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  • Blog - The problems with Barry’s “The Great Influenza”

    The problems with Barry’s “The Great Influenza”
    by Vincent Racaniello on 14 August 2009

    When the 2009 H1N1 pandemic influenza virus emerged earlier this year, I began re-reading John Barry’s The Great Influenza. I came across the sentences that I had underlined during my first read identifying errors in basic virology. Because this is a very popular book, it’s important to identify the mistakes and correct them.

    Barry is not a virologist, or any type of scientist. He’s a historian who happens to have written on influenza. This does not excuse the virological errors in his book; he should have had a virologist fact-check the manuscript before publication.

    Page citations refer to the Penguin Books paperbound version.

    When a virus successfully invades a cell, it inserts its own genes into the cell’s genome, and the viral genes seize control from the cell’s own genes. [page 100]

    This sentence implies that the reproductive cycle of every virus includes integration of the genome into that of the host. Barry’s statement is incorrect; only genomes of certain viruses (e.g. retroviruses) are introduced into the host DNA.

    Soon a pit forms in the cell membrane beneath the virus, and the virus slips through the pit to enter entirely within the cell… [page 103]

    Only some viruses enter the cell from the ‘pit’ formed at the plasma membrane. In many cases the ‘pit’ eventually becomes a vesicle known as an endosome which moves deep into the cytoplasm. Influenza viruses enter cells from endosomes.

    If for some reason the influenza virus cannot penetrate the cell membrane, it can detach itself and then bind to another cell that it can penetrate. Few other viruses can do this. [page 104]

    I presume Barry is referring to the ability of influenza NA to remove sialic acids from the cell surface, thereby liberating surface-bound virions. Other viruses have this ability. Viruses that do not possess a neuraminidase probably have other ways to leave the cell surface, such as a weak virus-receptor interaction.

    The following description concerns the entry of influenza virus into cells:

    Inside this vesicle, this bubble, shape and form shift and create new possibilities as the hemagglutinin faces a more acidic environment. This acidity makes it cleave in two and refold itself into an entirely different shape. [page 104]

    Cleavage of the HA does not occur during endosomal entry. Whether or not the viral HA is cleaved (which is required for infectivity) is determined during assembly of the virus particle.

    In the following sentence, Barry seems intent on making a retrovirus out of influenza virus:

    Soon the genes of the virus spill into the cell, then penetrate to the cell nucleus, insert themselves into the cell’s genome, displace some of the cell’s own genes, and begin issuing orders. [page 104]

    The influenza virus genome does not integrate into the DNA of the host cell, as noted above.

    The neuraminidase guarantees that new viruses can escape to invade other cells. Again, few viruses do anything similar. [page 104]

    Members of other virus families do have neuraminidases which probably serve similar functions during infection as the influenza NA. It’s not correct to write that ‘few’ viruses do anything similar.

    Antibodies, for example, carry thousands of receptors on their surface to recognize and bind to a target antigen. [page 108]

    A single antibody does not have the ability to bind thousands of antigens; only one. Collectively, antibodies can recognize thousands of epitopes.

    Dendritic cells attack bacteria and viruses indiscriminately, engulf them, then “process” their antigens and “present” those antigens – in effect they chop up an invading microorganism into pieces and display the antigens like a trophy flag. [page 108]

    Dendritic cells don’t engulf viruses and bacteria – they take up extracellular proteins by endocytosis, then display them to lymphocytes. Perhaps Barry is thinking of phagocytic cells such as macrophages.

    But of all parts of the influenza virus that mutate, the hemagglutinin and neuraminidase mutate the fastest. [page 109]

    The mutation rate of all influenza virus RNA segments is similar. What Barry means is that the HA and NA proteins vary more than do other viral proteins. This is because the HA and NA are structurally plastic and can accommodate amino acid substitutions. Changes in the protein are not mutations; this term refers specifically to nucleic acid.

    When an organism of weak pathogenicity passes from living animal to living animal, it reproduces more proficiently, growing and spreading more efficiently. This often increases virulence. [page 177]

    These conclusions simply are not correct. I discussed this issue previously.

    Initially Ebola has extremely high mortality rates, but after it goes through several generations of human passages, it becomes far milder and not particularly threatening. [page 177]

    One of the problems with The Great Influenza is that statements such as this one are not supported by literature references. There has been so little person to person spread of ebolavirus that this conclusion cannot be made.

    The following statements that implies that there were multiple waves of influenza in 1918 accompanied by mutation to higher and then lower virulence:

    All over the world, the virus was adapting to humans, achieving maximum efficiency. And all over the world, the virus was turning lethal. [page 193]

    Even when the virus mutated toward mildness, it still killed efficiently. [page 363]

    At first those processes had made the virus more lethal. Whether it first jumped from an animal host to man in Kansas or in some other place, as it passed from person to person it adapted to its new host, became increasingly efficient in its ability to infect, and changed from the virus that caused a generally mild first wave of the disease in the spring of 1918 to the lethal and explosive killer of the second wave in the fall. [page 370]

    As time went on, it became less lethal. [page 371]

    But it mutated enough, its antigens drifted enough, to rekindle the epidemic. [page 373]

    It continued to attack, but with far less virulence, partly because the virus mutated further toward its mean, toward the behavior of most influenza viruses. [391]

    As I’ve written before, we have no evidence for an increase or decrease of the 1918 virus with time, because there are no virus isolates other than one reconstructed from November 1918. All these statements are therefore without any proof and remain highly speculative.

    It’s not my intent to severely criticize the book – it’s a compelling description of a very serious pandemic. I simply want to ensure that everyone understands the scientific underpinnings of the outbreak. When authors write about science for a general audience, they have an obligation to get the science right.

    http://www.virology.ws/2009/08/14/th...eat-influenza/
    "Safety and security don't just happen, they are the result of collective consensus and public investment. We owe our children, the most vulnerable citizens in our society, a life free of violence and fear."
    -Nelson Mandela

  • #2
    Re: The problems with Barry’s “The Great Influenza”

    John Barry radio interview this week:

    http://www.radiosandysprings.com/sho...nfectious2.php
    "May the long time sun
    Shine upon you,
    All love surround you,
    And the pure light within you
    Guide your way on."

    "Where your talents and the needs of the world cross, lies your calling."
    Aristotle

    “In a gentle way, you can shake the world.”
    Mohandas Gandhi

    Be the light that is within.

    Comment


    • #3
      Re: The problems with Barry’s “The Great Influenza”

      someone (Racaniello ?) please rewrite chapter 7

      or make a wiki
      I'm interested in expert panflu damage estimates
      my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

      Comment


      • #4
        Re: The problems with Barry’s “The Great Influenza”

        Originally posted by gsgs View Post
        someone (Racaniello ?) please rewrite chapter 7

        or make a wiki
        Perhaps someone besides Vincent. Some of what he writes makes very little sense. At least Barry is understandable, even though he may sometimes be wrong.

        Comment


        • #5
          Re: Blog - The problems with Barry’s “The Great Influenza”

          I'm John Barry and plan to post a more detailed reply in the future-- if anyone still cares. However, let me respond briefly here.

          First, I certainly know the difference between a retrovirus and other viruses. In fact, nearly 20 years ago I co-authored a book with Steve Rosenberg, who while best known for his work pioneering immunotherapy for cancer also participated in the first sanctioned gene therapy experiments, and he used a retrovirus as a vector to insert the therapeutic gene into the genome. I was present as an observer at some of those experiments. I thank my critic for pointing out the imprecision of my language. In future printings of the book, this will be corrected. Any other factual error will also be corrected.

          But most of his comments reflect either errors on his part-- such as on dendritic cells, some of which (although not all) do do what the book says they do-- willful misreading of the book, overkill on the interpretation of relative statement (such as just what "a few" means), or matters of opinion. I will limit my response now to the most important point he raises-- since it's the only one that is relevant to our present predicament.

          He disputes my hypothesis that the H1N1 of 1918 changed virulence from spring to fall. He starts out by attacking my comments on passage. The point the book makes about passage is absolutely accurate. When an organism enters a new environment, it adapts. As the book says, sometimes an organism increases virulence, sometimes it decreases. Sometimes other aspects change. The polio virus investigators worked with was grown in nerve tissue so long in the lab, people believed it would only grow in nerve tissue. Several investigators even proved that was the case-- and it was the case for the lab virus, which through passage had lost abilities that wild virus had. Enders won a Nobel Prize because he did not believe that proof.

          Back to whether influenza changed virulence in 1918: My critic mentions Taubenberger's recent article in this regard, suggesting that it did not. My critic's and Taubenberger's chief complaint seems to be that there's no molecular evidence that the spring and fall waves were caused by the same virus. But since the first wave was generally so mild, and killed so few-- the British Grand Fleet, which patrolled the coast of Europe, saw 10,313 cases but suffered only 4 deaths-- it's unlikely we'll ever get enough molecular evidence to prove or disprove this opinion. Nonetheless, he seems to feel that only molecular evidence matters.

          Yet the reality is even molecular evidence would not be conclusive. If we had a sample from the spring and it was the same H1N1 virus as the fall, all that would prove was that the fall virus did circulate in the spring. It would not prove that the fall virus caused the spring wave. Similarly, if the spring sample was not H1N1, that would only prove that that single sample was not. We would expect a new pandemic virus to co-circulate with the old virus initially. How many samples would it take to prove things one way or another? More than we are likely ever to get.

          I think the evidence is very strong that the spring wave in 1918 was caused by the same virus as the second wave, and hence that virulence did change. This evidence is epidemiological, but it is in my opinion compelling.

          There is no doubt a new pandemic virus erupted in the spring, long before "late June" when Taubenberger's article is willing concede that a pandemic began. In fact, the pandemic picked up its name "Spanish Influenza" when it struck Spain-- in May, before Taubenberger agrees that a pandemic existed. There were many contemporaneous journal articles about the spring wave published in the literature all over the world.

          So there are two possibilites. Either one pandemic virus was supplanted by another, or the same virus caused both waves. The first hypothesis is possible, and many people now fear that H1N1 could be supplanted by an H5N1 pandemc (or by a reassortant of H1 and H5, or another reassortant, or by an entirely different virus). But this seems quite unlikely.

          More importantly, there is overwhelming evidence that spring wave exposure provided protection against the lethal wave. This protection was much greater than can be explained by the cross-protection that one strain might provide another. In fact it was equal to or better than a good modern vaccine. A modern vaccine is considered decent at 70% effectiveness, and a few years ago the vaccine was only 44% effetcive. Spring exposure protected against the fall wave often with 80-90% effectiveness. I wrote about this at length. See: Barry, JM, Viboud, C, Simonsen, L,, Cross Protection Between Successive Waves of the 1918-19 Influenza Pandemic: Epidemiological Evidence from US Army Camps and Britain, J Infect Dis. 2008 Nov 15;198(10):1427-34.

          I wrote that article hoping to convince those who speculated that the waves were caused by different viruses that they were wrong. Apparently I was unsuccessful in this.

          Those who argue the virus did not change virulence in 1918 are not being logical. They're being tautological. They are saying that influenza viruses don't change virulence; waves in 1918 were of different virulence; therefore the viruses were different.

          There are other puzzling instances besides 1918 that suggest the influenza virus has changed. Going backwards in time:

          In July 2002 in Madagascar, influenza suddenly attacked several provinces; morbidity reached as high as 70% in some towns and a death toll suggestive of 1918. (many references, see for example MMWR, November 15, 2002 / 51(45);1016-1018.) World Health Organization experts, worried that it was a new pandemic virus, immediately investigated. It was not a new pandemic virus. It turned out to be ordinary seasonal influenza, H3N2/1999/panama, which soon returned to its ordinary ways after affecting only 11 of 113 health districts in Madagascar. Coming 34 years after H3N2 started circulating, there is no adequate explanation for this.Some have argued this region was particularly stressed by civil war and malnourishment, but much of the world is under such stresses and no similar influenza outbreaks ahve been noted. So regular seasonal influenza has shown the ability to fire lethal bursts.

          In the 1968 pandemic, 70% of the mortality in the US occurred in 1968-69, and 30% occurred in 1969-70. In Europe it was the precise opposite. (Viboud, et al, Multinational Impact of the 1968 Influenza Pandemic: Evidence for a Smoldering Pandemic, Jour. Inf. Dis., 2005:192 (15 July), 233-248.) There are speculative explanations of such an occurrence that do not include changes in the virus, but a change in the virus has to be a possible explanation. All are speculative. And in 1957 CDC (CDC had a different name then but the same initials) investigators speculated that the virus "had increased in virulence" to account for mortality in 1958 despite less morbidity (Trotter, Yates, et al, Asian Influenza in the United States, 1957-58, Am. Jour. Hygiene, 1959, vol 70, 34-50). And the 1889 pandemic began in May of that year, but it was not truly pandemic. A contemporary invetsigator wrote, “In 1890 the influenza outbreaks were as a rule single or isolated and occurred in only a few places in Europe, particularly in Lisbon, Nuremberg, Paris, Copenhagen, London, etc.” And a different investigator said it was not for two more years before, “The third real epidemic spread of influenza was a true pandemic which began in October 1891 and lasted through the whole winter until the spring of 1892.” (WT Vaughan, Influenza, 1921, 45-46.) It's not clear if it increased in virulence (though the third wave was the worst), but it certainly seems to have increased its ability to infect people.

          Did the 1918 virus increase in virulence? We will never know with certainty. But until H5N1 surfaced, most people did not believe influenza could jump directly from birds to people either.
          Last edited by JMBarry; August 16th, 2009, 11:29 AM. Reason: changed comments

          Comment


          • #6
            Re: Blog - The problems with Barry’s “The Great Influenza”

            Welcome and thank you for responding John.
            "May the long time sun
            Shine upon you,
            All love surround you,
            And the pure light within you
            Guide your way on."

            "Where your talents and the needs of the world cross, lies your calling."
            Aristotle

            “In a gentle way, you can shake the world.”
            Mohandas Gandhi

            Be the light that is within.

            Comment


            • #7
              Re: Blog - The problems with Barry’s “The Great Influenza”

              Firstly, I would like to express my congratulation to Mr Barry for his great work in historical research and for better knowledge of the great public about Spanish Influenza pandemic in 1918.

              I am also pleased you have joined at least for a moment to our ''circle'' of flubies.

              That said, I think that a lot remains to be known about viruses in general and influenza viruses in special.

              Those researchers that pointed as less likely a 1918 scenario for current 2009 pandemic perhaps have a in depht knowledge about biological properties of the re-constructed 1918-H1N1 virus.

              So, we have a group of people that continues to highlight a prudent position about pandemic prediction and on the other hand, we have the need to be prepared for a worst case scenario, even the term ''worst'' could not mean anything else if not a 1918-pandemic re-run.

              We know that influenza viruses have been for a long time a ''neglected'' pathogens, since most of the scientific establishment denied a pharmacological solution for influenza infection.

              Decades passed without significant advances in vaccine manufacturing process or to broad the spectrum of immune response. Very few drugs were developed.

              So, we are now in the midst of a pandemic and we should remain aware of the dramatic past humankind experienced and try to find possible ways to save the higher number of people possible.

              Thank you Mr Barry, again.

              Comment


              • #8
                Re: Blog - The problems with Barry’s “The Great Influenza”

                cooperate to make a better and more updated version of chapter 7 !
                The sources are from 1942,1996,1998, which is old.
                I'd like it to be online, "scientific details to the book" or such
                with discussion and wiki ... see, what wikipedia achieved in the last years
                about flu-science
                I'm interested in expert panflu damage estimates
                my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

                Comment


                • #9
                  Re: Blog - The problems with Barry’s “The Great Influenza”

                  Thank you Mr Barry for bringing such a complicated issue into all of our living rooms in understandable terms, and providing us a sound basis for pandemic preparation and response.

                  Comment


                  • #10
                    Re: Blog - The problems with Barry’s “The Great Influenza”

                    Humbleness is Mass Communication is a Boost that just cannot be bought ot marketing (sorry english is not my language)

                    Thank you for everything Mr Barry you have blaze the Minds of Millions.

                    Please keep on.

                    Snowy Owl

                    With all Heartfelt Respect

                    Comment


                    • #11
                      Re: Blog - The problems with Barry’s “The Great Influenza”

                      Great book, JVBarry.
                      Congratulation!

                      #5: 1918 flu:
                      "More importantly, there is overwhelming evidence that spring wave exposure provided protection against the lethal wave comparable to a very good modern vaccine. I wrote about this at length. See: Barry, JM, Viboud, C, Simonsen, L,, Cross Protection Between Successive Waves of the 1918-19 Influenza Pandemic: Epidemiological Evidence from US Army Camps and Britain, J Infect Dis. 2008 Nov 15;198(10):1427-34. In fact my motivation for writing the article was because I hoped to convince those who speculated the waves were caused by different viruses that they were wrong. Apparently I was unsuccessful in this."

                      Comment


                      • #12
                        Re: Blog - The problems with Barry’s “The Great Influenza”

                        one wave can protect against an entirely different (flu-A) virus.
                        We see it with seasonal flu - there are H3N2-years and H1N1-years
                        one dominates. (except 2007/8 in USA, I think ?)

                        could a good vaccine do the same ? I assume not - it's T-cell
                        immunity (?)
                        I'm interested in expert panflu damage estimates
                        my current links: [url]http://bit.ly/hFI7H[/url] ILI-charts: [url]http://bit.ly/CcRgT[/url]

                        Comment


                        • #13
                          Re: Blog - The problems with Barry’s “The Great Influenza”

                          Gsgs I am sure you are aware of this.

                          When Russian Grippe went pandemic 1889 in Quebec, Catholic Clergy took refuge in Hygiene, hand washing often, coughing properly and no spitting.

                          The daughter of my great-grand-mother was excessive in 1918 on this and none of my grand-mother sisters or brothers got it.

                          Snowy

                          Comment


                          • #14
                            Re: Blog - The problems with Barry’s “The Great Influenza”

                            Welcome Mr. Barry,
                            It is an honor!

                            A quick reply to this comment,

                            But since the first wave was so mild, and killed so few,

                            My great-grandmother died from Spanish Flu March, 1918.

                            Guess i'm related to one of the few!

                            Thank you for all you've done!

                            Comment


                            • #15
                              Re: Blog - The problems with Barry’s “The Great Influenza”

                              Originally posted by gsgs View Post
                              one wave can protect against an entirely different (flu-A) virus.
                              We see it with seasonal flu - there are H3N2-years and H1N1-years
                              one dominates. (except 2007/8 in USA, I think ?)

                              could a good vaccine do the same ? I assume not - it's T-cell
                              immunity (?)
                              T-cells relate to severity, which is why Swine Flu may not currently be a problem for the older generation even though they may become infected with the new virus. The seasonal flu vacs may be providing some protection through the internal gene antigens.

                              But when H3N2 dominates in the US, it is typically a deadly year for flu.

                              Younger folks have not had enough years to accumulate T-cell vaccine protection.

                              Comment

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