What does this mean? It could be that receptor binding is only important in an on/off fashion, and not as a matter of degree. That is, as long as there is some affinity, it is sufficient for the virus to do the rest of the job, and the degree of affinity does not affect the outcome at all.

I’m done for today!

Thank you. “JKT says �if we study one pandemic, we learn about one pandemic�.

Sort of like studying about one volcano’s event, eh?

Still on the topic of what we don’t know or whether what we know is valid, remember that all current human flu viruses are descendants of the 1918 virus H1N1. In 1957, it acquired a new HA, NA, and PB1, and became H2N2. In 1968, it acquired a new HA and PB1, and became H3N2. But the rest of the internal genes, are from one virus only. So when we say ‘flu viruses in human tend to do this that and the other’, we are only talking about H1N1 and its descendants, and the observations may not apply to other strains at all.

Put in another way, our understanding of seasonal and pandemic flu is based on the statistically (in)significant sample of 1.

If that doesn’t blow your minds out…..

:-)

anon_22 � at 19:20 … all current human flu viruses are descendants of the 1918 virus H1N1.

What became of the influenza viruses that caused the pandemics of 1510 and 1889 (H2N8?)?

What became of the influenza viruses that caused the pandemics of 1510 and 1889 (H2N8?)?

Do we know that it was H2N8?

Anyway, whatever was in circulation, got wiped out by the 1918 virus. JKT and his team are putting together fragments from autopsy samples from London pre-1918, and have found several that are clearly H3. I asked him whether there is any significance that we now have an H3 as circulating strain, and the answer, as expected, was that he doesn’t know.

:-)

And when you tackfully asked his opinion or his thoughts on the probability of a pandemic….

His answer was?

Same question as Florida Girl, and thank you for sharing all of the info.

I didn’t actually, not in so many words. Cos if you connect the dots of his thinking, we just don’t know.

But I will jump the gun and give you my answer in a different way. This came not from Taubenberger but from talking to one of the revers. He had written on Effect Measure about WHO chart H5N1 by onset date and country (first one from the link) and commented on how there are now no gaps between the bar charts. I asked him what are the chances etc, and he said that this is what new virus outbreaks look like.

The lesson for me is this, if we stop thinking of this as a flu virus, and just look at it as an emerging infection, then the smoldering over the past few years, the increasing clusters, the fact that it is now widespread in birds, etc, all these sign tell us that this is a virus that is ready to break out at any time. We just do not have the ability to know what the timeframe will be, that’s all.

I did ask him one useful question related to this though. I said if a pandemic was to break out say in the next 12 months, and we only have limited time for research, what is the one question that you want to find the answer to?

And he said it would be host gene response, or more specifically how exactly does the virus cross into a new host, what are the virus-host interactions necessary for that to happen.

anon_22: Reading your summary, I felt as if I might be reading Barry’s next book. Taubenberger does, as you noted earlier, sound a lot like Welch. What I find remarkable here is that we seem to be at a point similar to that which they found themselves at in 1918, from a macro point of view. Then, they had just begun to really understand the germ theory of disease and had only just begun to recognize the most basic facts about viruses, or understand that they indeed existed at all. Now, we have begun to understand genetics which helps us in broad terms. But we are just now at the point of beginning to ask the questions which will lead to the next level of understanding about how the virus goes about its day to day existance. We are really at a point very similar to where they were in 1918 - we are beginning to understand what we don’t know, and now the race is on.

anon_22 � at 19:36 Do we know that it was H2N8?

http://medicine.science-tips.org/health/diseases-and-conditions/bird-flu.html
“Known as the “Asiatic Flu”, the pandemic of 1889 was believed to have been caused by the H2N8 type of flu virus.”

http://www.nus.edu.sg/osh/bulletin/apr06/avian.htm
“First reported in May of 1889 in … Purported to be caused by the H2N8 flu virus.”

http://cmr.asm.org
“The 1889–1890 pandemic has been attributed to an H2N8 virus, and the 1900 pandemic has been attributed to an H3N8 virus (126, 132). The devastating pandemic of 1918 was almost certainly caused by a swinelike HlNl strain (40, 154).”

I’m not yet clear on why it is posited that “whatever was in cirulation got wiped out by the 1918 virus.” It is an interesting theory and I would like to understand it more clearly.

My own thoughts on the probability of a pandemic are now even more dire….

Despite the fact that on a big picture level, JKT also said that mother nature is the biggest laboratory. Flu viruses are mutating changing all the time. The fact is we’ve only had 3 pandemics in 100 years. That tells us that it actually may be quite hard for a novel flu virus to cross into humans and establish sufficient foothold for a pandemic to happen.

Jesus Anon_22,

He is definitely the scientist of the year. For a mind to think that deep and see the implications of the answer to that question…. I had to think for a minute.

I would have said something real simple… like… How can we affect viral replication.

:)

…”suppose one of these days we encounter one particularly unusual strain that actually had very different characteristics from the �normal� ones that we observe,

then we have no data on which we can base to build our assumptions.”…

Nor - our vaccines??…

 :-/

Dennis in Colorado � at 19:54

About the 1889 pandemic virus, here is a good review from Influenza A virus recycling revisited, Dowdle, WHO Bulletin, 1999

Abstract here

crfullmoon � at 20:22

then we have no data on which we can base to build our assumptions.�� Nor - our vaccines??�

Well, he’s not a vaccine guy. And vaccines are a different ballgame, cos it may be possible to make effective vaccines with limited understanding of the evolution of viruses. Just as we can use aspirin to treat a whole number of conditions without necessarily understanding exactly how it works.

Dennis, skipping back to your questions:

Most scientists would agree that the 1889 pandemic virus was an H3 and not an H2

As to how come old strains are wiped out, its the same as what happens every year with seasonal flu. Remember that viruses do not survive on their own, they have to keep infecting new hosts. When a new strain emerges, because of the large number of hosts with insufficient immunity, people will get infected by the new strain far more easily. Older strains cannot get a foothold because the patient’s immune system is strongly stimulated, but is more effective in killing the old than the new strains. That’s why each year, new seasonal vaccines have to be made, cos basically last year’s strains die out and disappear from circulation.

You can also get a better idea by reading this thread Influenza Genome Project and especially look at this chart. If you follow horizontally, what you are seeing is a change of the circulating human flu virus over time. You will notice that at certain times, eg at the beginning of the 2001–2 flu season there might be a mutation or sudden change in strain, and then after that subsequent samples show only the new strain and not the old one.

To anon_22 � at 20:27. Ok, but I’m still living in a nation/neighborhood that thinks they know all about volcanos, since they live on one, which hasn’t erupted in their lifetimes…

crfullmoon � at 20:42 To anon_22 � at 20:27. Ok, but I�m still living in a nation/neighborhood that thinks they know all about volcanos, since they live on one, which hasn�t erupted in their lifetimes�

I know, that’s why I get a bit disoriented sometimes putting on different hats to think when talking to different people. The difficulty is in trying to distill all this (which is pretty much about what we don’t know) and still make a convincing case.

anon_22 � at 20:41

Thanks.

anon_22 � at 20:50

I think your doing a great job dispensing the info.

‘dispensing’?

Oh dear…

:-)

Good job Anon_22.

Science is science. Observation is observation… and from what i have been observing, H5N1 is moving toward a pandemic position.

Did you get a sense from him about that? Is he nervous?

Anon_22-Great thread, most illuminating in weeks. A few weeks ago I read a study on how way back in evolutionary history humans incorporated part of a virus into the genome that was more efficient at preventing miscarriage in humans and so it replaced what was originally there. Could it be that much more of this previously-labeled “junk DNA” is viral debris. And that we are maybe “File 13″ for these “expired” influenzas?

And maybe being part of us that confers some kind of immunity?

Goju,

Did you get a sense from him about that? Is he nervous?

You are asking me to go inside the guy’s head to figure out what he is thinking. :-) No, he didn’t share with me whether he is nervous. I guess that’s private.

And his professional opinion would be that its possible, but hard to say.

Moving on a little, here’s one insight that looks minor but to me is not.

I asked him this question “you know the words virulence, pathogenicity, fitness, transmissibility, what do they mean? How are they different? What are we talking about when we use these terms?”

And the answer was “That’s a good question! (which he said pretty often) Cos we don’t really know. (which he also said pretty often). Its more like we are looking at different sides of a dice from slightly different angles, and we are not quite sure what the boundaries are between these terms.”

That is, they are all inter-related, you can’t really talk about one without some reference to the others. For the purpose of scientific exploration you do have to define them and try to measure them, sometimes separatelly, but conceptually there are many nuanced interconnections, so piecemeal science is not sufficient to answer our questions. We need the science, and we also need the thinking. (This paragraph is from me, btw.)

Let’s have a closer look at this one:

7. This is discussed in the recent paper Avian Influenza Virus Exhibits Rapid Evolutionary Dynamics, Chen and Holmes, Aug 06 Abstract: Influenza A viruses from wild aquatic birds, their natural reservoir species, are thought to have reached a form of stasis, characterized by low rates of evolutionary change. We tested this hypothesis by estimating rates of nucleotide substitution in a diverse array of avian influenza viruses (AIV) and allowing for rate variation among lineages. The rates observed were extremely high, at >10�3 substitutions per site, per year, with little difference among wild and domestic host species or viral subtypes, and were similar to those seen in mammalian influenza A viruses. Influenza A virus therefore exhibits rapid evolutionary dynamics across its host range, consistent with a high background mutation rate and rapid replication. Using the same approach, we also estimated that the common ancestors of the hemagglutinin and neuraminidase sequences of AIV arose within the last 3000 years, with most intra-subtype diversity emerging within the last 100 years, and suggestive of a continual selective turnover. ======================= This paper relies heavily on the idea of homogenous random mutation. It ignores issues such as recombination.

Now consider this, from Niman:

============== Originally Posted by niman The sequence of

http://www.ncbi.nlm.nih.gov/entrez/q…6&dopt=genbank DQ997110 A/chicken/Hubei/wi/1997 PB2 (1) 2341 1997 H5N1

has long streches of IDENTITY with

DQ073400 A/tree sparrow/Henan/2/2004 PB2 (1) 2280 2004 H5N1 DQ073401 A/tree sparrow/Henan/3/2004 PB2 (1) 2280 2004 H5N1

These wild bird sequences will look much like the Canadian swine

http://www.recombinomics.com/phylo/C…Swine_PB2.html

http://www.recombinomics.com/phylo/C…_Swine_PA.html

…

Between positions 685–2146 there are`only 3 differences between tree sparrow 2 and the 1997 isolate. Three differences over 7 years indicates seasonal variation is NOT due to random mutation. ==============================

The sequence data increasingly are at odds with the random mutation concept. The assumption of evolutionary stasis is obviously not based on any consideration of the sequence database, which would show that ‘stasis’ hardly describes the huge variety of variation in the sequences. And the variation is hardly random, either; many motifs recur in different strains and different species. If a motif moves from one strain to another, is that included in the so-called random mutation category? Or does the calculation of mutation rates rigorously exclude all the portions of the sequences that show considerable variablity via stable motifs? Three differences in 7 years over more than 1000 bases would yield quite a different age for the start of influenza.

More holes than a colander.

I’m re-posting this from yesterday in the old thread, cos I read over it just now, after writing up the above, and find that its a powerful reflection of the kind of thoughts that go on inside a great mind.

(from yesterday, before I wrote the above posts)

It has taken me a long time to start figuring out what to write about this, this �conversation� with Taubenberger. It�s a little weird, cos I had an almost 3 hour discussion with him. It was profoundly educational at the time, and now I�m left with the feeling that I know less than I thought I did.

Or to put it more precisely, it isn�t so much the content of what we talked about, but the way that he approaches problems that makes it all so profoundly powerful.

I was reading �The Great Influenza� tonight, and I encountered this description of one of the most important scientists of the time, William Henry Welch at Johns Hopkins. It struck me that what John Barry was saying that Welch was NOT, describes best (although still inadequately) what I experienced when talking to JKT. I am going to quote some excerpts:

“His failing was this: in science as in the rest of his life, he lived upon the surface and did not root. His attention never settled upon one important or profound question.

“The research he did was first-rate. But it was only first-rate � thorough, rounded, and even irrefutable, but not deep enough or provocative enough or profound enough to set himself or others down new paths, to show the world in a new way, to make sense out of great mysteries.

“The greatest challenge of science, its art, lies in asking an important question and framing it in a way that allows it to be broken into manageable pieces, into experiments that can be conducted that ultimately lead to answers. To do this requires a certain kind of genius, one that probes vertically and sees horizontally.

“Horizontal vision allows someone to assimilate and weave together seemingly unconnected bits of information. It allows an investigator to see what others do not see, and to make leaps of connectivity and creativity. Probing vertically, going deeper and deeper into something, creates new information. Sometimes what one finds will shine brilliantly enough to illuminate the whole world.

“To see questions in these ways requires a wonder, a deep wonder focused by discipline, like a lens focusing the sun�s rays on a spot of paper until it bursts into flame. It requires a kind of conjury.

“Welch had a vital and wide curiosity, but he did not have this deep wonder. The large aroused him. But he could not see the large in the small. No question ever aroused a great passion in him, no question ever became a compulsion, no question ever forced him to pursue it until it was either exhausted or led him to new questions. Instead he examined a question, then moved on.”

I will have to think some more to put together the best of what I learnt from talking to JKT.

disgruntled, these are very rare exceptions. It’s not normal. We can’t explain this.


It seems, that JKT is just not the right guy when you are looking for quick answers. Give him some more decades and he might come up with something interesting. But I don’t expect that he can help us very much with this possible H5N1 pandemic.

anonymous, then you’re not trying very hard. Hint: Lose the high rate of random mutation idea, and look into dual infections spreading polymorphisms around. Let recombination be a form of error correction. Bingo. Problem solved. And be more careful when you throw around the term ‘normal’, especially when you haven’t fairly evaluated all the alternatives. And note that taking and amplifying a single sample will naturally select against =detecting= dual infections.

From the sound of it, JKT likes to be an expert, and likes having supplicants beseech him for information, but he’s not above playing the fish on the line a bit, and making his part sound harder than it really is. And a lot of his answers sounded a lot like chaff to me, a lot of sparkly stuff but not much meat. If he is being paid with public money, then he owes the public an accounting of what he is finding out.

no Bingo yet. That generates a lot of other questions and can’t explain what we observe to satisfaction. E.g. why does that error correction happen in some rare cases but not normally ? “normal” means that the genbank database had been searched for such cases in H5N1,H1N1,

at least he owes the public a better description of his own H5N1-threat perception !

Sounds to me like JKT is a bench scientist and not a political hack. I’m astounded that so little data has been acquired on the personal lives of viruses. It’s almost like swine flu sent scientists into a freefall. It was not the PC field after that. He can’t predict a threat—he said as clear as sunlight the science is elementary! For the record he’s not like Welch. Welch functioned on cronyism, his forte was seeing the gifts others had and providing them with what they needed to do the job. JKT is a plodder with his eye attached to a microscope. It wasn’t easy to reverse engineer 1918. What I find interesting is how TomDVM through powers of observation in his field, came almost as close in his predictions of the viral pattern. Amazing.

Anon 22-thanks for sharing your information and deductions.

anon_22 � at 20:41 As to how come old strains are wiped out, its the same as what happens every year with seasonal flu.

Then why label 1918′s strain as the mother of all of today’s strains? Why not 1510, 1889, 1957, or 1968? If old strains are wiped out by the presence of the new dominant strain, why single out 1918?

Dennis in Colorado �C at 07:05

Then why label 1918��s strain as the mother of all of today��s strains? Why not 1510, 1889, 1957, or 1968? If old strains are wiped out by the presence of the new dominant strain, why single out 1918?

Because the 1957 and 68 viruses still had most of the genetic material from 1918, which was different from what happened in the 1918 pandemic. Read my summary on the Questions for Taubenberger thread, about the origins of the 1918 virus, and follow the logic on why it is thought it was not from something in circulation at the time. Which was what made the mystery of 1918 so fascinating.

anonymous � at 01:59 at least he owes the public a better description of his own H5N1-threat perception !

a) He doesn’t owe anybody anything. He already makes great contributions to science, and he was doing FluWiki a favor by helping me understand virology better.

b) He already freely gives his H5N1-threat perception and that is it’s hard to say. He says that in open seminars, its no big secret, and its consistent with all the other things that he talks about either in seminar or in conversation.

anon_22 � at 09:20 “anonymous � at 01:59 at least he owes the public a better description of his own H5N1-threat perception !

a) He doesn�t owe anybody anything. He already makes great contributions to science, and he was doing FluWiki a favor by helping me understand virology better.”

Bravo. You took the words right out of my mouth. You are correct. He does not owe anybody anything.

Leo7 at 3:06-Yes, Tom shows us that there is “more than one way to skin a cat”. : )

To my way of mind, experience in the field, subconscious synthesizing, and intuitive leaps are a hell of a lot more fun.

AND, more often than not, guys like Tom beat “the plodders” in the lab. Not to say that there are not innovative and genius-level plodders, I am just saying there is another way. You “zig” instead of zag.

disgruntled � at 01:06 From the sound of it, JKT likes to be an expert, and likes having supplicants beseech him for information, but he�s not above playing the fish on the line a bit, and making his part sound harder than it really is. And a lot of his answers sounded a lot like chaff to me, a lot of sparkly stuff but not much meat. If he is being paid with public money, then he owes the public an accounting of what he is finding out.

Hey, Disgruntled, You have a lot of firsthand experience reconstructing 100-year-old pandemic virii? When you do, then maybe you can cast stones on leading world scientists who take time from their extraordinarily jammed schedules to help people like we here on the Wiki.

anonymous � at 01:59 at least he owes the public a better description of his own H5N1-threat perception !

No, he doesn’t owe us a thing.

Edna, Thanks for your insight. I have a healthy skepticism of Experts, mainly because I play one in Real Life. If you want to accept everything from experts uncritically, then you have my blessing.

If tptb and jkt do not owe us a thing then why is it little ole me feels like I owe it to others to spread the word regarding panflu.Its kind of a contridiction there dont ya think Edna.One that makes me very sick to my tummy.

Each of us - whether working for the powers that be, a scientist trying to work out the hows whats and why’s in thier area of speciality so that we can outwit or outsmart the natural course of events, someone following our conscience or just an individual who wants to look after thier nearest and dearest - does what they can in whatever way they can. We each contribute something different to a common goal, and just because we dont have the answers to everything does not reduce our overall contribution. Some will be greater in their contributions than others.

Therefore thanks to all who put their bit in, however they do it. And please remember that no-one can do everyting.

Each of us - whether working for the powers that be, a scientist trying to work out the hows whats and why’s in thier area of speciality so that we can outwit or outsmart the natural course of events, someone following our conscience or just an individual who wants to look after thier nearest and dearest - does what they can in whatever way they can. We each contribute something different to a common goal, and just because we dont have the answers to everything does not reduce our overall contribution. Some will be greater in their contributions than others.

Therefore thanks to all who put their bit in, however they do it. And please remember that no-one can do everything.

I think it is a very valid position for Taubenberger to take that he has more questions than answers. It is also a valid answer to say “I don’t know” when asked about his own insights as to when a pandemic will happen. I think that we dismiss him much too lightly when we don’t give his statement weight. That Taubenberger doesn’t know says volumes. (And, he most definitely did not say he knows but doesn’t want to tell, which is entirely another thing and might be how some are taking his answer).

Leavitt says he doesn’t know when a pandemic will happen, and that the government will not be able to help us much. Taubenberger says he doesn’t know when a pandemic will happen, and I am going to infer from the fact that he has more questions than answers that science may also not be able to help us much, particularly if our timeframe is short. We might not want to hear those answers, but that seems to be what they are saying and we’d be wise to listen.

disgruntled

It’s good to have a healthy skepticism of experts, and no one is asking anyone else to accept anything uncritically. In fact, I would have thought the whole theme of this thread revolves around how we should not accept uncritically the ‘conventional wisdom’ about influenza. It doesn’t mean that JKT is necessarily right, but just that its good practice to challenge our thinking from time to time, and find where the holes might be. I started out wanting to ask him very specific questions about H5N1 or 1918, but found that the lessons in how to approach problems far more important to post here than specifics. Nobody needs to agree with what I wrote, I’m just responding to requests to write about this.

anon_22 � at 09:17 Read my summary on the Questions for Taubenberger thread, about the origins of the 1918 virus, and follow the logic on why it is thought it was not from something in circulation at the time,

I did read that, but had concerns at the time about the size of the sample used to reach such a conclusion. In the overall scheme of things, though, it is not an important issue (i.e., it does not affect the manner of or the extent to which I will prepare). Thanks.

disgruntled � at 01:06

If he is being paid with public money, then he owes the public an accounting of what he is finding out.

Erh…He works for the NIH, and I trust they will get their money’s worth out of him. It will be up to the NIH to decide what to share with us lowly mortals.

Dennis in Colorado � at 14:17

I did read that, but had concerns at the time about the size of the sample used to reach such a conclusion. In the overall scheme of things, though, it is not an important issue (i.e., it does not affect the manner of or the extent to which I will prepare). Thanks.

Oh but it is an important question, even if it does not affect your preps. :-) If you want to ask me more specifically, I’ll have a go at answering your questions about 1918.

disgruntled � at 13:06 Edna, Thanks for your insight. I have a healthy skepticism of Experts, mainly because I play one in Real Life. If you want to accept everything from experts uncritically…

I’m the consummate skeptic, and I take very little at face value. I just think a little grace is called for. And if you play an “expert” in real life and have something meaningful to contribute other than ridiculing a colleague, by all means, do tell. You have an eager audience. :)

Edna, Thanks again for your helpful advice. It grieves me that you have found nothing of value in any of my contributions, and for that I am sorry for taking up your valuable time. But your feedback is useful, and I will be sure to give your advice the consideration it deserves.

Disgruntled @ 14:34 You could start by raining in your superior attitude and sarcasm. It is not constructive. You can take exception without being vindictive, illuminate without being disparaging and treat everyone with respect without lessening your opinion of yourself or the merit of your points. Grin. If you were my child and you made comments like those above to adult guests at my house, I would have sent you to your room.

Dude, Just a clarification: Does what you just said apply to Edna, or not?

Hey can we get off being personal please? Everyone? thanks! :-)

Disgruntled:

I’ve read your posts with fascination because clearly you’re in the know more than the (average) rest of us. Are you one of the disgruntled who left the CDC recently? Your comments about the sequences was excellent, so don’t run off. So what do you know and when did you learn it? And no sparkly chaff interspersed to cloud the facts.

It’s Niman

LOL

Not niman.

NS1:

How do you know?

“I have said my piece and counted to ten.” No further comments. Grin.

Language pattern. 95%.

Pixie thinks the “we don’t know”-statements deserve more weight. ;-) Taubenberger doesn’t nkow, what apparantly Osterholm,Webster,Standard & Poor’s etc. do know. Although those seem to contradict some of their each others.

But shouldn’t we better ignore those people who claim that they don’t know and concentrate on those who claim that they do know and evaluate the arguments of the latter group ? I mean, you could philosopjize on the silence, but that leads to nothing when we are facing catastrophe. So, anon_22 can’t you switch to another expert instead ?

be up to the NIH to decide what to share with us lowly mortals.
yeah and it’s up to us to decide whether we accept such a behaviour or elect another government or start a revolution. They are saying: “give us your taxes, but we won’t tell you what we are doing with the money.”

Not that I think, Taubenberger’s research is useless. Just that we should better keep looking for others to help us estimating the threats from these H5N1-pandemics.

100% not Niman, by spelling alone.

disgrantled at 01:06,

I’ve been tracking this very concept for many months . . . promiscuous gene pool with a set of rules or potentially a physical / chemical framework on which polymorphisms may appear.

Please contact me using my profile.

I could figure out who disgruntled is but am not going to…

…disgruntled…you just keep being disgruntled…

…and please teach us, in plain language that everyone including me can understand, everything you know about H5N1.

Thanks to you and the rest of the musketeers. /:0)

anonymous � at 20:10

So, anon_22 can�t you switch to another expert instead ?

I’m happy to talk to whoever is willing to talk to me. :-) Not every scientist is. Some I don’t have access to, some might not want to talk to me, some talk but only briefly, some don’t want their name to appear on anything, etc etc/.

Just doing my best. And there is only 24 hours a day and one of me.

But this is a free world and an open forum, so we are happy to read posts from anyone who has access to experts! So go out and make those contacts, you guys. :-)

All,

JKT most certainly weighed the risk of our past and current bad behaviour when he graciously agreed to be interviewed by A22.

Whether we enjoyed our colleague’s hard-thought interpretation of JKT’s answers is not really all that important, is it? If we learned even one piece of information or countered even a single argued point, then we sit before our research richer today.

Am I happy that we don’t know . . . be serious.

Am I exultant that Jeffrey displays the courage to say, “We don’t know.” Absolutely. In fact, I’m honored to follow his work even more today than yesterday.

Good work, A22, and great courage, JKT!

maybe they only don’t know, because each one is working in a well defined special area, but when they would communicate more and put their knowledge together, then they would know ? When Taubenberger says, “we don’t know”, then that doesn’t probably mean, that they know nothing. Just not enough that he dares to make a statement. But even those small pieces of knowledge which fall below the threshold of “we don’t know” could be useful for us or for other experts working in other areas…

anonymous � at 20:59

But even those small pieces of knowledge which fall below the threshold of �we don�t know� could be useful for us or for other experts working in other areas�

That is a very valid observation. I think for those of us who do not have confidential access to such information, the only way to get that kind of understanding is to listen for the kinds of questions that they ask, the things they wonder about.

Disgranulation,

Sharpie landing zones and shoelace strands?

NS1 � at 20:42

Exactly.

but you have to wonder why this is being kept “confidential”. The result is, that the less confidential non-experts are getting louder and that finally the politicians and people base their opinion how much to prep an those louder non-experts. Now we already have the Osterholms and Gojus on one side and the actuaries on the other. Sure, they are also experts in their areas, but not the sort of experts which I would like to decide this issue.

Edna,

What do you think of disgruntled’s post at 1:06 regarding rate of polymorphic activity and pattern suggestions of polymorphic activity?

Are you US-based?

NS1, This is not an area that I have been following closely, and since I definitely don’t play an expert/scientist in real life, I’m not even going to take a stab. Sorry for the disappointing, albeit honest, answer. In general, from my lay person’s understanding, I think that there is so much we do not know in influenza research that to come down definitively on one side or the other is probably not possible at this time.

For me, the point of what JKT was saying to anon_22 is that there is so much we don’t know that we don’t even know what we *can* say definitively about H5N1 or flu in general.

It reminded me of a reaction I had yesterday upon hearing an NPR story about two scientists who were awarded Nobel prizes. The story focused on the fact that the data these men recorded essentially confirmed the big bang theory. The story had a quote in it to the effect that the research was so brilliant because the big bang theory was “the only one” that could support the data.

My immediate reaction was, “Yeah. The only one you’ve thought of so far.”

(To say nothing of the fact that I thought the data were supposed to support the theory, but that’s another discussion.)

I think it is grandiose for scientists—even the greatest of them—to assume that they understand anything 100%. Every day we learn much new information about all manner of things, things we couldn’t even conceive of just a few years ago.

I respect Taubenberger for having the confidence, humility, and self awareness to say, “We don’t know.”

All things are not known. Some things will never be knowable. For Taubenberger to say, “We don’t know,” is, IMO, a perfectly valid—albeit not particularly satiating—statement.

Edna,

So often we craft our data to fit the hypothesis instead of discarding the disproven hypothesis.

I guess we get very attached to the works of our own hands, don’t we?

I am grouped in the same sentence as Osterholm? Oh my!

can someone help me here on a couple points?

when many of you talk about recombination in context of “dual infections spreading polymorphisms around” is this the Eddie Holmes etal story your talking about [Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol. 2005 Sep;3(9):e300. Epub 2005 Jul 26. ]?

And then, in the contxt of the as-yet-to-be-published JKT NIH pre-1918 sequence data: has he said how totaly novel these pre-1918 virus seq really are supposed to be? So maybe it’s an H3 unlike current human H3. But the rest of the virus? Any news on this? And these are just a few viruses he’s extrapolating out to some big assumptions on. (JKT is a human being, a wonderful, brilliant human being who oughta be invited into the NAS already, but he is human and can be wrong.)

And does anyone remember the MJ Gibbs etal paper “Recombination in the hemagglutinin gene of the 1918 “Spanish flu”. Science. 2001 Sep 7;293(5536):1842–5. What was the problem with it (please describe in terms suitable for a non-evolutionary virologist).

thanks

Anon_nyc,

Please have a look at Monotreme’s exploration on your topic beginning with Random Mutation, Reassortment and Recombination.

8 threads that are long are deep on the general topic.

instead of saying : “we don’t know” he could also say something like: this is controverse, undecided but I personally speculate by giving it a -say- 60% probability. I guess, it’s his involvement with the military that he’s beeing so secretive.

for the Gibbs-paper, see this discussion.

anon_nyc � at 22:58

when many of you talk about recombination in context of �dual infections spreading polymorphisms around� is this the Eddie Holmes etal story your talking about [Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol. 2005 Sep;3(9):e300. Epub 2005 Jul 26. ]? ===================== No. And Yes. There’s a difference between reassortment and recombination, mainly in the mechanism and the size of the swapped sequence. The mechanisms of the two are probably different, but they both result from dual infections, so in that way they are similar. The conclusions, however, are similar to the conclusions reached by analysis of the polymorphism substitutions among different samples: that there are persistent smaller motifs that can be traced from continent to continent going back in time, and these are not new mutations, but old motifs that are swapped around. There are also long segments of identity that persist for many years, a sort of ‘negative motif’ if you will. It’s hard to reconcile these to the idea that all changes in the genome between two samples are the result of rapid random mutation.

It will be interesting to see the results of sequencing the older H3 material. If most of the variation is driven by random mutation, then what we will see is a sequence with little in common with modern H3. If most of the variation is driven by recombination or reassortment, then we will see a lot of familiar motifs within the sequence. The rapidly growing collection of sequences in the public database provide a lot of material to compare it to, unlike the situation even a few years ago. The presence of the same mammalian polymorphisms across many species and many types of influenza A strongly suggests that looking at the pre-1918 H3 we will see a lot of very familiar sequences.

disgruntled et al. I haven’t followed this thread cause it makes my head hurt and it takes a lot of concentration I don’t have tonight…

…but I would make one comment about your post above.

Three of the last six…or three of the last seven pandemics which occurred in the 1800′s and 1900′s were approx. comparable to 1918 H1N1).

I believe that these high CFR pandemics have one thing in common…a direct hop from birds to humans…no reassortment…

…the milder pandemics including 1957 are as a result of recombinations and reassortments…

…the 1968 pandemic is the only true outlier in the group.

Disgruntled,

Monotreme sees conserved motifs as rare, as does GS. I expect to see a pattern emerge with more data of highly conserved and highly volatile areas, allowing for ORFs, shifts and such.

What is your expectation?

TomDVM, Three of the last six�cor three of the last seven pandemics which occurred in the 1800��s and 1900��s were approx. comparable to 1918 H1N1)[in CFR]

you should mention, that it’s only you who sees it this way and strangely insists. See the post of Marble in the other thread.

disgruntled, you needn’t go back to 1900. Just compare the 1968 H3N2 with today’s H3N2. Pretty random i.e. at the 3rd bases. Or look at the genes other than HA,NA,PB1, which are still the same as 1918.

Tom DVM � at 00:20 … Three of the last six�or three of the last seven pandemics which occurred in the 1800′s and 1900′s were approx. comparable to 1918 H1N1).

I believe that these high CFR pandemics have one thing in common�a direct hop from birds to humans�no reassortment�

The accumulating sequence data show that there isn’t any such thing as a pure avian form of AI. AI sequences have motifs that are shared across species, including mammals, and across different H and N subtypes. One striking polymorphism, the invariant region in H1N1, tends to hang out in swine. It’s odd, then, that the swine sequence showed up in the so-called pure avian 1918 H5N1.

And the sequence data also show that the difference between hip-path and low-path lies in the polybasic cleavage site. Low-path is 3 bits long, and hi-path is over 5 bits long. High to low transitions are likely recombinants.

The release of many new sequences is helping sort all this stuff out.

NS1 � at 00:21

Disgruntled,

Monotreme sees conserved motifs as rare, as does GS. I expect to see a pattern emerge with more data of highly conserved and highly volatile areas, allowing for ORFs, shifts and such.

What is your expectation?

  I think there is a lot of sampling bias that undercounts dual infections, and makes them look rare when they aren’t.  The growing pile of sequence data is starting to show that specific polymorphisms are conserved and abundant, and can’t be explained by repeated random mutations.  Mapping polymorphisms onto the 3-D folding structures ought to be very interesting, and might give a lot of insight into why some regions vary and some are conserved.  

Well, we certainly have lots of opinions here, almost none of which bear any relationship to what I was trying to report about my conversation with JKT. Makes me wonder whether there is any point in writing up the rest of it….

Just saying….

Can those of you who want to comment on recombinations start a recombinations thread, so as not to confuse others, including myself who have no intention of going down that quagmire again, since I have written extensively on it previously and have found no reason to change my views since then.

anon_nyc � at 22:58 can someone help me here on a couple points?

when many of you talk about recombination in context of �dual infections spreading polymorphisms around� is this the Eddie Holmes etal story your talking about [Whole-genome analysis of human influenza A virus reveals multiple persistent lineages and reassortment among recent H3N2 viruses. PLoS Biol. 2005 Sep;3(9):e300. Epub 2005 Jul 26. ]?

No.

And then, in the contxt of the as-yet-to-be-published JKT NIH pre-1918 sequence data: has he said how totaly novel these pre-1918 virus seq really are supposed to be?

No

So maybe it�s an H3 unlike current human H3.

I didn’t hear anything like that.

But the rest of the virus? Any news on this?

Nothing.

And these are just a few viruses he�s extrapolating out to some big assumptions on.

I haven’t heard him extrapolate this to any big assumptions. All he’s mentioned to me is that they have identified them as H3′s

(JKT is a human being, a wonderful, brilliant human being who oughta be invited into the NAS already, but he is human and can be wrong.)

Agree

And does anyone remember the MJ Gibbs etal paper �Recombination in the hemagglutinin gene of the 1918 �Spanish flu�. Science. 2001 Sep 7;293(5536):1842�5. What was the problem with it (please describe in terms suitable for a non-evolutionary virologist).

Go here for brief comments I made at 12:25 and here, last post

thanks

You’re welcome.

re-posting for visibility

Can those of you who want to comment on recombinations start a recombinations thread, so as not to confuse others, including myself who have no intention of going down that quagmire again, since I have written extensively on it previously and have found no reason to change my views since then.

22, just ignore them, you needn’t comment. Continue with your stuff.

Edna Mode � at 22:29

In general, from my lay person�s understanding, I think that there is so much we do not know in influenza research that to come down definitively on one side or the other is probably not possible at this time.

For me, the point of what JKT was saying to anon_22 is that there is so much we don�t know that we don�t even know what we *can* say definitively about H5N1 or flu in general.

So true.

I’m working on that last one. :-)

anonymous � at 01:47 22, just ignore them, you needn�t comment. Continue with your stuff.

I will, tomorrow, but they still need to take it somewhere else, otherwise people can’t find what they want to find, and I’m frustrated in wasting my time writing stuff that people can’t find, it you know what I mean.

Sorry, anon_22, your’re right, the thread has drifted too far. Recombination seems to be a bit of a touchy subject. Perhaps you could continue with a new page. But it’s interesting that the thread started to drift when people realized that instead of getting some answers, they found out that the questions just keep expanding. There seems to be a great thirst for hard information instead of opinions.

the questions just keep expanding

That was one reason I got into a state of semi-disorientation for a few days before I could start writing about it.

There seems to be a great thirst for hard information instead of opinions.

We need information, opinions, hypothesis, theories, critiques, methodology, approaches,…everything.

Concepts… almost left out this important one.

we can also easily make another thread later or even a wiki-page with only the direct reports about JKT without discussion. And then link to this thread for those who want more discussion. I mean, once it’s there - reorganizing is not so difficult. We’ll find a volunteer…

google “recombination site:fluwikie2.com” brings up

• Forum.RandomMutationReassortmentAndRecombination8 which is still open
• Forum.RESRRKKR not sure if related
• Forum.LPH5RecombinesWithItsOwnNPToBecomeHPH5?
• Forum.AssumingRecombinationOccursFrequently?

looking at Forum Topics there’s this:

• http://www.fluwikie.com/pmwiki.php?n=Opinion.ForumTopics#Science

This should be enough, no? Thanks, all! I hope this helps …

Back to JKT, then?

A22,

Just chasing part of the drift and a wonderful idea came into focus in describing the observational science . . . recombination.

An old friend for some and an arch-nemesis for others . . . this space intentionally left blank.

Please continue with your impressions of the interview and studies. We appreciate your hard work.

Sorry Anon_22 if you’ve answered this, (I lost the thread somewhere down this post because it got so complicated) but am I right in thinking that if much of what is known about flu viruses is based on grandkiddies of the 1918 virus then assumptions about fatality rate and infection rates of a possible H5N1 pandemic might be completely wrong?

Great work you’re doing by the way.

Thanks for your time and effort, anon_22. Get set with a wiki page, and please give some more of your Taubenberger interview, as you’re ready.

Anon_22,

Noting your comments above about his thoughts on the chickens, ducks, pigs and the testing of same….. Noting the lack of testing in other species….

Did he mention anything about the spread of this virus in relation to what he has found with the 1918 virus?

Did he not also look in (stuffed) birds for the 1918 virus to find simularities?

And did he talk about his findings about the virulence in the 1918 virus and the current H5N1 virus? Why are they so different from regular viruses?

I don’t have time to write about this until I finish sending out PFAW UK press releases.

Those of you who have found my contribution helpful please pull your weight by helping me get that done ASAP!

I’m not above bartering for services. It’s a skill that we will all need. :-)

Will work for Mastiff feed.

you can also help in my statins efforts. Latest update here

uk bird � at 05:47 Sorry Anon_22 if you�ve answered this, (I lost the thread somewhere down this post because it got so complicated) but am I right in thinking that if much of what is known about flu viruses is based on grandkiddies of the 1918 virus then assumptions about fatality rate and infection rates of a possible H5N1 pandemic might be completely wrong?

Yes

FloridaGirl � at 08:18 Anon_22,

Noting your comments above about his thoughts on the chickens, ducks, pigs and the testing of same�.. Noting the lack of testing in other species�. Did he mention anything about the spread of this virus in relation to what he has found with the 1918 virus?

No

Did he not also look in (stuffed) birds for the 1918 virus to find simularities?

Yes, I wrote about it here

And did he talk about his findings about the virulence in the 1918 virus and the current H5N1 virus? Why are they so different from regular viruses?

Oh that IS the big question, isn’t it? The most recent paper in Nature which he co-authored Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus, Kash, et al has been elegantly written up by revere at Effect Measure. Well, I will blog his blog and quote this one sentence

“Moreover the pathology of the lung lesions looked distinctly different with r1918 compared to the other viruses, suggesting that the pathology and virulence of the virus is not due to specific genes but rather the cooperation or combinations of proteins from genes on different segments.” which I think is the most important thing to remember at our level of discussion.

I don’t know the answer to your questions (now she’s saying!) but I think the host genetic response to a particular type of polymerase complex may be the key. That is, there may be specific genetic requirements both within the virus genome and possibly the host’s genetic susceptibility, which we know nothing about. But which we can hypothesize might be the place to look for answers. (also see 19:50 post, most important question for research)

So purely from genetic point of view, it may not be easy to produce a pandemic virus as lethal as H5N1 or 1918 (see 19:54 post) , but from the epidemiological point of view (see 19:48 post), the situation looks very scary.

More irritating because the H5N1 appears to be changing in a completely different way toward pandemic PF51.

Perhaps many roads lead to Rome (pandemic)?

 Perhaps many roads lead to Rome (pandemic)?

 could be.

Thread closed for length.

Continued and renamed Conversations With A Virologist to reflect a continuous learning process rather than specific events or comments.