From Flu Wiki 2

Forum: Random Mutation Reassortment and Recombination Part 3

07 July 2006

Bronco Bill – at 16:28

Continued from Part 2.

Original thread is found here.

Racter – at 19:05

TomDVM:

If we agree that sometimes things happen randomly in nature than by definition there cant be rules?

No, no, not at all.

The second law of thermodynamics is a good example. It doesn’t say that heat can never be transferred from a cold object to a warmer one, but that in a system where heat is being distributed between objects (particles) it is more likely to move from warmer ones to colder ones. Individual instances of heat transfer can break the rules, but taken as a whole, the system can’t.

The race goes not to the swift, nor the battle to the strong, nor yet wisdom to men of understanding, etc. Biological organisms are systems (systems within systems), and are based on rules. Like any other system based on rules, some of these may be bent; others may be broken. But they’re still rules.

FloridaGirlat 19:23

Monotreme at 21:18 (last night)

The problem is: what is the selective pressure that is driving this? In my original tutorial, I should have distinguished between mutation rate and evolution rate - they arent the same. A gene may mutate at a high rate, but the protein it gives rise to may evolve at a slow rate.
. . .

The below are studies (& online textbook) that talk about selective pressure and evolution. There are accepted theories in these that can be applied to viruses. Sometimes you have to reach a little to apply it to viruses.. But, This is an area where we are just starting to learn, so there is lots of room to think out of the box.

My thoughts are. Viruses respond to their environment; they either adapt or die. The environment within the human cell is essentially human; with human enzymes, human proteins, and other human chemicals. Therefore, the virus has to adapt to survive. One of these links talks about why mutations happen faster at first and then slow as they become stable.\\
Read and use your imagination. . .

Biochemical Evolution

http://tinyurl.com/fga79


Some variant offspring may, by chance, be better suited for survival and replication under the prevailing conditions than are their parent molecules. The prevailing conditions exert a selective pressure that gives an advantage to one of the variants. Those molecules that are best able to survive and to replicate themselves will increase in relative concentration. Thus, new molecules arise that are better able to replicate under the conditions of their environment. The same principles hold true for modern organisms.

STRUCTURES, PHYLOGENIES, AND GENOMES: THE INTEGRATED STUDY OF PROTEIN EVOLUTION R.A. GOLDSTEIN D.D. POLLOCK J.L. THORNE
http://tinyurl.com/z6mya
(Change DNA to RNA and you have a concept)

In general, purifying selection will inhibit changes at the amino acid level, but will have a much reduced effect on mutations of the DNA that do not cause changes in the protein sequence, so-called “synonymous” or “silent” mutations. Conversely, positive adaptation may result in DNA mutations resulting in changes at the amino acid being accepted at a faster rate than silent mutations. The ratio of non-synonymous to synonymous substitutions provides a measure of whether the changes are made under purifying or adaptive pressure.\\
http://tinyurl.com/gf7c7
‘“Identification of physicochemical selective pressure on protein encoding nucleotide sequences’”
Wendy SW Wong Raazesh Sainudiin and Rasmus Nielsen
Site-specific information regarding the physicochemical properties that have been subject to positive selection is of great interest in many systems. For example, in viral genes, site-specific information regarding physicochemical properties targeted by selection may shed evolutionary light on the biochemistry underlying mutational evasion of an immune response (e.g. [10]). Therefore, it would be very helpful to have statistical methods that can determine the physicochemical properties subject to selection at specific sites.

‘“Mobile DNA: Genomic Studies Illuminate Antibiotic Resistance’”
http://tinyurl.com/jgsz8

\\ Bacteriodes, enterococcus and staph are just a few examples of bugs that are becoming increasingly difficult to treat. The widespread use of antibiotics puts selective pressure on only the hardiest bacteria to survivewhich often carry virulence or drug resistance genes.

Just a thought on why H5N1 behaves outside of known scientific knowledge

The following addresses the virulence of H5N1. Some of these studies have been posted before. I am including them for ease of use.

http://tinyurl.com/kgmq5

J Exp Med. 2006 Mar 20;203(3)
689–97. Epub 2006 Mar

\\”’The polymerase complex genes contribute to the high virulence of the human H5N1 influenza virus isolate A/Vietnam/1203/04.”’ Salomon et al.

http://jvi.asm.org/cgi/reprint/79/23/14933

JOURNAL OF VIROLOGY, Sept. 2005, p. 1178811800 Vol. 79, No. 18
Avian Influenza (H5N1) Viruses Isolated from Humans in Asia in 2004 Exhibit Increased Virulence in Mammals Taronna R. Maines,1 Xui Hua Lu,1 Steven M. Erb,1 Lindsay Edwards,1 Jeannette Guarner,2 Patricia W. Greer,2 Doan C. Nguyen,1 Kristy J. Szretter,1 Li-Mei Chen,1 Pranee Thawatsupha,

http://tinyurl.com/f9bpt

 
JOURNAL OF VIROLOGY, Sept. 2004, p. 94999511 Vol. 78, No. 17


‘“Global Host Immune Response: Pathogenesis and Transcriptional Profiling of Type A Influenza Viruses Expressing the Hemagglutinin and Neuraminidase Genes from the 1918 Pandemic Virus’” John C. Kash et al

This is consistent with the hypothesis that the HA and NA proteins contributed to the virulence and unusual pathology of the 1918 influenza virus by facilitating viral replication, broadening cellular tropism, and/or triggering a more severe and sustained inflammatory response.

Taking these studies into consideration, learning about how selective pressure is determined could go a long way toward watching the next pandemic evolve. It might even offer up a way to stop a pandemic.

Leo7 – at 22:03

Monotreme:

The last time you looked at sequences you saw what others missed. Some people are better than others at finding unusual patterns or occurences. It really gripped me Niman wouldn’t concede that you found something unusual when clearly you did. I think it might be one of the bright spots Tom DVM is looking for when you said you’re going to arrange them and examine them. If the sequences could be examined by date then the process might offer up a “Greek key.” Holding them in desks or just not submitting them is as stupid as not taking samples from mamimals to prove or disprove theories. Good Luck!

Monotreme – at 22:19

Leo7 at 22:03

Thanks. I plan to get started this weekend. Lot’s of new sequences to look at.

Tom DVM – at 22:34

Leo7. Some people seem to think this lull is a good indicator but my experience tells me this is exactly what should be expected.

Honestly, I haven’t seen a shred of any evidence of a bright spot. It seems to me that if I was writing a story following the growing threat of a common pathogen that gained ‘freakish’ tendencies…I think it would follow pretty much exactly the progression taken over the last nine years by H5N1.

The worst thing is that among all the variables pushing the adaption and/or evolution of this virus is China…who seems to taking every possible action to help virus development rather than eradicating it.

I am not a great geographer but if you look at a map there is one constant affecting everything. China sits in the middle, countries on it’s border eradicate the disease for a few months and then it is re-introduced from China and away they go again.

If a virus is going away it should not easily re-infect areas previously the victim of outbreaks. Look at Quingyi Lake. Outbreak last summer…outbreak this summer. If you are looking at the overall picture, this is a very very bad tendency and development.

We go around this racetrack enough times and we will be in for it…but I think most regulatory authorities have come to this conclusion already. They are just not speaking about it publically.

From my point of view, H5N1 is doing everything right, we are basically doing everything wrong… and I don’t think there is much of a possibilty to stop it other than hope Dr. Butcher is right and there is some barrier preventing it from jumping to a pandemic…it will have to be one miraculous barrier with the continuing evolutionary pressure of H5N1!!

Monotreme – at 22:43

Racter at 11:19

The importance of chance in evolution can never be dismissed. Life is a casino.

Sorry, but I don’t think chance has much to do with evolution. It has lots to do with mutations. And at an individual level, chance plays a big role, but in a general sense, I think evolution is pretty predictable. For example, if all winged animals were destroyed tomorrow, I can predict with 100% certainty that new winged animals would evolve. I could not predict which particular species would evolve wings or how long it would take, but the open niche would be filled. If you are fixated on individuals or particular species, much of evolution looks random. However, if you look at ecological niches, you notice that they get filled. Look at Australia and the marsupials. Convergent evolution rules. It is predictable.

Survival of the fittest is a 19th-century concept which remains well entrenched in common folklore despite having been long abandoned by modern theorists.

I disagree. First, the 19th-century is one of my favorites. No PC or post-modern nonsense to wade through. Scientists explained things clearly and did not hide behind jargon. Second, the Neutralist viewpoint is under attack on a number of fronts. As you may guess, I’m a strong Selectionist. And the data is supporting the importance of selection in evolution, even in humans. This debate is beyond the scope of this board, but I can provide references, if needed. Expect an avalanche of surprisingly strong selectionist papers to come out in the next few years, in humans. This is not to say that there is no such thing as neutral evolution, there clearly is at the genome level. But all the action is in selection. Everyone is hoping their favorite gene shows signs of selection, if not, people conclude it isn’t important.

Your example of island colonisation is surprising, given it was precisely the obvious effects of selection on finches descended from a common ancestor that gave Darwin the idea of Natural Selection.

Its the luck of the draw as much as anything, and sometimes more than anything.

At an individual level yes. Even at a species level. After all, all individuals die. All species too. But the selective powers of specific environments act on whatever biological creature lives there.

And this then is the issue for H5N1. By looking at it’s behaviour one must conclude that it is under some sort of selective pressure to adapt to mammals. [virluence and transmissibility are not the same thing, but one can facilitate the other]. I have a hunch I’m not alone in trying to figure out the source of the selective pressure.

Tom DVM – at 23:07

Monotreme If H1N1 (1918) was a pure avian virus that did not interact or reassort with other influenza’s…then would we expect that no intermediary mammal was involved in its eventual pandemic status?

Did the pandemic strain occur as a result of genetic drift…mutation alone.

Monotreme – at 23:12

Tom, we don’t know whether there was an intermediate mammal in 1918. It does not appear to have reassorted, so yes it appears to have been mutation alone. But how the virus changed - mutation, reassortment or recombination - is a separate issue from selective pressure. So, the virus could have changed solely by mutation and been under selective pressure in a mammal. That could have been the case in 1918, it could be the case now.

Tom DVM – at 23:18

Monotreme. Thanks. Could it have done it without the assistance of selective pressure in a mammal?

Hurricane Alley RN – at 23:21

It seems to me this virus is just trying to find the best way to survive or it is getting help. China is becomming more secretive. Could the situation with North Korea just be a cover story to try to divert attention away from China? Two poor communist countries working together. This is truely not that unrealistic. gina

Perplexity – at 23:54

Hello there : I am new here….I have a question for Monotreme and Tom DMV : According to the records, H1N1 of 1918 started in fact in Fort Riley Kansas in summer 1917 after the shoveling of tons of manure by the soldiers on station there….At six PM the sickbay received the first casualty the morning after 500 soldiers were hospitalized ….The rest is history.

Doesn’t this serie of unfortunate events call for a more detailed study?

Doesn’it looks like a cofactor ,possibly present in the manure, triggered and increased the virulence of the H1N1 virus? Or are we blinded by this precise event? Did the contamination occured much earlier and this manure stuff was just a circumstantial event? ( What was the incubation period?)…. And what then would have been the contaminant agent?

08 July 2006

CashBat 00:01

The often heard argument is that if H5N1 was going to be easily transmissible between humans, it would have done so by now having had 10 years. The canine flu H3N8 jumped species from horses and is now readily transmissible between dogs. This happening after 40 years in horses only!! When it occured in greyhounds in 2000, it was the first time it was documented to have jumped species. To me, this shoots that theory in the foot… And there is supposedly scientific concern about the possiblility of it jumping to humans. It, too, was an avian flu before settling in equines. Any thoughts?

Leo7 – at 02:01

Monotreme and Tom DVM thanks:

Tom, I have also wondered about the constant reinfection going on. Ten years does seem like a long time but I have to remind myself that HIV took a while too before it became a silent pandemic. Maybe the slower it mutates the more viral and lethal it becomes. The long gap of time allows the virus to adapt to what should normally kill it. But why do they call H1N1 and H5N1 kissing cousins when we’re told the 1918 flu jumped from birds to humans without other mammialian hosts? One thing for certain, is there’s lots we don’t know. For all we know, most infectious viruses take this slow meandering ten year course as a norm? I’ve come to accept that information is bathed and blow dried before we get it, and I think there are probably a lot of scientific papers in desks across the world that won’t be published either. Therefore, unless there are little sparks of hope (the statins for example)to tuck in around the bad news, we won’t get real news.

Back to the cousins: Have you or anyone else actually seen a comparison slide of these two deadly viruses? I would love to see a link to that peep show. I’d like to see the threat wouldn’t you?

Melanie – at 02:04

Leo7,

Minus the conspiracy theories, you told the truth,

there’s lots we don’t know.

Every scientist I know would sign on to that.

Racter – at 02:27

Mono: “Sorry, but I dont think chance has much to do with evolution. It has lots to do with mutations.

If I’m wrong, disagreeing with me is the first step on the path to me getting right, so please don’t feel a need to apologize for doing so. I’ll ignore the rather glaring contradiction in your two statements, since we both know I wasn’t talking about random mutations anyway.

And at an individual level, chance plays a big role

There it is. If you look closely, I think you’ll see that “chance” is a driving force even at the level of the individual cell. Just as an individual is the summed effects of massive numbers of micro-events at the level of the cell, micro-events at the level of the individual propagate upward and outward.

but in a general sense, I think evolution is pretty predictable

You’ve got to be kidding.

First, the 19th-century is one of my favorites. No PC or post-modern nonsense to wade through.

Yes, women had to keep their mouths shut, we could still beat our children, and we knew what “progress” was. If there ever was a golden age of virtue, that had to be it. And if accepting twenty-first century science means accepting postmodernism, I’ll blow my freakin’ brains out right now.

Second, the Neutralist viewpoint is under attack on a number of fronts.

The whole theory of evolution is under attack — but it’s winning.

And the data is supporting the importance of selection in evolution, even in humans.

It’s common knowledge that the wonders of modern medicine and technology have eliminated selective pressures on humans. Of course, most of those who “know” this haven’t spend much time in third world countries. Hold the references; no need to debate where we agree. Declaring oneself to be a “Selectionist” may turn out to be like declaring oneself to be a “Punctuationist”; the opponents against whom you struggle may turn out to be nothing but figments of your own imagination.

Scientists explained things clearly and did not hide behind jargon.

And a great many of those explanations, as we now know, were wrong. Many of them were oversimplifications at best, and it is therefore no surprise that less jargon was involved in delivering them. The very terms we are using in these discussions — reassortment, recombination, mutation, even “H2H” and “H5N1” — qualify as “jargon”, but I don’t believe any of us are “hiding” behind them. You just can’t take the time to expand every concept every single time.

One of the things the 19th century scientist would have explained is that small effects are overpowered by large effects. What we now know is that large effects are driven by small effects. Cut down a single tree in a rain forest, and you may trigger a cascade of events with implications no one could possibly hope to predict.

Clarence the guardian angel said it best: “Strange, isn’t it? Each man’s life touches so many other lives. When he isn’t around he leaves an awful hole, doesn’t he?

anonymous – at 02:55

theres lots we dont know.
there’s also lots we do know. So let’s summarize this to : “there’s a lot”.


agreed with Racter on most points.

anonymous – at 03:01

Monotreme, bH5N1 and mH5N1 are usually the same or very similar. No evolution in mammals was demonstrated yet. Can you show some mH5N1 where no similar bH5N1 is known ?

Monotreme – at 06:54

Tom DVM at 23:18

Monotreme. Thanks. Could it have done it without the assistance of selective pressure in a mammal?

Tom DVM,I have been wondering this for some time. I don’t think we know enough about what happened in 1918 to be sure.

Leo7 at 02:01

But why do they call H1N1 and H5N1 kissing cousins when were told the 1918 flu jumped from birds to humans without other mammialian hosts?

Actually, we don’t know that the 1918 flu jumped directly from birds to humans. It is thought that it did not reassort with a human virus as did the last two pandemic strains, but that is not the same as saying it didn’t adapt in an intermediate host. I think the reason these two things are conflated is because of the emphasis of the pig as a mixing vessel for allowing reassortment. It is equally possible that a bird virus could evolve into a pandemic virus in pigs or another mammal without reassorting. The only signature would be selection.

Monotreme – at 06:57

Perplexity at 23:54

Fecal-oral is certainly a concern and environmental contamination has been documented. Whether this played any role in the evolution of the 1918 strain would be hard to determine.

Monotreme – at 06:58

CashB at 00:01

I agree. Slow evolution of the virus doesn’t mean it’s not going to occur.

Monotreme – at 07:28

Racter at 02:27

Just as an individual is the summed effects of massive numbers of micro-events at the level of the cell, micro-events at the level of the individual propagate upward and outward.

Actually they don’t. If a specific mutation is deleterious, it isn’t propagated. Mutations that are advantageous are propagated. This is fundamental to evolution and why I still say it’s predictable. A test. Pick a toxic chemical. Apply to cells of your choice in concentrations such that 99.9% of all cells die. Repeat with higher levels of the toxin. Eventually you will have a large population of cells that are resistant to the toxin. Random muations will give a small number of cells a selective advantage over the others. They will propagate, the others will die. This is why we have made little progress in curing cancer in spite of chemotherapy (it does buy some time) and why antibiotic resistant bacteria are emerging. Predictable evolution in action.

Yes, women had to keep their mouths shut, we could still beat our children, and we knew what progress was.

Unspeakable acts of savagery occur every day in American cities. Ask a cop. Most of the world lives in conditions that people of the 18th century would not envy.

And if accepting twenty-first century science means accepting postmodernism, Ill blow my freakin brains out right now.

I feel your pain.

The whole theory of evolution is under attack but its winning.

Yikes. Let’s not conflate the fate of Neutralism with the fate of Evolution. Neutralism is doomed, Evolution has already won.

Declaring oneself to be a Selectionist may turn out to be like declaring oneself to be a Punctuationist; the opponents against whom you struggle may turn out to be nothing but figments of your own imagination.

Not really. This is an extremely contentious subject in biology right now.

Neutral theory of molecular evolution

Neutralism and selectionism: the molecular clock

And a great many of those explanations, as we now know, were wrong.

True, but educated people could judge the arguments for themselves. Today, it is very difficult for educated laymen to penetrate the jargon of many fields. It’s true that a certain number of new terms are necessary to discuss new ideas, but these can be kept to a minimum and plain english words could be chosen. Like Natural Selection - what a great choice of words!

The impression I get is that some people in the sciences and other fields deliberately invent many jargon words, not to communicate new ideas, but to imply great knowledge and intelligence on their part.

I notice you neglect to address my strongest argument: the predictability of convergent evolution.

Perplexy – at 09:22

Monotreme at 6.57 Thanks for your answer, but do you infer that the soldiers in Kansas would have been directly infected through the fecal-oral route? …In that case it raises a huge question: If this was the case, can H5N1 follow the same pattern ? Do the present clusters of H2H contaminations exist precisely because of special conditions similar to the events in fort Riley?…(Like manure or abondance of feces,animal droppings etc…)…. Equally important if we look at H1N1 is the fact that the troups send from Fort Riley to Europe, shortly after this situation, arrived directly on the battlefield. This is not a simple detail: The whole western front had been under intense artillery pounding and had become the equivalent of a huge sewer where everything was mixed, dead bodies feces …etc. This had lasted for years…Could it have been that at that point the soil itself had become a possible “Co-factor” and was responsible of the extension of the pandemia?

anonymous – at 09:30

H1N1 is still around and has been studied a lot. No fecal-oral was reported.

anonymous – at 09:39

Re: H5N1 evolutionary pressures. I firmly beleive that mass use of vaccinations in poultry is adding signiicant evolutionary pressure. Vaccine match viruses will swiftly be dealt with by the hosts immune system, leaving those with mutations that cause a mismatch to survive and thrive. The greater the degree of vaccination, unless 100% coverage is achieved (and even then it would be iffy)the more it is going to poistvely select for mutations.

Chinas extensive use of poultry vaccinations combined with high population densities in close proximity with poultry is bound to be a hothouse for viral evolution.

anonymous – at 09:46

Sorry - follow on point to above. If people accept that vaccination of poultry adds evolutionary pressure, the more frequently vaccines are used the greater the selective pressures for viruses to mutate more rapidly, as it is those viruses which are most genetically unstable that will be most successful in avoiding the vaccine pre-sensitisation of the host. Then we have viruses which are hard for us to keep up with as they have an increased rate of mutation.

I beleive we are seeing this across a range of viruses, from Influenza to JE, dengue, and others. I hope this phenomenom will be properly studied.

anon_22 – at 11:18

Leo7,

“But why do they call H1N1 and H5N1 kissing cousins when were told the 1918 flu jumped from birds to humans without other mammialian hosts?”

Actually, all they (mainly Taubenberger et al) said was that the virus was of avian origin. You can have other mammals being infected with an avian virus just like human beings were infected with an avian virus.

From my conversations with Taubenberger, he is still musing about possibilities including a mammalian host that we don’t know about.

anon_22 – at 11:21

Poultry vaccines is a difficult and emotive subject IMHO. Yes, I think their use adds or alters evolutionary pressure but the significant reduction of outbreaks may also be reducing by a very wide margin the exposure of humans, other birds, pigs, cats, in fact any possible hosts, which would give the virus more chances to diversity and/or acquire the necessary mutations for a pandemic.

beehiver – at 11:38

Concerning Perplexity’s post at 23:54.

Does anyone know what kind of manure was shoveled (cow, pig, horse, or chicken)? Another question, are some strains of infl A capable of creating clinical symptoms in humans in less than 24 hours. I am recalling here Webster’s H5N1 tests in which his lab animals were dead within about 24 hours, but can something similar happen in humans? The soldiers were reporting ill within 24 hours of exposure to whatever agent was in the manure. Thanks.

Racter – at 11:43

Mono:

Mutations that are advantageous are propagated

Not if their “hosts” (if you will) fall off a cliff, or get caught in a wildfire, or an ice storm, or eat poison, or get flattened by a UPS truck, or any of the bazillion other things that happen to healthy, elegantly designed organisms every day.

Lets not conflate the fate of Neutralism with the fate of Evolution

Then let’s not conflate “under attack” with “doomed”. The importance of drift has been debated ever since Kimura first published, as have any number of other ideas. Punctuated equilibria appeared to be a extremely contentious subject a while back, but what seems most contentious about it now is whether it ever was contentious in the first place.

Today, it is very difficult for educated laymen to penetrate the jargon of many fields.

I sense a pointing finger there, but I’m not sure at whom it’s pointed. Today, many of these fields are difficult to penetrate even for educated experts. At some point in the past, an educated person could have absorbed the entire body of scientific knowledge and still had perhaps twenty or thirty years of life remaining in which to apply it, if his life wasn’t cut even shorter by a case of pneumonia or measles or cholera. Physicists were unburdened by non-Euclidian geometry, relativity, and quantum mechanics, and biologists didn’t have to struggle with the subtleties of protein folding, cell differentiation, or HOX genes. Those were the days, all right.

I notice you neglect to address my strongest argument: the predictability of convergent evolution.

We can posit that a region of design-space includes certain attractor points, but we cannot predict whether a given developmental path will actually find them. The first mistake I see you making is in placing too much emphasis on selection in the form of organism-versus-environment, and not enough on organism-versus-organism. Most design problems can be solved in multiple ways, but that does not mean that equal freedom always exists to choose between them (whether the “choosing” is being done by a human designer or a blind process).

The second mistake I see you making (evidenced by statements like: “all the action is in selection”) is in assuming that the argument is “selectionism versus neutralism”.

Here’s a quote by Matt Ridley:

In physics, there is no great difference between a why question and a how question. How does the earth go arund the sun? By gravitiational attraction. Why does the earth go around the sun? Because of gravity. Evolution, however, causes biology to be a very different game because it includes contingent history. […] When a neo-Darwinian asks, “Why?” he is really asking “How did this come about?” He is a historian.

It’s called “Natural History” for a reason.

I’m sure having fun here; hope we don’t get in trouble.

Perplexity – at 12:08

Beehiver at 11:38 On a previous thread, here on Fluwiki, there was quite a discussion : Some argued that it was some horse manure the other was routing for pigs manure… Now remember that it was a cavalry regiment,they were certainly having more horses than pigs in this outfit…So indeed my take is that it was horse manure.

Perplexity – at 12:09

……Or may be a mixture…

anon_22 – at 12:29

Racter,

“. The first mistake I see you making is in placing too much emphasis on selection in the form of organism-versus-environment, and not enough on organism-versus-organism. Most design problems can be solved in multiple ways, but that does not mean that equal freedom always exists to choose between them (whether the choosing is being done by a human designer or a blind process).

The second mistake I see you making (evidenced by statements like: all the action is in selection) is in assuming that the argument is selectionism versus neutralism.”

Interesting comments. Can I ask you to elaborate on organism-versus-organism? And how whould you address the second problem differently?

I am currently :-) agnostic as to the role of evolution, selection, how it all works, etc. It would be great to hear many different opinions. Thanks!

Monotreme – at 13:20

anon_22 at 11:18

From my conversations with Taubenberger, he is still musing about possibilities including a mammalian host that we dont know about.

Very interesting. Is he considering the possibility of a mammalian reservoir for H5N1?

anon_22 – at 13:26

Monotreme,

“Very interesting. Is he considering the possibility of a mammalian reservoir for H5N1?”

We didn’t talk about H5N1 specifically in that context. I suspect this line of thinking would still apply.

beehiver – at 13:43

Perplexity at 12:08. We were talking about this here at lunch, and also came up with the strong horse manure possibility. Makes one want to take a quick peek at the changes in H3N8 that might be involved in the jump from horse to dog.

BTW, you have a neat handle.

Monotreme – at 13:46

Racter at 11:43

Not if their hosts (if you will) fall off a cliff, or get caught in a wildfire, or an ice storm, or eat poison, or get flattened by a UPS truck, or any of the bazillion other things that happen to healthy, elegantly designed organisms every day.

You’re still focused on the individual. I’m trying to shift the emphasis to populations, with no luck, thus far. In my proposed toxin experiment, which you don’t address, I indicated that some individuals would happen to have the right mutations to propagate themselves. Note, I don’t claim in advance to know which ones will. From an evolutionary perspective, it doesn’t really matter if some of some really neato mutations don’t get propagated because an individual carrying them falls off a cliff. If the neato mutations occur in a large enough population, they will eventually occur in an individual that doesn’t fall off a cliff. To use your casino analogy, the house is guaranteed to make money over the course of a year even though the results of a particular game are not predictable. The probabilities are in the houses favor. The same thing is true with favorable mutations. In a large enough population, over time, favorable mutations will accumulate and unfavorable mutations will be removed. This doesn’t mean we can predict the fate of a particular individual.

Then lets not conflate under attack with doomed.

A deliberately inflammatory comment on my part, I admit. Actually, I am sure that neutral evolution occurs, but it has been overempasized in the past few decades. Partially, I suspect, because it is more PC than “nature, red in tooth and claw”. The sequence data is moving the pendulum back towards selectionism. We could talk about Ka/Ks ratios, but I don’t know if that would bore everyone else.

I sense a pointing finger there, but Im not sure at whom its pointed.

Not at you. You write very clearly. Actually, it’s pointed at some people in the social science. Some of them have physics envy. Also my finger is very firmly pointed at post-modernists, a common foe, I believe. But that is way off topic. Also, as a biologist, I confess that some of our nomenclature is not helpful. There are more logical ways to name genes than the ones currently in use.

We can posit that a region of design-space includes certain attractor points, but we cannot predict whether a given developmental path will actually find them.

Didn’t say we could. Just said some developmental pathway would find them. I stand by my winged creature scenario.

The first mistake I see you making is in placing too much emphasis on selection in the form of organism-versus-environment, and not enough on organism-versus-organism. Most design problems can be solved in multiple ways, but that does not mean that equal freedom always exists to choose between them (whether the choosing is being done by a human designer or a blind process).

Well, I’m not sure what too much is, but I don’t dispute the importance of organism-versus-organism evolution. Run, little gazelle, run. Use your speed. Oh, no, the lion is getting closer. Oh, the horror!

Nature, red in tooth in claw. Bet that gazelle wished he had a mutation that would have make him run faster.

The second mistake I see you making (evidenced by statements like: all the action is in selection) is in assuming that the argument is selectionism versus neutralism.

Well, some people think it’s an argument. There are lots of papers to this effect, and more coming.

When a neo-Darwinian asks, Why? he is really asking How did this come about? He is a historian.

Ah, those were the days. And now. On to engineering.

Im sure having fun here; hope we dont get in trouble.

Who is going to stop us? The evolution police?

Racter – at 14:25

Monotreme:

Youre still focused on the individual. Im trying to shift the emphasis to populations, with no luck, thus far.

To succeed, you’ll need to convince me that the future of the population does not reside with the success of the individual. We have no way of knowing where or how many times the course of some evolutionary pathway has been altered in some major way by the absence (or presence) of some critical “George Bailey” organism, but it doesn’t have to have been very often to have been very significant.

From an evolutionary perspective, it doesnt really matter if some of some really neato mutations dont get propagated because an individual carrying them falls off a cliff. If the neato mutations occur in a large enough population, they will eventually occur in an individual that doesnt fall off a cliff.

That may be the crux of our disagreement right there. What if it doesn’t occur in a large enough population? What if it occurs in a population so small as to be threatened by extinction? “Every man on that transport died! Harry wasn’t there to save them, because you weren’t there to save Harry.” Now, what if that threatened species happened to be the only predator of some massively fecund grazing animal…

Also my finger is very firmly pointed at post-modernists, a common foe, I believe.

Anytime you want to go pointing more than fingers at them, I’m in. One of my favorite weapons against them is the hysterically funny Postmodernism Generator, though I suppose most everybody’s seen it already.

(Me): “We can posit that a region of design-space includes certain attractor points, but we cannot predict whether a given developmental path will actually find them.”

Didnt say we could. Just said some developmental pathway would find them. I stand by my winged creature scenario.

Allow me to rephrase: We can posit that a region of design-space includes certain attractor points, but we cannot predict whether a given developmental path will actually find them, nor can we predict that any developmental path will actually find them, because that involves contingent history.

Well, some people think its an argument. There are lots of papers to this effect, and more coming.

We’ll have to remember to argue some more later about whether or not there is an argument.

Ah, those were the days. And now. On to engineering.

You’ve got a terrific point there, I must admit.

Anon_22:

Can I ask you to elaborate on organism-versus-organism?

If you’re sure you want to encourage me.

Looking only at the environmental features of an ecological niche, say a mountainous terrain, we might attempt to predict the sort of physical traits a particular type of animal living there would be likely to develop. Strong legs and a keen sense of balance might be among those, extra efficient lungs, maybe some sort of grippy pads on the bottoms of the feet. Since a low center of gravity would be a particularly good idea, we certainly wouldn’t expect to see that compromised by the placement of an enormous set of heavy horns way up on the head — like those of a ram, for instance.

Leo7 – at 15:02

Thanks for replies Monotreme and Anon 22:

Anon 22- Did you see virus on slides at the conference. If so will you be posting? Thanks.

Monotreme – at 15:36

To succeed, youll need to convince me that the future of the population does not reside with the success of the individual.

Well, if the population of a particular species, then random events do loom larger. But in a broader sense, so what? If a species is doing so poorly that it only has a small number of individuals it might not make it anyways. If so, another species will take over that niche. See marsupials vs. placentals for many examples. Bye-bye thylacine wolf, hello dingos.

Now, what if that threatened species happened to be the only predator of some massively fecund grazing animal

No problem. A new predator will evolve. Count on it.

Allow me to rephrase: We can posit that a region of design-space includes certain attractor points, but we cannot predict whether a given developmental path will actually find them, nor can we predict that any developmental path will actually find them, because that involves contingent history.

Oh, I’m pretty sure about this. Many examples of convergent evolution. Mammals occupied various dinosaur niches after the dinosaurs were gone. Cichlids in Lake Malawi. Many examples of this.

CashBat 16:35

Beehiver, according to MSM, H3N8 jumped intact from horses to dogs with little to no changes… Why so, after 40 years of close contact? Beats me…

anon_22 – at 18:16

Leo7

“Anon 22- Did you see virus on slides at the conference. If so will you be posting? Thanks.2

I’m not sure exactly what you are referring to. Sequences? Pathology slides? Or something else? In any case, the only slides that I do have are the ones that some of the presenters are willing to send to me, which is not many. For the rest, I just make do with my notes. The quality of what I can post unfortunately depends a lot on the quality of my notes :-) Also, since I did go to quite a few, it’s not always easy to separate the different sources for things that I learnt. So the best I can do it try to post the most important references with links when I can. :-)

Racter – at 18:31

Monotreme:

If a species is doing so poorly that it only has a small number of individuals it might not make it anyways

Might, might not. That’s why we call it “chance”.

A new predator will evolve. Count on it.

We can’t count on that, though. It didn’t happen in Hawaii. What we can count on is that if it does happen, it will take millions of years, and during that time, the fecund grazer may drive other species of either plants or animals to extinction, permanently changing the local ecology (and, indirectly, perhaps even the local geology). Another likely prospect is that before a new predator evolves, a new predator may arrive, due to some event which (from the perspective of evolution) may be referred to as the result of chance — such as the melting of a glacial barrier, the emergence of a land bridge, or sudden introduction through the sort of freak event I described above in the “floating log” scenario.

There are indeed many examples of convergent evolution. There are also many examples of evolutionary paths that did not converge on neighboring points in design-space, but we can’t count them all, for the approximately the same reason that we can’t count the number of meteors that failed to leave detectable craters by virtue of having missed the earth.

The giraffe was mot inevitable. Wind the clock back some millions of years, and you’d probably not see anything remotely resembling a platypus evolve again. Humans either.

You are a fluke of the universe. You have no right to be here. And whether you can hear it or not, The universe is laughing behind your back.

Medical Maven – at 18:51

Racter at 18:31: “You are a fluke of the universe. You have no right to be here. And whether you can hear it or not, the universe is laughing behind your back”.

Relativity

You are not yet born, and dead to boot, These lofty thoughts……. an eternal hoot. : )

Monotreme – at 19:46

The giraffe was not inevitable.

True, but a long-necked creature that could get the leaves on the tall trees probably was, see Brontosaurus for previous niche-holder.

You are a fluke of the universe. You have no right to be here. And whether you can hear it or not, The universe is laughing behind your back.

Jeeze, you too? Do you have any idea how many people have told me that?

As an individual, I’m sure this is true. However, I think it was inevitable that some sentient life-form would evolve on earth, eventually. If H5N1 wipes out humanity, my bet on our successor is the raccoons, assuming they survive.

Tom DVM – at 22:38

Hi Guys. I’m not quite sure what you two are on about but it is interesting reading.

Monotreme I’m with you on the Racoons. When every other life form is gone they will definitely be the ones to turn out the lights.

This may be a dumb question but I might not be the only person on flu wiki that has no idea what you are talking about with Post Modernism and its relationship to the practise of science…

…If you could point to a history lesson or write a short description, I and others would probably appreciate it.

Also, I got lost in the jungle so if one or both of you could summarize your arguments, that would be great. Thanks.

Melanie – at 22:40

Raccoons and spiny anteaters. This thread is getting funny.

Tom DVM – at 23:12

One other thing I wondered about. You both use the shortform PC in the same context as the term Post Modernism. What does PC mean?

Melanie – at 23:17

Tom,

Here is the Wikipedia short course in postmodernism, which I find quite unsatisfying. I have a degree in this.

PC usually means “political correctness.”

Tom DVM – at 23:20

Melanie. Thanks.

Monotreme – at 23:38

Tom DVM, with your first hand experience with critters, your vote of confidence in the racoon is reassuring.

Melanie answered the questions re: PC and postmodernism. Pretty much off topic, but at least one thing Racter and I agree on.

Here’s my summary of the debate: Both Racter and I agree that Evolution can be occur Randomly (Neutralism) and as a result of Selection (Selectivism). We disagree on the relative importance of each.

My bottomline is that I think H5N1 is under selection. H1N1 may have been as well.

The most interesting comment on this thread was nothing that either Racter or I said. It was anon_22′s comment that Dr. Taubenberger thinks there may have been a mammalian reservoir for H1N1. She thinks he may think this about H5N1 as well. This would imply to me that he might agree with the idea that H5N1 is under selection, although it would be nice if would comment directly so we don’t misinterpret him.

Although this debate may seem esoteric, it has practical importance. If H5N1 is under selection in a hidden mammalian reservoir, it is of the utmost importance that we identify the reservoir and eliminate it. There is no way we can eliminate the avian reservoir, but maybe, just maybe, we could eliminate a mammalian reservoir. And then we could all sleep better at night.

beehiver – at 23:43

CashB at 16:35 according to MSM, H3N8 jumped intact from horses to dogs with little to no changes

Trying to find every excuse possible not to wash windows this afternoon…I took A/equine/Kentucky/5/02, and blasted against A/canine/Florida/242/2003, to see what of any changes were involved in those equine vs. canine strains. These were the two most complete set of sequences with fairly close occurrence dates. Having no idea what MSM said on this subject (maybe they need to hire new advisors, lol), here are the protein changes (mutations) from the 2002 equine to the 2003 canine. Many but not all of them are in the hemagglutinin, and all the segments have at least one change.

PB2 - L374I, V731X PB1 - A366T, K390E PA - D27N, S388N, N675D HA - G22D, N69K, V93A, N98S, N174S, W237L, A287V, I343T, N498T NP - S450N NA - A9T, G40R, G42D, A70T, P78S, R337S M - K208R NS - I48S, R140G

I don’t perceive any of these changes as being due to recombination. Also, two of the changes in HA (N174S and N498T) may have resulted in loss of glycosylation sites, but I am not absolutely sure of this and someone more knowledgeable would need to check that. The hemagglutinin accession numbers are: AAX23575 (equine) and ABA39842 (canine), if anyone wants to check.

beehiver – at 23:47

Oh dear, no line breaks in my post at 23:43! Let’s try this again.

PB2 - L374I, V731X
PB1 - A366T, K390E
PA - D27N, S388N, N675D
HA - G22D, N69K, V93A, N98S, N174S, W237L, A287V, I343T, N498T
NP - S450N
NA - A9T, G40R, G42D, A70T, P78S, R337S
M - K208R
NS - I48S, R140G

beehiver – at 23:53

That was most definitely an instance of devolution of line breaks. Sorry for the cross-eyed experience!

09 July 2006

Racter – at 02:58

Monotreme:

Both Racter and I agree that Evolution can be occur Randomly (Neutralism) and as a result of Selection (Selectivism). We disagree on the relative importance of each.

I’d say that sums it up pretty well.

Monotreme believes that over any considerable period of time, selective pressure will be the single most influential factor in the evolution of any given organism, while I maintain that random events can be at least as important.

The argument is reminiscent of one that took place between two of the founders of theoretical population genetics, R. A. Fisher and Sewall Wright. Wright believed that in small populations, changes in gene frequencies due to random distribution could play an important role in evolutionary change, allowing random wandering over “fitness landscapes” (Wright’s term). Fisher argued that since most populations are too large for such effects to have significant impact, a population would invariably climb the nearest available fitness peak. Motoo Kimura came along later, and after fiddling with the math some, stunned the scientific community with the announcement that genetic drift is the main driving force of evolutionary change. A lot of biologists didn’t like to hear that, and a lot still don’t.

Our differing views on the importance of drift probably go a long way toward explaining the different ways we view the H5N1 threat. Monotreme is convinced that the virus is evolving toward mammalian hosts, and looks for the mammalian reservoir which must exist somewhere if this is true. I see the observed human clusters as chance events; encounters between particularly susceptible humans and virions that somehow got lost while out bird hunting.

Part of the problem with trying to figure out what evolution is or isn’t doing to a virus is that a virus doesn’t really have much of anything you’d really call a phenotype. We can look at the sequences, but we still can’t tell all that much from just looking at sequences; if you want to know what’s going on, you have to look at the critter itself, and the only real way to do that with a virus is indirectly; you look at its effect on its host.

Accurately interpreting what you’re seeing is the trick.

anonymous – at 04:10

Nucleotide-differences


(1)-(2)-(3)-(4)
(1) A/Canine/Florida/242/2003(H3N8) ,---,050,077,087
(2) A/Canine/Florida/43/2004(H3N8) ,050,---,118,128
(3) A/equine/Wisconsin/1/03(H3N8) ,077,118,---,107
(4) A/equine/Kentucky/5/02(H3N8) ,087,128,107,---
anonymous – at 06:34

correction
Nucleotide-differences:
……………………………….(1)-(2)-(3)-(4)
(1) A/Canine/Florida/242/2003(H3N8) ,---,050,063,072
(2) A/Canine/Florida/43/2004(H3N8). ,050,---,105,112
(3) A/equine/Wisconsin/1/03(H3N8).. ,063,105,---,097
(4) A/equine/Kentucky/5/02(H3N8)… ,072,112,097,---


15 differences (1,2)-(3,4) {PB2(2),PB1,PA(5),HA(6),NS}
1 difference (1,3)-(2,4)
I think, only these 15 should be considered species-specific.

anon_22 – at 07:27

Racter,

Monotreme believes that over any considerable period of time, selective pressure will be the single most influential factor in the evolution of any given organism, while I maintain that random events can be at least as important.

Monotreme is convinced that the virus is evolving toward mammalian hosts, and looks for the mammalian reservoir which must exist somewhere if this is true. I see the observed human clusters as chance events.

I must say I am with you on this one: I think selection may be important on the grand scheme of where the virus might go, but the occurrences of human cases even at 200+ is such a small sample that one can’t use that to draw any conclusions, and the chance meeting of susceptible individuals and ‘fit’ strains in the ‘right’ physical and social environment may contribute equally to the process.

Part of the problem with trying to figure out what evolution is or isnt doing to a virus is that a virus doesnt really have much of anything youd really call a phenotype. We can look at the sequences, but we still cant tell all that much from just looking at sequences; if you want to know whats going on, you have to look at the critter itself, and the only real way to do that with a virus is indirectly; you look at its effect on its host.

Accurately interpreting what youre seeing is the trick.

Yes, I personally think epidemiological data is going to be far more predictive of where the virus is going in the short and maybe medium term, eg size of cluster, whether they are related by blood, whether it is really true that the high incidence and high death rate of the young is due to increased exposure and not host immune system responses unique to that age.

Tom DVM – at 07:34

Racter Monotreme Thanks!!

Tom DVM – at 07:40

Racter

“Part of the problem with trying to figure out what evolution is or isnt doing to a virus is that a virus doesnt really have much of anything youd really call a phenotype. We can look at the sequences, but we still cant tell all that much from just looking at sequences; if you want to know whats going on, you have to look at the critter itself, and the only real way to do that with a virus is indirectly; you look at its effect on its host.”

“Accurately interpreting what youre seeing is the trick.”

I agree with this segment that should be re-emphasized.

anon_22 – at 07:43

Monotreme,

The most interesting comment on this thread was nothing that either Racter or I said. It was anon_22s comment that Dr. Taubenberger thinks there may have been a mammalian reservoir for H1N1. She thinks he may think this about H5N1 as well. This would imply to me that he might agree with the idea that H5N1 is under selection, although it would be nice if would comment directly so we donft misinterpret him.

It would be useful to ask JKT his views on this aspect of where H5N1 is going. He has just moved to the NIH and I am waiting to get his new email address so I might ask him.

:-)

Although this debate may seem esoteric, it has practical importance. If H5N1 is under selection in a hidden mammalian reservoir, it is of the utmost importance that we identify the reservoir and eliminate it. There is no way we can eliminate the avian reservoir, but maybe, just maybe, we could eliminate a mammalian reservoir. And then we could all sleep better at night.

Although that is a worthwhile goal, I’m not sure that is feasible. The most likely place for such a reservoir would be in rural China. If you think of SARS and the civet cat, not only can they not eliminate it, it is extremely hard even to try and ban people from capturing or selling them for culinary purposes.

Tom DVM – at 07:55

For what its worth, I think you’re both right.

There must be specific characteristics that set outliers like H1N1 and H5N1 apart from the myriad of influenza viruses in the world today. I believe the difference is in the ruthless efficiency in the way they evolve among other things…

…therefore, if these viruses are special, it is because they take take advantage of every opportunity to evolve and I would expect are taking a two-pronged approach to evolution and three or four pronged if there are other ways we don’t know about.

Monotreme is right as usual. There is a third wave…another or group of mammals that are being exploited probably asymptomatically by this virus. The funny thing is that we hear repeated reports of infections in pigs but these infections must be very mild or asymptomatic because we aren’t hearing of any epidemics or smaller outbreaks in pig herds. Therefore, it appears to already have the ability to affect at least one mammal asymptomatically, a pre-requisite to Monotreme’s hypothesis.

While a plants phenotype (phenotypic expression) may be flower colour, a viri’s phenotype is disease…and if we look at the changes in H5N1 phenotype in the past twelve months, H5N1 is rapidly evolving…how fast it finishes the job is too me the last unknown.

In addition, its apparent similarity to H1N1 genotypically and phenotypically seals the deal.

Perplexity – at 08:20

Monotreme at 19:46 You wrote “…..If H5N1 wipes out the humanity….etc.” Scarry thought BUT highly improbable! Here is why: 5 or 6 million years ago the “Humanoid Genus” branched out of a strange line of small mamalians, apparantly close to a lemur found today in Madagascar….Ramapithequs, australopithecus,paranthropus,homo erectus, homo abilis.neanderthal…etc…….during these six million years this line of mamalians has been exposed to a “zillion” different viruses, They pulled through…. By the way:In term of Biological warfare the spaniards did somethiing very new at the time of their conquest: Facing a rebellion on Easter Island they brought the chief of the rebellion to santiago in Chile ..In jail he got Smallpox, they sent him back to easter island, 90% of the population was wiped out…but there again there was enough survivor to re-jump start a small population. My point is : aren’t we making too much of this H5N1…is this virus “All by itself” as virulent as we see it :60% lethality, or are we missing something ( And there I reffer to my first question regarding a possible co-factor “hidden” ….Like in fort Riley In the manure?) But in any case : The long History of human specie tells us that NO virus has ever had and will never have the “Ability” to wipe us out of the surface of this planet.

Medical Maven – at 09:03

Perplexity: Yes, it is highly unlikely. BUT, a series of catastrophic events could, a doomsday panflu being one of the series.

Remember, it was recently interpreted from DNA research that 70,000 years ago the population of modern humans collapsed to about 2,000 to 20,000 individuals. The primary cause was most likely the climate change caused by the volcanic eruption of Toba in Indonesia. One bad panflu at that point could have been the end of us. Those bad luck streaks have finished off many a species. We humans are no different. We think we have safety in numbers. Think again, our numbers are working against us.

Medical Maven – at 09:17

One last recent example: Recently researchers in Australia were working with the mousepox virus to try to modify it to reduce fertility in mice. They wanted to introduce it into the wild so as to control runaway populations of mice, an alien species in Australia. By mistake they succeeded in creating a mousepox virus that killed every single mouse exposed to it. The researchers, of course, did not realease that virus into the wild, but they wondered what could be done with the smallpox virus.

Weaponized viruses, whether by intent or not, could very well be the end of us.

Monotreme – at 09:44

Medical Maven at 09:17

Weaponized viruses, whether by intent or not, could very well be the end of us.

This is very true. Mutations and selective pressures can be applied in the laboratory that would never occur in nature. A virus may also be weaponized in a laboratory unintentionally. A poorly thought out live vaccine could be as dangerous as a deliberate weapon. This is my concern about China.

This is one reason why I think we need to get explanations for the identical sequences Dr. Niman has identified. Even if there is a very small probability that these represent lab strains, the implications are staggering.

Just to remind people.

Here are the accession numbers for the Chinese swine isolates:

AY747617.1 and DQ419819. These are H5N1 HA gene sequences from swine isolates from 2 years apart. They are 100% identical. DQ419819 was retracted by submitters.

Here are the accession numbers for the American swine sequences:

M73513.1 and DQ280229.1. These are PB2 sequences from swine isolates that are about 30 years apart. M73513.1 is from a H1N1 virus isolated in 1977. DQ280229.1 is from a H1N2 virus isolated in 2004. DQ280229.1 looks like a recombinant and a reassortant. The identical sequence is from nt 217–1878 of DQ280229.1. So, over 1500 nts of identity. DQ280229.1 was deposited by a group from Wisconsin. M73513.1 was deposited by Webster’s group in Tennessee.

Monotreme – at 10:11

I agree that phenotype is a hard issue with to resolve with viruses. However, we do have some data to suggest that the phenotype of H5N1 is evolving towards a pandemic strain:

Lethality to Ferrets of H5N1 Influenza Viruses Isolated from Humans and Poultry in 2004

We studied the pathogenicity of four human and nine avian H5N1/04 influenza viruses in ferrets (an excellent model for influenza studies). All four human isolates were fatal to intranasally inoculated ferrets. [snip] Two avian H5N1/04 isolates were as pathogenic as the human viruses, causing lethal systemic infections in ferrets. Seven of nine H5N1/04 viruses isolated from avian species caused mild infections, with virus replication restricted to the upper respiratory tract. All chicken isolates were nonlethal to ferrets. A sequence analysis revealed polybasic amino acids in the hemagglutinin connecting peptides of all H5N1/04 viruses, indicating that multiple molecular differences in other genes are important for a high level of virulence.

Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus

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

H5N1 is not there yet.

Glycan microarray analysis of this Viet04 HA reveals an avian alpha2–3 sialic acid receptor binding preference.

We may not get there the same way that 1918 got there.

Introduction of mutations that can convert H1 serotype HAs to human alpha2–6 receptor specificity only enhanced or reduced affinity for avian-type receptors.

But there is another way to get there.

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

My concern is that we are seeing signs of convergent evolution between the 1918 virus and H5N1. 1918 got it’s wings and flew. H5N1 is still flying squirell that can only leap from tree to tree. The big question is, is there selective pressure driving it to develop full functional wings?

LMWatBullRunat 11:18

A couple of comments from a layman.

First off, I do take some issue with the concept of “selection pressure” The implication is that the virus is being “moved” because of “selection pressure”. The idea that certain environments favor certain types of viral development is fine as far as it goes, but to take that concept and turn it around as some appear to have done and start anthropomorphizing is a dangerously incorrect approach, IMVHO.

The virus may evolve by using any of the ‘3 Rs’ in a random fashion. The ability of any of the resulting viral changes to propogate is due entirely to chance and the results of the responses of the infected populations. The virus does not exercise volition. It just does what it does and we don’t know much of that activity. Individual response to infection

Another comment is that there is no innate reason why H5N1 or other viral diseases could not evolve to kill all of H. Sap. Unlikely, but possible. I agree with Medical Maven’s comment on that, above. (What I would think would be a greater concern would be the level of infection and mortality that would cause a civilization collapse. May start a thread on that….)

If there was a mammalian reservoir in 1918, and my personal guess is that there was ( I doubt that influenza develops new tricks; I think we just don’t know what all the old ones are. Yet.) then I doubt that there was only one species. Just as influenza is endemic in a wide variety of birds, so I suspect that it will infect as broad a spectrum of ammals as it can adapt to.

The last comment is that I am most interested in what factors contribute to effective immune system response. I would think that the shape of the hemagluttin would be one of the things that govern immune system response. If H5(N1) evolves to a similar hemagluttin shape as H1(N1), would the immunity to H1 presently extant transfer to H5?

I’m A Believer – at 11:54

In MHO, and I am by no means in your leagues in this arguement, but this makes sense to me. The H5N1, and all viruses as I can figure, go from lower lifeforms to higher ones. That is the path, they do not start in humans and work their way down. So, therefore, H5N1 is working itself up to us. Is this wrong? Are there viruses that start in humans and then go to pigs and then to birds? They mutate or recombine along the way to us, and sometimes passed back to lower animals after they mutate in us, but they have all started in lower lifeforms and then <worked their way up>. After we get the virus and pass it around and develope anti-bodies (or whatever), it dies out or becomes less severe. We also pass these anti-bodies around to the lower lifeforms and they pass some around to us. Until another virus mutates or recombines, and then here we go all over again. From everything I have read, this original mutation takes place in birds and where they get it no one knows. I think it is the same one, it just keeps mutating or recombining. And if it is the same one, isn’t there a basic stucture (their DNA or genetic makeup) that we should be looking at, rather than this virus individually? In other words, I’m saying that there is definate selective pressure to drive the virsus to humans, that is what they do, their purpose so to speak. So shouldn’t we be looking at why that is from a standpoint of their basic nature and then we could fight them, totally, wipe them off the face of the earth. Or am I just dreaming that this is possible and I should go back to lurking.

Racter – at 12:07

Monotreme:

H5N1 is becoming increasingly virulent in mammals.

Making a case for H5N1 evolving toward a pandemic strain requires showing that selection is at work. It’s easy to see how those traits conferring better transmissibility could quickly come under strong selection once the virus had established at least some kind of beachhead in a suitable mammalian host. Factors increasing virulence might lead to increased transmissibility — but then again, they might not.

The flying squirrel is one of my favorite examples of an organism changing under selective pressure. But the big question isn’t: “Is there selective pressure driving it to develop fully functional wings?” The big question is: “Is that selective pressure stronger than other selective pressures which might favor traits not compatable with fully functional wings?” Another biggie is: “From the starting point of the creature’s existing morphology, are fully functional wings a reachable point in design space, or would getting there involve doing something an ultra-selectionist could never accept, which is to back down an adaptive peak?” And yet another is: “As the organism approaches an adaptive optimum, will selective pressure remain strong enough to continue to drive it further, or will it fade out upon encountering some point of diminishing returns?

Medical Maven – at 12:10

Viruses no doubt helped us and all LIVING things to evolve. Every once in a while they want a payback. What can you do?

Perplexity – at 12:17

Medical Maven: I agree with you regarding the genetic “Bottleneck” due to the Toba Volcano in Indonesia,but what I am talking about are the viruses: I don’t think any of them has been totally “Genocidal” for the human “genus” .on the other hand it seems that the Aztecs ,for exemple,have been wiped out(among other factors) by an Hemolytic Anemia whose gene became expressed through permanent consanguinity…here is the real danger: A lack of genetic diversity. And here again it’s this diversity which will protect us from total extinction, NOT the numbers…… Also in term of Phylogenetic devellopement :How long has this Influenza virus been around? The first “recorded” epidemy was in Italy in the 15th.century, but I suspect that it has been around for many more centuries ..or milleniums..or more ..And we are still here. I agree with the Idea of a mamalian reservoir, kept unscathed by the virus….. For the rest I am still very perplex.I don’t think we fully understand the ‘natural history’ of the influenza viruses. If I was an “Expert” in virology : I would intensely try to find THE co-factor which triggered the 1918 pandemia. Thanks.

Medical Maven – at 12:25

Racter at 12:07: But even assuming H5N1 at that “point of diminishing returns”, (selectionism has run its course), H5N1 would still have neutralism (randomness) available to stumble into our realm and achieve panflu. Correct? And with H5N1 being endemic in many areas and spreading it will have a lot of hosts and time in which to play “pocket pool”.

But has selectionism run its course? Avian flu viruses, once they have reached this stage (H1N1), tend not to stop at “gliding from tree to tree”.

Medical Maven – at 13:02

Are viruses in a class by themselves in regards to applying concepts of evolution whether it be neutralism, selectionism, or convergent evolution?

In other words, do they really follow the same rules that we see in LIVING species of animals? Is that part of what we are missing? Hope this is not the “dumb and dumber” question of the year? : )

Racter – at 13:12

Medical Maven:

But even assuming H5N1 at that point of diminishing returns, (selectionism has run its course), H5N1 would still have neutralism (randomness) available to stumble into our realm and achieve panflu. Correct?

Yes, absolutely. And, due to the way its genome is packaged and replicated, it has quite a bit more of this available than does a flying squirrel. In addition to that, its generation time is shorter by many orders of magnitude, so it does its stumbling at hyperspeed.

But has selectionism run its course? Avian flu viruses, once they have reached this stage (H1N1), tend not to stop at gliding from tree to tree.

Who knows? Again, we can gain a lot more by looking at squirrel morphology than we can by looking at viral morphology. One squirrel tries to leap a gap and drops like a stone, another glides like a frisbee, that’s pretty clear cut. With a virus, you can’t observe the gliding directly, you have to infer it from its effect on the host. We don’t know what stage the virus is at.

Are viruses in a class by themselves in regards to applying concepts of evolution whether it be neutralism, selectionism, or convergent evolution?

Well, yes and no. The fundamental principles still apply, but the details of implementation are significantly impacted by “horizontal gene transfer”; like a bacteria, a virus doesn’t have to inherit all of its genetic information from a parent, but can aquire changes from “passers-by”.

Medical Maven – at 13:12

I am talking about something beyond and more elemental than the theory that recombination is a primary driver of viral evolution.

Medical Maven – at 13:34

Maybe the “hyperspeed” of a virus’s generation time and the extremely high levels of “horizontal gene transfer” that occurs almost simultaneously within any given host changes the rules of evolution or creates new ones? Like extreme cold can change the normal laws of physics. So with a virus we are at the limits of life, speed, magnitude of change, and the minuteness of change.

anon_22 – at 13:50

I’m A Believer,

And if it is the same one, isnt there a basic stucture (their DNA or genetic makeup) that we should be looking at, rather than this virus individually? In other words, Im saying that there is definate selective pressure to drive the virsus to humans, that is what they do, their purpose so to speak. So shouldnt we be looking at why that is from a standpoint of their basic nature and then we could fight them, totally, wipe them off the face of the earth. Or am I just dreaming that this is possible and I should go back to lurking.

Unfortunately, it would seem that there is no single way for influenza viruses to acquire the characteristics of a pandemic strain eg H1, H3, and H5 have different ways of adapting eg to receptor binding requirements. And we know too little about what we are looking for in the genotype to use the sequences as a way of assessing their evolution.

The example that Racter gave of the morphology of squirrels vs morphology of viruses is a good one to illustrate the problem. The closest thing to ‘squirrel’s wings’ that we can use to observe flu virus’s ‘basic nature’ as you called it is still their behavior, either in the laboratory or in nature. So pathogenicity studies on mice, ferrets, mammals, and epidemiological information tell us a lot more about the degree of adaptation (cf how far has the squirrel sprouted wings) than viral morphology. But since these are all inferred, rather than directly observed information, we are still at least one step removed from being able to judge viral evolution directly.

I’m A Believer – at 14:40

anon_22 at 13:50 I will still believe, then, that we can do it someday. I have so much faith in humankind, having seen so much more good in my lifetime than bad. An believe me, I’m old, I’ve seen an aweful lot of bad. We carry each other, in ways we don’t even realize. A scientist somewhere will see Monotreme’s and yours and all the others posts, and put 2 and 2 together. I carry on, back to prepping.

Monotreme – at 16:05

Racter at 12:07

I pretty much agree with your comments there. H5N1 could stop at the flying squirrel stage, but I sure wouldn’t bet on it. My fear is that once it gets a foothold in humans or another mammal close enough to humans, the selective pressure for it to evolve transmissibility will increase dramatically. This is why I found the Karo cluster so scary. While H5N1 was being spread human to human to human, it was under intense selective pressure to improve transmissibility. Although we are all relieved that it failed, that time, how many more such opportunities will it have in the future? How many does it need before it becomes a pandemic strain? I confess I don’t know the answers to these questions, but I see no reason to be optimistic.

NS1 – at 16:48

Medical Maven at 13:34

Maybe the hyperspeed of a viruss generation time and the extremely high levels of horizontal gene transfer that occurs almost simultaneously within any given host changes the rules of evolution or creates new ones?

I’m with you here.

This is my primary postulate for the past 6 months. The rules of genetic acquisition in the wild operate differently than in a lab.

anonymous – at 17:25

it didn’t succeed earlier in documented human history

Monotreme – at 17:51

What didn’t succeed?

There were three documented pandemics in the 20th century of varying case fatality rates.

Racter – at 20:21

Monotreme:

My fear is that once it gets a foothold in humans or another mammal close enough to humans, the selective pressure for it to evolve transmissibility will increase dramatically. This is why I found the Karo cluster so scary.

This is the main thing I worry about. Since I am (as you know) a proponent of the “genetic susceptibility” hypothesis, I see a group of close-contact susceptibles as a “runway”, and perhaps the main reason the virus hasn’t taken off already is that the runways it has tried simply haven’t been long enough. There appears to me an excellent chance that somewhere in the world a sufficiently long runway may be waiting, whether it’s Mennonites, or Pigmies, or Eskimos, or whatever.

I confess I dont know the answers to these questions, but I see no reason to be optimistic.

The only reason I can see for doing so is as a necessary part of an emotionally balanced lifestyle. As long as I have taken what reasonable precautions I can, I give myself permission to go ahead and make the best of the time I am given, all the while eagerly anticipating dancing at my great-grandchildrens’ weddings.

Medical Maven:

Maybe the hyperspeed of a viruss generation time and the extremely high levels of horizontal gene transfer that occurs almost simultaneously within any given host changes the rules of evolution or creates new ones?

No. The fundamental rules still apply: selection acting on variation aquired through mutation (or: differential success among imperfect replicators — which don’t actually even have to be biological organisms, really). The biggest difference is in the way the variation is distributed.

Monotreme – at 21:06

Racter at 20:21

Since I am (as you know) a proponent of the genetic susceptibility hypothesis, I see a group of close-contact susceptibles as a runway, and perhaps the main reason the virus hasnt taken off already is that the runways it has tried simply havent been long enough. There appears to me an excellent chance that somewhere in the world a sufficiently long runway may be waiting, whether its Mennonites, or Pigmies, or Eskimos, or whatever.

I have been swayed somewhat by the discussion on genetic susceptibility, so I won’t argue with the runway hypothesis. The only place where we differ is that I think there may be another runway that we don’t know about - pigs, weasels or maybe Orang-Utans.

As long as I have taken what reasonable precautions I can, I give myself permission to go ahead and make the best of the time I am given, all the while eagerly anticipating dancing at my great-grandchildrens weddings.

Agree completely. I am much calmer since taking precautions. Even the Karo cluster didn’t rattle me as much as some and I honestly thought that might be *it*. The only way to avoid the emotional roller coaster of fear and complaceny is sensible prepping, IMO.

anon_22 – at 22:03

Racter,

I see a group of close-contact susceptibles as a runway, and perhaps the main reason the virus hasnt taken off already is that the runways it has tried simply havent been long enough.

Or maybe it wasn’t even trying at all, at least not the strain that turns up in each group of susceptible hosts.

Only the collective effort of all the different subtypes, by continuing to diversity and creating multiple sublineages, may, by simply developing such a huge variety of genotypes as to cover all possibilities, eventually cause one subtype to take off, genetic susceptibility or not.

Monotreme,

“The only place where we differ is that I think there may be another runway that we dont know about- pigs, weasels or maybe Orang-Utans.”

There is no reason to limit your thinking to only one other runway IMO. Multiple paths do already exist, simply by genetic diversity.

The fact that viruses can acquire genetic diversity on a timescale of days, weeks, or months, whereas human beings require maybe centuries to do the same, bode ill for us all.

Monotreme – at 22:52

anon_22 at 22:03

There is no reason to limit your thinking to only one other runway IMO. Multiple paths do already exist, simply by genetic diversity.

If I can convince Racter that there is one additional runway, I will consider myself lucky ;-) Seriously, I’m sure that H5N1 is infecting many animals that we don’t know about. But they aren’t all equally relevant. Whatever changes that H5N1 picks up in one animal may be lost when it infects another species if the changes are not advantageous in the new species. If the virus were just bouncing around randomly between different species, I would not expect to see the progressive adaptations to mammals that appear to be occuring. Something more specific is occuring, IMO.

The fact that viruses can acquire genetic diversity on a timescale of days, weeks, or months, whereas human beings require maybe centuries to do the same, bode ill for us all.

Can’t argue with that.

NJ. Preppie – at 23:08

Im scrutinizing a Taubenberger article from Jan. 2005 Scientific American. I can see more implications regarding the 1918 virus development now, than when I originally read over it. Since the question keeps coming up about the origins of the 1918, I will repeat the interesting ideas from the article titled, Capturing a Killer Flu Virus. (I cant get a free online link, but someone else could)

Wild Avian H1N1 sequences have changed little over 80 years, from a 1917 sample to a modern wild bird sample. It may be that no avian H1 will be found resembling the 1918 strain because, in fact, the HA did not reassort directly from a bird strain. In that case, it must have had some intermediate host

In looking at the swine H1N1 lineage, it looks like the transmission was from humans to pigs during the pandemic and not the other way around. H1N1 has become established in European swine for 25 years. There have not been as many changes in 20 years in swine H1N1, as there were in the 1918 pandemic strain from the normal avian H1N1. How do we account for the 1918 changes?

the virus that sparked the 1918 pandemic could well have been an avian strain that was evolutionarily isolated from the typical wild waterfowl influenza gene pool for some time one that, like the SARS coronavirus, emerged into circulation among humans from an as yet unknown animal host.

The 1918 pandemic strain is even more puzzling, because its gene sequences are consistent neither with direct reassortment from a known avian strain nor with adaptation of an avian strain in a swine An alternative origin might even have contributed to the 1918 strains exceptional virulence. Sequencing of many more avian influenza viruses and research into alternative intermediate hosts other than swine, such as poultry, wild birds, horses, may provide clues to the origins to the 1918 pandemics source. Until the origins of such strains are better understood, detection and prevention efforts may overlook the beginning of the next pandemic.

By the way, the SARS virus came originally from bats before civet cats, and Ebola has been found to be older in bats than in primates; such is the possibility of mammalian hosts.

Monotreme – at 23:31

Just found this paper and haven’t had time to read the whole thing, but some interesting excerpts from the abstract below:

Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam

Here, we genetically characterize 82 H5N1 viruses isolated from poultry throughout Indonesia and Vietnam and 11 human isolates from southern Vietnam together with sequence data available in public databases to address questions relevant to virus introduction, endemicity and evolution.

[snip]

Within Indonesia and Vietnam, H5N1 viruses have evolved over time into geographically distinct groups within each country. Molecular analysis of the H5N1 genotype Z genome shows that only the M2 and PB1-F2 genes were under positive selection, suggesting that these genes might be involved in adaptation of this virus to new hosts following interspecies transmission. At the amino acid level 12 residues were under positive selection in those genotype Z viruses, in the HA and PB1-F2 proteins. Some of these residues were more frequently observed in human isolates than in avian isolates and are related to viral antigenicity and receptor binding.

10 July 2006

Closed and Continued - Bronco Bill – at 00:56

Closed due to length. Conversation is continued here.

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