Evolutionary biology and dangerous diseases

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    Martin W

      Evolutionary Biology Important re Bird and Human Flu

      Interesting paper (to me!) by Professor Paul Ewald

      Guarding Against the Most Dangerous Emerging Pathogens: Insights from Evolutionary Biology

      – covers pathogen characteristics that indicate they could cause dangerous diseases.

      Has a checklist, to assess if a pathogen could be dangerous – it could be if answer is yes to any of the following:

      Does it have a tendency for waterborne transmission?

      Is it vector-borne with the ability to use humans as part of the life cycle?

      If it is directly transmitted, is it durable in the external environment? Is it attendant-borne? Is it needle-borne?*

      If it is sexually transmitted, is it mutation-prone with a tropism for critical cell types or does it have invasive or oncogenic tendencies?

      Relevant to human and bird (poultry) flu:

      With regard to the emergence of virulent variants from established pathogens, the influenza viruses circulating at the Western Front during World War I would be considered dangerous because barriers to transmission from immobile hosts were removed by cultural practices and because influenza virus is mutation prone. It is, therefore, not surprising that the Western Front has been identified as the source of the highly lethal variants of the 1918 influenza pandemic and that a pandemic of this severity has never recurred. More importantly, evolutionary considerations suggest that such a lethal pandemic will not recur unless influenza viruses are again exposed to opportunities that allow transmission from immobile hosts, as they are on poultry farms where highly lethal influenza outbreaks periodically emerge.

      (I learned of this through an article in New Republic, by Wendy Orent, saying we are not facing a pandemic of highly lethal flu, as don’t have the necessary conditions [inc chance for people laid low by flu to still readily transmit to others]; subscription needed to view article I believe.)

      Martin W

        Related article – mentioning flu evolution and comparisons with 1918 – argues Fear is more likely to get you than the avian flu

        Martin W

          Article by Carl Zimmer – TAMING PATHOGENS: AN ELEGANT IDEA, BUT WILL IT WORK? – mentions some criticisms of evolutionary biology and pathogens, but doesn’t seem they are by any means watertight. Includes:

          Ewald complains … the critics … leave out a crucial component of his work, for example, the mode by which a disease infects new hosts. If hosts become so sick they can’t move, a parasite can only infect other people who come close, unless a vector such as a mosquito can transport it. This factor is crucial in Ewald’s explanation of Spanish flu. … "My argument was that at the Western Front you had conditions in which people who were completely immobilized could contact hundreds or thousands of people." Sick soldiers were moved on stretchers to triage areas, then to makeshift hospitals, then onto crowded trains. In these conditions, a flu virus could devastate its host but still infect vast numbers of people. "My argument was that we wouldn’t see a 1918 pandemic arise unless we duplicated this situation which occurred on the Western Front," says Ewald.

          – relevant to birds, too. Poultry farms can become "disease factories" (as Wendy Orent puts it); but in the wild, bird flus are mild, because Dead Ducks Don’t Fly.

          Martin W

            Scientific American blogger (editor of the magazine) made post with sume criticisms of evolutionary biology and flu at:

            Don’t Fear The (Bird) Reaper

            led to detailed responses: Bird Reaper, Pt II: Wendy Orent replies

            Bird Reaper, Pt III: Paul Ewald replies

            Above replies give useful info re evolutionary biology. I just fired off something simpler:

            C’mon, the post with the muddled stuff about H5N1 and evolutionary biology’s a red herring. The real issue’s surely the remarkable Lindsay Beyerstein – remarkable not so much for her blog posts but because (from the photo), Dang, She’s Hot!

            Otherwise, what with extensively citing an anonymous muddleheaded blogger who bandies big words about in sentences without clear conclusions (or, to demonstrate his belief in Unintelligent Design?) would suggest you were making a contribution to what the November Esquire calls Idiot America. Toodlepip (from citizen but not currently resident of UK, which has faults but at least doesn’t need Oprah to explain global warming)

            Martin W

              A blogger with the moniker Mike the Mad Biologist has written short critique of ideas from Ewald (and covered by Wendy Orent in several articles); seems to hinge largely on flu being transmissible before symptoms.

              Evolution, Tradeoffs, Ignoring Biology, and Influenza

              Doesn’t seem arguments are real substantial; not helped by what seems to me a rather curious quote re a colleague referring to "those stupid fucking natural history facts." Main one of these facts being again related to flu being transmissible before symptoms (tho as Orent notes, h5n1 is not transmissible – or darn near not transmissible – in humans). I’ve just added comment: Is flu just as contagious during asymptomatic phase. as when symptoms evident (and those with bad cases become immobile)? What of 1918 flu? Just coincidence it evolved – Ewald argues – during Western Front conditions? (And human flu otherwise not major problem; if it could readily evolve to high virulence, shouldn’t it do so more often, and even stay that way?) And why are regular bird flus "mild", yet crowd poultry in "disease factories" and get a flurry of highly pathogenic flus evolving? To me – a birder not biologist – latter seem to be neatly explained by ideas Orent writes of. (Any other theories able to explain these latter facts? Poultry farms would seem "good", accidental experiments that help confirm Ewald’s theory.)

              Martin W

                Just come across blog post by John Hawks, Assistant Professor of Anthropology at the University of Wisconsin—Madison; on the arguments between Ewald and Revere.

                He notes:

                1. Almost no mainstream press accounts of the bird flu threat discuss anything about the evolution of influenza. This is probably the most important public impact of evolutionary theory today, but we hear almost nothing of the evolutionary modeling of how the virus may change.

                2. Ewald is very well known for studying the evolutionary dynamics of disease. He is making an argument that is sound, as far as the dynamics of selection are concerned. Thus, there are good reasons to think that the worst will not happen, and this is a perspective that has been underplayed.

                3. So far, the theory has only been tested by a relatively small number of instances — there just haven’t been so many pandemics that we can infer accurately from past events what the future will be like. It could certainly happen that some new influenza strain could violate the model in some unexpected way, and for this reason governments should play it safe rather than assume that no high-virulence pandemic will emerge.

                4. A lot of public health scientists are going to be well-employed for as long as the bird flu remains in the public perception. This doesn’t mean that they are wrong to convey alarm, but it does mean that they don’t benefit by playing down the threat. It’s sort of like NASA and the asteroid impact threat — partly they are more concerned because they know more about the threat and its terrible effects, partly because it’s their job to be concerned.

                5. There are a lot of biologists who don’t use or understand selection.

                Ewald bird flu spat

                Martin W

                  from correspondent re point 4 in above post:

                  Perhaps I understand the background more correctly. The asteroid
                  impact threat was not a final target of the study, but it was more
                  important that the same research tools (wide-field automated telescopes
                  and pipeline analysis) can be applied to different targets of
                  academic interest. They will not be very appealing (at least for
                  the beginning) to the public. The NASA people needed a different,
                  more popular target in pursuit of their original scientific interest.
                  These telescopes are now being used to rapid follow-up observations of
                  gamma-ray bursts, recovery of dead comets, and other targets of current
                  popular astronomy problems. The “blue book” of the Hubble Space
                  Telescope was similar, but produced far greater results than originally

                  I don’t know whether influenza specialists are taking the similar
                  course, or they regard pandemic a real, foreseeable threat. But
                  as far as I read, top virologists look like to have been more
                  deliberate, and have warned the public against alarmism. I think
                  that these people regard it a real threat, and urge governments
                  to prepare for the “upper limit” disaster. They probably think it
                  insufficient to prepare for the “expected mean” (as might be derived
                  from evolutionary biology).

                  Martin W

                    Had lengthy correspondence re natural selection and H5N1, with “a correspondent”; also led to comments from Wendy Orent.
                    > Indicates quoted text within the chunks of quoted text – gets a bit complex like this I’m afraid.

                    Lest of interest, here goes:

                    Again, the paper by Ewald, with predictions re evolution of pathogens including flu:

                    Yes, this is well-known. This is a famous piece in learning
                    ecology in terms of natural selection. This is a reason why experts
                    more fear a long-range transport (either by humans or birds) than
                    gradual geographical invasion.

                    But we can’t predict exactly, particularly when various species
                    are involved. We don’t even know why LPAIs are so “evolutionary
                    static” in wild ducks, while they can be so pathogenic to humans
                    when they happen to enter the human world. The only truth is
                    “natural selection works”, but we may not know or deal with all
                    factors of natural selection.

                    But again: Ewald makes predictions re flus becoming pathogenic entering human world.

                    Takes special conditions – very sick people able to readily transmit – to evolve a dangerous flu.
                    Most extreme in 1918: First World War.

                    Mao maybe helped cause 1957 and 1968 flus.

                    No such special conditions today; so Ewald argues that we won’t get a highly pathogenic human flu today.

                    His theory predicts avian flus will be mild in wild birds. Need to have birds flying to carry the flus, so evolution to mild strains. So, to me, we do know why LPAIs are “evolutionary static” in wild birds.
                    High path strains into wild birds, and quickly to low path. Or extinction.

                    Quoting Ewald directly:

                    “With regard to the future I am predicting that such a highly lethal pandemic (i.e., 1 death per 50 infections) will not occur, not from H5N1 and not from any other influenza virus that will arise unless regional conditions allow transmission from immobile hosts, as they did on the Western Front in 1918. This is not “speculation” as is claimed by our hooded critic with the self-aggrandizing name. It is a prediction based on careful consideration of theory and evidence. The future will demonstrate whether it is accurate.”

                    Makes sense to me.

                    Can make analagous predictions for birds (Ewald does so for poultry):
                    – crowd together, indefinitely, so sick birds can readily transmit: and evolve dangerous flus
                    – wild situations, need birds to fly to transmit, and equilibrium when flus are mild

                    That is, predictions fit what we observe. Which to me is science; and not speculation.

                    Only mystery to me is why this is so widely ignored.

                    > No such special conditions today; so Ewald argues that we won’t get a
                    highly pathogenic human flu today.

                    As I have (indirectly) heard from flu experts, some argue the virus
                    will not enter the human world in the HP form, but others’ claim
                    is different — we (even virologists) don’t know how HPAI will behave.

                    “Most extreme in 1918: First World War”

                    > No such special conditions today

                    Wouldn’t airplanes, locomotion, population density be special?
                    We have never met a pandemic strain in such extremely globalized
                    world — we don’t really have an experience.

                    > His theory predicts avian flus will be mild in wild birds. Need to have
                    birds flying to carry the flus, so evolution to mild strains. So, to
                    me, we do know why LPAIs are “evolutionary static” in wild birds.

                    Yes, this explains “why”. We don’t exactly know “how”. This
                    means we don’t know exactly how selection pressure works. (Also
                    we don’t know how Zq strain retained high path to natural hosts).
                    As we haven’t seen LPAIs arising from Zq strain, we don’t know the
                    time-scale this process would require (may not be “very quickly”).

                    > High path strains into wild birds, and quickly to low path. Or

                    Most look like to be going extinction (i.e. R0 But planes, crowded conditions etc not enough to him; not so special.
                    Need to have very sick people – immobile with disease – able to readily
                    transmit the virus.
                    Crowding doesn’t matter here, if very sick people stay

                    But flu is already contagious during the incubation period.
                    Less traffic than in WW I? Less packed people? (imagine Tokyo
                    trains) Though I can’t figure out the effect, all present factors
                    seem to increase the risk of a more virulent pandemic.

                    > I’d figure that with wild birds, there’s always potential for virulent
                    flus to evolve.
                    Spectrum of virulence it seems to me (this from chemistry background,
                    not viruses): get some higher path, others lower path. Get an
                    equilibrium, depending on prevailing conditions.
                    As need flying birds to transmit flu in the wild, the equilibrium is
                    greatly towards non virulent forms. High path forms stay rare. (This
                    again from chemistry; some memories from when I did this re systems
                    reaching equilibrium.)

                    Thanks! This is much easier to understand. If “random” distribution
                    of mutated form is close to Gaussian, natural selection would work
                    in this way (for a specific species). If it is very far from Gaussian,
                    we can’t be sure (because there is no effective average — this might
                    explain some of social phenomena like Zipf’s law). What if some
                    populations (due to genetic diversity) are more resistant (not all
                    infected individuals die, but can excrete substantial amount of the
                    virus) — we probably need a more complex view. Natural selection on
                    incubation period may also occur.

                    > Could well be that doesn’t matter what bird species is: if cram into
                    captivity, infect with flu, and have substantial chance that birds with
                    high path forms can transmit flu, then will get evolution towards
                    higher pathogenic forms.

                    If this is population density-dependent, how can we be sure our
                    population density is below a threshold where high path strains can
                    be sustained for a meaningful (effective transmission to a next
                    cluster) time? What is the major difference from poultry chickens?
                    (Well, some of recent pandemic plans from various companies seem to
                    assume “forced working” of employees with milder symptoms — they
                    will mix healthy populations during movement or in taxis — we may
                    eventually be poultry chickens ;-)

                    One more on “equilibrium theory”, why we have never seen a human
                    pandemic strain eventually forming a non-pathogenic form (as in LPAIs
                    in wild ducks?) What would be the difference between ducks and humans?
                    (Why “evolutionary stasis” is never reached)

                    By the way, when considering selection pressure, won’t the extensive
                    use of Tamiflu in pandemic lead to a more virulent strain? Not
                    necessarily drug resistance, but won’t we be selecting a more neurotrophic
                    strain (since Tamiflu doesn’t effectively cross the blood-brain barrier),
                    I casted this question to a public health expert, but haven’t received
                    a reply. This might be another factor different from past pandemics.

                    Well, now you ask questions I wish I had all answers for! – should really go directly to Paul Ewald, as I have some understanding but relatively superficial (I’ll forward to science writer Wendy Orent, who has written several articles based on his ideas, and with whom I’ve had some correspondence; she’s now in aiwatch).

                    The packed people, Tokyo trains or Hong Kong malls, not so important – if people who get sick, v quickly go to bed/hospital.

                    Seen re flu becoming infectious before symptoms; queried Wendy re this.
                    How infectious, I wonder, if not coughing/sneezing? How do you transmit virus without doing these things?

                    Gaussian curve: not sure, but it’s my way of understanding things, as noted based on (physical) chemistry.

                    Main thing w poultry farms, to Ewald, is that can have (ready) transmission from even very sick chickens – so dangerous forms can transmit, even intensify.

                    Wendy notes that 1918 flu did become non-virulent, and still circulates.

                    I also don’t know re Tamiflu; hadn’t known this re brain.
                    Doesn’t seem wise, to me, to use it extensively; cf antibiotics and resistance.
                    Rather as I’m also sceptical re vaccinations, perhaps helping sustain h5n1 (when vaccinations and surveillance less than near perfect).

                    > Seen re flu becoming infectious before symptoms; queried Wendy re this.
                    How infectious, I wonder, if not coughing/sneezing? How do you transmit
                    virus without doing these things?

                    If high path mechanism (replicate without trypsin) indeed works,
                    we don’t necessarily require respiratory organs. Virus replicates
                    everywhere in the body.

                    > Wendy notes that 1918 flu did become non-virulent, and still circulates.

                    The 1918 flu once disappeared (around 1950), reappeared later
                    (likely from a lab) and now circulating.

                    What if some
                    populations (due to genetic diversity) are more resistant (not all
                    infected individuals die, but can excrete substantial amount of the
                    virus) — we probably need a more complex view.

                    I’ve noticed that this possibility is a real concern. If such
                    individuals (or individuals of different species) are sporadic, we
                    don’t need to worry. But if chains of such individuals are
                    established? — This corresponds to the “percolation theory”.
                    (You may have read Simon Levin’s “Fragile Dominion” or Kauffman’s
                    “At Home in the Universe” in relation to percolation leading to
                    phase transition and its role in ecosystem).

                    > Well, not sure if water-borne disease should be more specialised to
                    this transmission route, between humans. Like cholera.
                    And like cholera, can’t imagine it becoming widespread, but more in few
                    places w bad sanitation.
                    Worst SARS outbreak outside hospital (that we know of) was evidently
                    from sewage (apparently from toilet, somehow reached people’s showers,
                    and several people infected in an apartment block). Looked scary, but
                    proved isolated.

                    Natural selection works as if a pathogen is seeking for a higher basic
                    reproduction number (not plainly necessarily less lethal). If a pathogen
                    has an ability to spread in a more efficient way, this would become
                    a primary route of transmission. If the virus replicates in intestines
                    or kidneys, sewage would be an efficient place for viral adaptation
                    (much resembling avian infections??).

                    > As discussed, I don’t believe Osterholm is correct re predictions.

                    > What may happen though, is that if get pandemic – and no matter if it’s
                    relatively mild – panic will lead to problems.
                    Already too many problems (such as worry, Tamiflu stocking etc), even
                    in US – where no H5N1, just fear of the disease.

                    As we know, our existence is dependent on the present biodiversity
                    — a product of ecosystem evolution, to which we best adapt.
                    We don’t know when our present existence is threatened how much and
                    how rapidly biodiversity is degraded, but there should be some number
                    (not easily predicted). The same is true for our society; our life
                    is dependent on the present social system — a product of social
                    evolution, to which we best adapt. We don’t know when our present
                    world is threatened how much and how rapidly social system is degraded.
                    These two problems are alike, both arising from a complex adaptive
                    system. Complex social systems could amplify the effect of a minor

                    Time-scales also play a role. If any change is slow enough, we
                    can, or ecosystem would adapt to a new form. If the change is rapid
                    enough, they may fail. There is a simple physical analogy; the
                    adaptation of gas is limited by the sound speed. If change goes
                    faster than the sound speed, the gas fails to adapt — the net result
                    is a well-known supersonic shock. The same would be true for our
                    society. If the spread of the pandemic is rapid enough, our system
                    would fail to adapt. Of course, with the advent of the internet,
                    we have a better chance of adaptation before the wave comes. But the
                    expected result of adaptation is so drastically different from the
                    current social system, the arrival of pandemic flu will trigger
                    a reaction that looks like to change the world overnight.
                    I’m skeptical about such a drastic change in social systems could be
                    done overnight (even officials declare “immediately”), since no one
                    is accustomed to the change, and expect the situations something
                    between adapted (with a drastic change) to less-adapted (little
                    reaction before the wave reaches, and an immediate panic is

                    Post edited by: martin, at: 2006/02/02 00:49

                    Martin W

                      Right, time to break things up a little; still re the above correspondence, but here, some comments from Wendy Orent:

                      Dear Martin,

                      These are all good questions. I wish we could make it clear to
                      everyone that it isn’t crowding, per se, that is the crucial
                      condition. It’s the ability to transmit the germ repeatedly from
                      immobilized hosts to the well. People can be packed like sardines on
                      a train, subway, or plane, even for many hours, and not do anything
                      to advance the virulence of a respiratory pathogen like influenza. If
                      you’re that deathly ill, you are not getting on the plane, unless
                      you’re carried on. Even if that happened, and a number of people
                      caught a disease like that, whatever they caught would quickly lose
                      virulence – unless you kept people packed in together for weeks, or
                      months, or whatever it ttakes – no one knows. I.e., you’d need a
                      disease factory to develop virulence and transmissibility, and to
                      keep it going. I can’t think of any disease factory conditions on the
                      planet right not – World War One doesn’t happen frequently.
                      The whole plane thing is a red herring. We are not talking about
                      spreading a disease around the world; we’re talking about the
                      evolution of virulence. That is not going to happen on a plane in
                      normal circumstances – I mean, absent a plane getting hijacked with
                      someone deathly ill on board, and keeping people trapped on boared
                      with that person for weeks. Even then, it’s iffy…we don’t know how
                      long the evolution of virulence, or of transmissibility, takes.

                      As for contagiousness before symptoms: people love to trot that out.
                      But how does it work? You really can’t shed too much virus if there
                      isn’t a huge buildup in your upper respiratory tract. You might be a
                      little contagious, but only a little. It’s the symptoms that make you
                      contagious – the sneezing, the coughing – the virus’s little way of
                      making its host shed it into the world, where it hopes, so to speak,
                      someone else will pick it up. Anyway, the severest disease appears to
                      be that where the virus or bacterium replicates most quickly and
                      exploits the host’s tissues most thoroughly. It doesn’t give itself
                      the long window of being shed. Plague – the right sort of plague
                      (from marmots), not all plague – was pretty good at this – it’s
                      what’s been called a “stealth infection” – it suppresses the immune
                      response, inflammation, fever, everything – so the body doesn’t know
                      it’s under siege. That’s what people appear to keel over and die so
                      suddenly from pneumonic plague. They’re half dead while they’re still
                      walking around. But they aren’t shedding that much virulent bacteria
                      for all that time – their lungs have to get pretty destroyed before
                      they start coughing the blood-tinged sputum that’s infectious. That’s
                      plague – that’s not flu…you’d cough earlier in flu, but it’s just
                      not that deadly a disease – even 1918 killed 2-5% of its victims
                      (pneumonic plague kills 99.9% – it’s too lethal to people to exist
                      for long as a human-adapted disease.) So rule of thumb is –
                      contagiousness before symptoms is almost an oxymoron – you’d have to
                      be sneezing or coughing, at the least, to shed a lot of bugs. I
                      imagine that the deadlier the disease, the shorter the window of
                      contagiousness while you’re still up and walking around. Point being:
                      people with deadly flu aren’t going to be shedding it for very long
                      before they’re wiped off their feet.

                      You’re completely right about the wild birds, though I think the
                      Gaussian thing might be a red herring (though it’s also possible I
                      don’t clearly understand what you meant. It isn’t a question of the
                      mean in natural selection.) The thing is, wild birds can catch
                      high-path flu, die of it, even spread it a little, LOCALLY – but they
                      CAN’T maintain it. High-path flu can’t survive the sieve of natural

                      > Rather as I’m also sceptical re vaccinations, perhaps helping
                      sustain h5n1 (when vaccinations and surveillance less than near
                      A GOOD vaccine would be the way to go, if we had one – but for what
                      disease? Human-adapted H5N1 doesn’t exist yet, and no one knows what
                      it would look like if it did.

                      (I’d meant I was sceptical re vaccinations for poultry)

                      Equilibrium theory is for sure a red herring. Selection works on the
                      level of the individual organism or the individual strain or genetic
                      line – not on the population or species. A non-pathogenic strain in
                      people would mean that the virus wouldn’t get shed – it’s got to make
                      you sick to make you shed X;{ , or we’d all be infected with scads of
                      things we just pass around all the time, without ever getting sick
                      (some things, like staph epidermidis, do probably pass around this
                      way.) But wild birds just pass the bug in their feces – harmless
                      intestinal bugs, like most enteroviruses in people.
                      Martin W

                        back to “a correspondent”:

                        We need a genetic explanation. Like Niman and ProMED, some people
                        regard the genetic similarity as evidence for migration theory.
                        My genetic interpretation is completely the reverse. The lack of
                        genetic variation is a result of “no natural selection” (evolutionary
                        stasis), i.e. the observed similarity is a genetic proof against wild
                        birds as vectors. Such a degree of “no natural selection” (as well as
                        the lack of reassortment) certainly requires artificial environment,
                        i.e. poultry. Wouldn’t that be a breakthrough? What we need is an
                        expert’s verification.
                        I have been just informed of a domestic TV program tonight,
                        highlighting “novel transmission ways” of flu. According to the
                        program, two new ways will be presented: mildly symptomatic people
                        (less immune reaction) and Tamiflu-treated people (I have read
                        numerous reports Tamiflu-treated mildly symptomatic people enter
                        crowds, spreading the virus). The can easily become “transmission
                        hubs”, making the spread easier and more preserving the virulence.

                        Wendy again:

                        Nah, this doesn’t work at all. Mildly symptomatic people will produce mild strains…the disease will move towards mildness. That’s the whole point of Ewald’s argument. I don’t know how much Tamiful treatment changes this picture – very little, I would think. The “less immune reaction” is a complete red herring. Less immune reaction is caused by a less virulent strain. In all cases, having people well enough to walk about will only decrease virulence, not maintain it or add to it. I suspect Tamiful-treated people will just recover more quickly and be less effective transmitters – remember, the virus has got to make you sick – coughing and sneezing- to get itself out and into someone else.

                        and correspondent:

                        Not all individuals react to the same (or similar) strain in the
                        same way. While the virus is less virulent to some people, there
                        still remains a possibility of a higher virulence to the rest.
                        (We already know the present H5N1 has shown different reactions to
                        different ages, but the reason is unknown. An asymptomatic crow
                        infection, with systemic viral replication, is already experimentally
                        known, which excreted sufficient viral load to infect other birds.
                        This shows less symptomatic populations in the same species can emerge).

                        By the way, I am not trying to argue “how dangerous the virus is”,
                        but Ewald’s argument expects the “expected mean”, not clearly directed
                        to the “potential upper limit”. Predictions assuming some kind of
                        an equilibrium or “mean field approximation” would fail in certain
                        conditions, especially there is a background variation (different
                        responses in populations). This is the very point recently targeted
                        by the complex network theory or modern numerical ecology.

                        Martin W

                          From further email from Wendy Orent:

                          Natural selection works on a genetic and individual level, not a population level. When you are talking about viruses, think of a swarm of strains, some of which are going to be more effective under the particular conditions they find themselves in (a host, or group of hosts, under particular ecological conditions.)

                          These influenza strains (say) are all madly jockeying, so to speak, to outreproduce each other (of course, this intentionality is strictly metaphorical.) Now, let’s say we are talking about a population of wild ducks who are infested with low-path H5N1. If there is a wide range of strains within duck A, those strains best at exploiting that duck’s body will reproduce better and faster and more effectively than milder strains. So, in the competition to use up the duck, so to speak, MORE virulent strains will win out.

                          Now, here’s the thing. That duck is dead – wiped out, gone. But duck B, which happened to get a smaller or a milder set of strains, doesn’t die; he lives to pass whatever virus he is dealing with to ducks C and D. So those milder strains are going to win out – and spread through the duck population. It has nothing to do with equilibrium – only with the balance between within host and outside-host competition. You sometimes do find dead ducks in the wild, because natural selection is blind as a cavefish and can’t see what’s going to happen a duck or so down the road. If you get a mutant that increases virulence, that will put virulent strains at a temporary advantage. But that virulent strain won’t spread – that’s why Ewald speaks of the “sieve of natural selection” when he talks about flu in wild migrating birds.

                          Change the conditions, and you change the equation – that’s the point of “disease factory” conditions – you remove the penalties on viruses for being virulent.

                          Post edited by: martin, at: 2006/02/06 00:13

                          Martin W

                            Perhaps useful article, originally in Fortune:
                            How disease evolves


                            natural selection doesn’t favor very vicious bugs when transmission from sick hosts is difficult, for the hosts literally become dead ends before the bugs can leap to others. In such cases, milder strains tend to become the dominant ones in circulation.

                            Which in case of bird flu, is roughly summarised by Dead Ducks Don’t Fly :)

                            (Even though dead ducks n other birds said to be spreading H5N1)

                            Martin W

                              whew! – correspondence on this topic getting pretty long, but may be some useful guff within.

                              Another email from me, to Wendy Orent:

                              “Change the conditions, and you change the equation” looks to me like what I know of re equilibrium (from physical chemistry).

                              As you say, each strain (even indiv virus) responds to conditions: important here, what’s likelihood it can be passed to another host. Then, as many different strains/individual viruses, see an overall picture, a population.
                              To me, seems similar to ensemble (I think that called – some time ago now!) in phys chem. Whole lot of possible states – perhaps of atoms or molecules; as change one or more important variables, change likelihood of occurrence of each of them, and get shift in overall population.

                              So with ducks, being stubborn here (!), we see equilibrium for reasons you note: dead ones don’t fly/move, their virus populations go extinct (tho always latent potential for creating them in numbers), and see population of low-path virus.
                              Shove ducks together, so v sick ones can more readily pass high-path strains, and the higher path strains can increase. See a shift in the equilibrium point – overall virus population moves to higher path, tho still a mix, with potential to have lower path virus as well as higher path.
                              Move back to having ducks in wild conditions, needing to fly to transmit, and those higher path viruses will disappear again, the lower path ones will increase. Equilibrium point shifts back.
                              or am I talking codswallop; hazy thinking this morning for some reason

                              I hadn’t been aware re population biologists thinking on – err – population levels. Whole lot of giraffes growing longer necks, instead of some individuals born with longer, some shorter, and longer more successful (as it looks to me like you’re saying). Curious; treating at population levels would just seem convenient way of achieving some simplification, which could be useful, whilst surely should remain keenly aware of individuals.

                              Wenday again:

                              natural selection isn’t a population-level phenomenon. Evolution is – in the sense that individuals don’t evolve. But selection has everything to do with competition within populations. Population biologists know this, in a sense, but they often don’t keep the levels of selection straight and they keep slipping.

                              The term “equilibrium” as you used it in the last e-mail is very slippery – I think the analogy to chemistry may not be helpful. You do get different strains within a population of hosts, which is why, for example, you can’t just go get a marmot and hope to isolate from that marmot a killer strain of plague – or dig up any old anthrax spores from the soil and think you’re going to get a bioweapon. But that doesn’t mean the strains are in any sort of balance, or that it’s in the least helpful to think of them that way. Viruses are continuously generating variation: some changes will lead to greater virulence, some to less.

                              The reason many are so prone to copying error, which is what mutation is, is that they have to keep changing to meet changing conditions in their host population. (i.e. they might encounter stronger or less-strong immune systems; their hosts might be in a greater or worse position to pass strains on, etc.) Some of these “errors” will benefit the virus in a particular line, and they’ll be selected. That is what adaptation is.

                              You can see that process at work in one or two Turkish cases – scientists found that some of the swarms of strains in the host’s body showed some better adaptation to people. They were better able to adhere to non-ciliated cells (human flu receptors), and they were able to grow higher up in the nasal passages – therefore at cooler temperatures. But the hosts were dead and the new lineages died with them.

                              These results show that the H5N1 virus can adapt, at least a bit, to human beings. There was no reason to think it couldn’t. But you’d need a long chain of human beings passing on these changes from one to another for any real adaptation to occur – i.e. before bird-adapted H5N1 flu became human-adapted H5N1. Could it happen? Yes – if governments keep covering up their bird flu cases. Is it likely? Not very – but it is certainly possible.

                              Surveillance is the single best way to stop it – quarantine would work very well before the virus got very adapted to people. Once it is, you can’t control human-adapted flu with quarantine. But you can BEFORE it gets there. That’s why the phrase “mutate to transmissibility” is so ridiculous. It implies that one or two chance mutations can produce adaptation – in the absence of natural selection.

                              (translation: to “mutate to transmissibility” means that some chicken, somewhere, is carrying a strain that has somehow mutated to be adapted to people. It then infects a person, who passes it on – and bingo. But selection does not and cannot work this way. A change that pre-adapts the strain for human infection and transmissbility cannot survive in chickens. Someone would have to catch it before the miraculously-mutated human-adapted strain got pushed aside by selection for chicken flu within the chicken’s own body. Thinking probabilistically – this chance is, uh, vanishingly small. Not to say non-existent.)

                              You can talke about “evolve to transmissibility” – but that’s a host/pathogen activity – it requires long chains of human beings (no one know how long – but more than a few, simply because so many changes are obviously required.) This process can happen, and has happened, with earlier flus. That is not in doubt. But the human-adapted flu strains will lose virulence, or never evolve it, because of the requirements imposed by transmission. Res ipsa locutor.

                              me again:

                              My equilibrium notions from now somewhat hazy memories of phase space, from lectures. Think I retain the gist, and not slippery.
                              Continuous variation – multitude of potential states – crucial here too. But overall picture not random.

                              Key, perhaps, would be:
                              With flu – would we expect overall virus to have different levels of virulence, which could be predicted if we have all the equations and numbers (surely impossible)?
                              Suppose had variations as follows – and only these variations (would be considerably more complex in practice):

                              Zero or effectively zero probability of spread by immobile carriers.
                              10% probability of spread by immobile carriers
                              30% probability of spread by immobile carriers
                              70% probability of spread by immobile carriers

                              If, over time, virus [as population] would evolve to a certain level of virulence, and maintain it while conditions persist, would surely have equilibrium. (Even though in each case, still potential for individual viruses to replicate to different states. Equilibrium at macro level doesn’t mean that stopped the perpetual mutations etc to various states – it’s just that probabilities individual states can persist/increase have changed.)

                              If levels of virulence of virus population would just fluctuate wildly, not settling over time, then indeed no equilibrium.

                              From all I’d seen before, I’d thought “miraculously-mutated human-adapted strain” was what all disease experts believed in; hadn’t really thought more re this – if WHO etc said it was so that virus could mix in a pig, then go on to devastate humanity, maybe it was so.

                              Back to Wendy:

                              As for equilibrium, I think you make a reasonable argument – and that it is one way to look at what we’re seeing. The problem is that it is a species – or population-level argument – which is not Darwinian. (translation: no traits can evolve or be maintained anywhere, under any circumstances, that are bad for the individual or individual genetic line, and good for the group. Darwin himself that that if one such example could be found, it would destroy his entire theory.

                              Keeping a population at some sort of equilibrium suggests that there is an advantage to the population as a whole in having variants around. Sounds good, but evolution, if you will forgive my putting it so bluntly, doesn’t work that way. Any traits that exist for the benefit of the group that jeopardizes its carrier’s fitness will be swiftly eliminated.

                              Only the traits that enhance their carrier’s fitness will be represented in the next generation – there are accidents, of course, like a tree falling on all the fittest members of the group, but natural selection will zap the less fit in the next generation. Remember that natural selection is not “survival of the fittest” but rather “differential reproduction.” )

                              To say that, for instance, flu viruses in wild birds are essentially stable simply means, from the perspective of evolutionary biology, that the strategy of low virulence continues to work well, and that the environmental conditions the bug finds itself in are stable. It doesn’t mean the bug isn’t just as mutagenic as ever; it’s just that low-pathogenic strains will continue to be at a selective advantage, which keeps the phenotypic variability in check.

                              So from this perspective, “settling over time” just means that the environmental conditions are stable. Certainly viral evolution will occur more quickly as a virus adapts to a new host. The mutation rate doesn’t change, so far as we know, though it might…we just don’t know if there is an actual viral mechanism to increase copying error; it sure sounds unlikely to me, but you never know. But selection pressure is more intense. We could see intensive selection pressure to adapt to human beings – but you’d need a string of human beings, ad seriatum, for the virus to adapt to.

                              Have I misunderstood anything in your argument? Please let me know.

                              to which I added:
                              What you write doesn’t seem at variance with my picture, deluded as I may be!
                              Equilibrium at macro level doesn’t mean all is nice n stable for individual viruses.

                              Phase space, as I recall rather more dimly than i might wish, partly about probabilities for individual states.

                              So here with flu, there’s a host of probabilities for forms a virus might take – here, only worrying re those that are more or less virulent (but surely others that better for being passed on, several that utterly useless).
                              All occurring – so with a virus, surely can have carriers lacking fitness for being passed on, for replicating. Not many of them, and as they are dead ends with normal conditions (virus that could wipe out the planet, say), they remain tiny populations, so nigh on invisible when look at population as a whole.
                              Can get “sports” in larger animals – birds with oddly curved mandibles etc, but v few (large animal populations tiny compared to viruses), and not surviving long enough or well enough to continue. So, see variations around some kind of mean.
                              But, one example known in UK is a moth: usually pale, resting on silver birch during day; a few dark variants. Add pollution, darken trees, get more predation of normal light form, and dark form became dominant near factories etc.

                              Change the conditions w virus, here to immobile carriers, and those rare mutations leading to increased virulence can increase, as they are passed on, can multiply; so virus as a whole becomes more virulent. Still all the mutations happening.
                              Reduce immobile carrier transmission, and these virulent forms become scarcer again, the virus back to low virulence.

                              HIV again: i saw re drug resistant strains appearing in people taking drugs. Again, surely v rare normally – maybe examine the virus population and wouldn’t notice them. But, when regular HIV blocked, the resistant strains become dominant (which to me looks like shift in equilibrium point).
                              Stop the drugs with this person, and evolves back again, so that later can again use the drugs.

                              Post edited by: martin, at: 2006/02/09 12:26

                              Martin W

                                more from a correspondent:

                                Perhaps you know this “experimental” incidence (coevolution
                                of pathogens with hosts):

                                “Myxoma Virus and Rabbits”

                                This example was also referred to by our specialist in predicting
                                the future of H5N1, but he said “there is a tendency like this,
                                but uncertainties remain”. This myxoma virus (though it’a a vector-
                                mediated) once got less lethal, but regained half-lethal, perhaps
                                a result of some sort of host-pathogen equilibrium. A frequently
                                cited example in an ecology textbook.

                                Yet another – evolution of host-pathogen relation, and
                                possible emergence of virulence from population structure:

                                “Large Shifts in Pathogen Virulence Relate to Host Population

                                Here we show that rapid evolution of virulence can occur as
                                a consequence of bistability in the evolutionary dynamics of
                                pathogens associated with changes in host social structure.

                                Martin W

                                  Article by Paul Ewald on website of the Edge Foundation, in answer to question re what’s his dangerous idea includes:

                                  Today experts on infectious diseases and institutions entrusted to protect and improve human health sound the alarm in response to each novel threat. The current fears over a devastating pandemic of bird flu is a case in point. Some of the loudest voices offer a simplistic argument: failing to prepare for the worst-case scenarios is irresponsible and dangerous. This criticism has been recently leveled at me and others who question expert proclamations, such as those from the World Health Organization and the Centers for Disease Control.

                                  These proclamations inform us that H5N1 bird flu virus poses an imminent threat of an influenza pandemic similar to or even worse than the 1918 pandemic. I have decreased my popularity in such circles by suggesting that the threat of this scenario is essentially nonexistent. In brief I argue that the 1918 influenza viruses evolved their unique combination of high virulence and high transmissibility in the conditions at the Western Front of World War I.

                                  A New Golden Age of Medicine

                                  Martin W

                                    after I posted little info to a discussion group re H5N1 and conservation, this message from a virologist:

                                    Just a little point about influenza in humans- transmission is largely before any illness, as the peak of viral shedding occurrs before interferon release and the specific immune response e.g. T-cell response. This curtails viral replication and reduces shedding.

                                    Any person admitted to hospital ill from influenza will have already transmitted the virus to another/s. The epidemic peak is very sharp in human influenza and it is probably the percentage of immune individuals in the population that brings the epidemic to an end. Therefore I don’t agree with your evolutionary biology idea.

                                    It may be that the number of immune persons in the population after the circulation of the virus for a year forced changes in the HA molecule to escape from neutralising antibody and this had an effect on the virulence of H1N1 but the reason for the virulence of that virus and why it arose and then changed is I believe not known.

                                    I sent a reply:

                                    – evolutionary biology not my idea!

                                    Is peak of shedding always before main symptoms? I know little of this, but some info from WHO suggests virus shedding peaks with symptoms.
                                    How do asymptomatic people transmit virus – just by talking (if not coughing, sneezing)? – and if lower probability of transmission this way, might this have an impact on virus evolution? – to evolve/sustain a virulent flu, maybe need fair percentage of those infected to be able to transmit to others?
                                    Sadly, I’ve seen only fairly brief info from Paul Ewald, not his book, Evolution of Infectious Diseases.

                                    also contacted Wendy Orent, who responded:

                                    I believe she is incorrect about transmission before any illness. There may be (in human influenza after it is fully adapted to the human species) some slight transmission before symptoms set in. But not much. It would have to be shed by breathing and talking – these are not efficient means of transmission. What are symptoms for? Why do we ccough and sneeze?/ Viruses settle in the upper airways and irritate us precisely in order to get us to cough and sneeze. In certain diseases, measles for instance, you transmit fairly early in the course of the disease, before you’re bed-ridden. Measles makes you sneeze. But you are still symptomatic!

                                    Of course, before the disease has adapted to human beings, transmission tends to happen late in the illness, e.g. SARS. Had SARS continued to transmit, it would have adapted to people by becoming a more efficient shedder and spreading earlier in the course of the infection – it would have evolved to mildness like all coronaviruses, which are just common colds in people. It didn’t have that chance – it was wiped out before it became efficiently transmissible.

                                    Just read your answer [after I’d sent in second email], and you are absolutely right – except for the bit about the “fair percentage” – I think you are still thinking in population terms.

                                    She is also, I believe, incorrect about the “not known.” We have a very good idea why the virulence evolved, and why it diminished over time.

                                    [As noted above hin this thread I believe, but I sent to discussion group, maybe useful as summary:] I learned of evolutionary biology and diseases thro Wendy; don’t know all about it by any means (must read Ewald’s book!) – till then believed a monster human h5n1 pandemic flu was imminent. But to me, seems good, and explains a few things re flu that I’d otherwise find puzzling:
                                    – 1918 flu occurring at same time as major world war (with trench warfare)
                                    – human flus otherwise normally of low virulence
                                    – wild avian flus mild (maybe even 1961 in S Africa common terns was from farms)
                                    – ready transformation of wild flus in poultry farms, to viruses that are highly pathogenic for poultry (and, now, wild birds)
                                    – inability of wild birds to sustain HPAIs (not just H5N1)

                                    To me interesting that when Wendy mentioned to Paul Ewald re some ducks being able to survive H5N1, he predicted they shed only low amounts, as observed.

                                    Martin W

                                      Further evidence of evolutionary biology at work in poultry farms comes from UK's H7N3 outbreak. (Not conclusive here, but fits evol biology – as ever with flu.)

                                      Birds on the free range unit, however, suffered only a mild form of the flu and none died from the infection…. the virus was transported from the egg farm to the Banhams chicken farm, where it killed some 400 chickens and triggered a drop in egg production by other birds.

                                      note also, from intensive farms:

                                      Blood samples from birds on their farm showed that they had been exposed to the H7N3 virus as long ago as four weeks.

                                      – during which, presumably, the virus evolved towards virulence in the "disease factories" Vets track spread of bird flu strain

                                      Martin W

                                        Article by Wendy Orent, in LA Times, includes:

                                        … the factors that set off a pandemic remain unknown. No one has ever tracked the evolution of a new pandemic. All we have seen — in 1918, 1957 and 1968 — is the aftermath of that evolution. Still, we are told that all it would take for H5N1 to become a pandemic would be for the virus to mutate so it could spread in a sustained way from person to person. This is known as "mutation to transmissibility." … The H5N1 virus faces several barriers in jumping to and transmitting among humans. The most important is its ability to replicate in and adapt to human tissues, specifically the upper respiratory tract (not in deep lung tissue, where it now seems to grow). In the windpipe, the virus would be more likely to spread in a cough or sneeze, infecting other humans. …

                                        [Earl] Brown recognizes what seems to elude most people who worry about pandemic outbreaks: What's necessary to produce a human-adapted virus is humans — a series of person-to-person infections. Without that chain of transmission, any human adaptation of H5N1 is difficult to imagine. … interact with other viral genes in a human host to improve its ability to infect the host. This is an adaptive process — and it is true whether the new virus arises directly through mutation or even through recombination with a common flu strain. H5N1 is beautifully, tragically adapted to chickens and has proved a monstrous predator. It evolved this way by preying on chickens packed into huge commercial chicken farms in Asia. The bird flu virus is still at the starting gate when it comes to humans. But should any strain of H5N1 manage to survive many sequential transmissions, Darwin's charioteer may drive off. The best transmitters will be favored by selection, as evolutionary biologist Paul W. Ewald of the University of Louisville contends. The process will continue, human by human, until a fully human-adapted, explosive strain emerges. …

                                        At the beginning, viral adaptation to a host is slow. A disease just beginning to transmit is controllable. Surveillance, flexibility, willingness to impose or undergo quarantines, along with international cooperation, will be necessary to stop pandemic flu — or any other disease moving from animals to humans — before Darwin's driver gets ahead of us and nothing can be done.

                                        What Darwin has to say about bird flu Can the disease mutate into a widespread threat to humans? Possibly, but it won't happen overnight.

                                        I emailed Wendy to check whether this rather ominous last sentence (and "explosive strain") meant some change in her thinking re not being possible right now to evolve a virulent flu.

                                        Her reply:

                                        No, I haven't changed my position. A pandemic (without WWI etc. conditions) would NOT be a lethal pandemic – just an ordinary one, like 57 or 68. And quarantine would work in the early stages, as the virus adapts. An explosive strain merely means a highly transmissible strain, not a lethal strain. I am afraid many people may understand this the way you did. It's actually the same argument I've been making for years – just another piece of it. It would be awful if people think I've changed my position, under pressure maybe. Not at all. I haven't changed a bit – I just wanted to show why the phrase "mutate to transmissibility" is essentially meaningless, and that the evolution of any pandemic would have to come through natural selection. That's how it happened in the past; that's how it could happen in the future.

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