Effect Measure

A couple of days ago Dr. Marion Koopmans, chief of virology in the infectious diseases laboratory of the National Institute of Public Health, The Netherlands, notified the infectious disease community through the website/email list ProMed that two of their swine flu isolates showed a particular genetic change in one of the virus’s eight genetic segments. Even though this virus has been described as relatively stable genetically, individual viruses, even within the same patient, often have small differences in the thousands of letters that make up their genetic code. Influenza A virus is a very sloppy reproducer, and while its only objective in life is to make a copy of itself it often does single task very badly. But it’s like the guy who was asked how he could sell his gasoline for a penny less than he paid for it, his answer was, “volume.” The flu virus makes so many copies of itself when it infects a host cell that it can afford to make a lot of mistakes. Usually those mistakes are disastrous for the copy and it doesn’t replicate any more. Very many of the little mistakes are just little mistakes and don’t affect the virus at all. And some of them turn out to be good for the virus and possibly bad for the host in that they allow the virus to replicate faster, infect more and different kinds of cells and increase its ability to transmit from one host organism to another (transmissibility). So research groups like Koopmans’s keep an eye on the genetic make-up of this pandemic virus as it continues to spread globally. Everyone expects it to change and we are getting what we are expecting. So what’s the big deal — if there is one — that caused Koopmans to send around an alert?

It would be nice if we could look at the genetic sequence of the virus and read off its biology. For the most part we can’t. We have only little clues here and there about what makes one flu virus able to infect a bird but not a human or vice versa or both. Or what makes the virus easily transmissible from one person to another or from a bird to a human or a human to a pig. Or what made the 1918 pandemic strain so virulent (able to cause a lot of serious disease) while the usual seasonal flu does so in only a minority of cases. Each time we think we’ve got “the answer” the flu virus crosses us up. Take the mutation in question, designated E627K in PB2. PB2 is a protein coded by one of the flu’s eight genetic segments. It is an abbreviation for polymerase basic protein 2 and is part of a three part package consisting of PB1, PB2 and PA proteins the virus uses to copy its genetic material and translate the genetic material into other proteins it needs (including themselves, i.e., PB1, PB2 and PA). These three proteins work together as a team and interact with another protein (NP) that acts as a structural scaffolding for the genetic material itself, the RNA (humans carry genetic information in DNA but flu viruses use RNA). The E627K mutation means that at position 627 along the amino acid chain that makes up the PB2 protein, one amino acid, glutamic acid. whose one letter abbreviation is E, had been changed to lysine (abbreviation, K). Bird influenza viruses usually have the E version at this position while humans usually have the K version. It had been thought that the switch from E to K is needed for full adaptation to humans and everyone was ore than a little surprised when the new pandemic strain turned out to have the E version and not the K version. So people have been expecting to see the K version pop up and they’ve been looking for it. Koopmans was the first to find it.

So what does this mean? So far we really don’t know. By the time the first mutation was detected it was too late to do comprehensive contact tracing. Only one other isolate showed the same mutation but it wouldn’t be surprising if there were others that were undetected (you can read more about the investigation in Koopmans ProMed notice or in an excellent piece by Helen Branswell of Canaddian Press). But that doesn’t answer the question of the significance of this event — if any. Both cases typical flu cases and recovered. When the isolate was inoculated into ferrets, Koopmans did not report it appeared to be any more virulent than the E version. One of the big fears was that the mutation would make things worse. The origin of this is a finding that the mutation makes it easier for the virus to replicate at lower temperatures. Birds have relatively high body temps (about 41 degrees C.) compared to humans (37 degrees C., and the temperature in our upper respiratory tracts is even lower, around 33 degrees C. The concern about this mutation arose around the bird flu virus, H5N1, which is extremely virulent. Since the deeper parts of the lung are warmer than the upper respiratory tract, the fear was that switching from E to K would allow the bird flu virus to replicate in the human upper tract more easily and make it much more transmissible. At the moment H5N1 causes a disastrous infection in a few people (why these people and not others equally or more exposed we don’t know), but it doesn’t transmit from person to person (only a few documented instances exist). An elegant experiment by Kawaoka we discussed here two years ago demonstrated that this single mutation was enough to switch the propensity of H5N1 to infect upper or lower respiratory tract host cells. He had found the two variants in the same Vietnamese patient infected with H5N1. The isolate from deep in the lung was the E variant (bird), the one in the upper tract was the K variant (human), but both were in PB2 that were part of the H5N1 bird flu virus. When Kawaoka switched the two amino acids experimentally, he also switched where the virus liked to infect (upper or lower).

So the way the story was reading in 2007 was that the E variant was more virulent (because it infected cells deep in the lungs) but the K variant might make the virus more transmissible. That’s something we really didn’t want to happen with H5N1, which so far is so virulent it is killing over half of the people we know to be infected. The K variant was thought to be necessary for full adaptation in humans. And maybe that’s right for H5N1. But it sure isn’t right for H1N1, which has managed to more than fully adapt (it’s crowding out the seasonal viruses) and is spreading like crazy even thought virtually all of it is the E variant at 627. Nor has it seemed to change the virulence of the virus, although we don’t have a lot of isolates to play with at this point.

I’ve often quoted a noted flu scientist who once said to me, “I knew much more about flu 20 years ago than I do now” (meaning that things we thought we knew then we now realize we didn’t really know). With this pandemic and the pace of new science and discoveries in the flu world, we’ll have to modify this to, “We knew much more about flu 6 months ago than we do now.” The simple truth is that as much as we know, we haven’t yet been able to put the pieces together into a solid story. Every time we think we’ve got a handle on what’s going on the flu virus thumbs its nose at us.

We’ll get it eventually. But right now when I read that this mutation is popping up or that we have now discovered the “secret” of why flu does this or that, I don’t jump up with fear or anticipation. It’s going to be a long, hard climb until we reach a place where we can really see the broader landscape and not just what’s a few inches in front of our face.

Comments

  1. #1 Magpie
    October 1, 2009

    This blog always scares the crap out of me. Not with doom and gloom, but by reminding me that mum and dad don’t necessarily have all the answers. It’s like being 8 years old all over again.

    I expect that next week you’ll be telling us that lab results show the virus is somehow demon-based.

  2. #2 miso
    October 1, 2009

    Clearly no-one will be seeing a few inches in front of their face while their wearing Roche (rose) coloured glasses.
    Perhaps if you hadn’t been wearing Roche sunnies for years you’d know you were standing on the edge of a cavernous void (a long hard fall), and not just a long hard climb to a broader landscape.

    Since I don’t need eye wear to see the obvious, and I risk no funding cut, perhaps I could state the obvious.

    The unspeakable fear is that E627K will join with H274Y to cause unspeakable damage to Tamiflu sales, and cut Roche’s funding budget….

    …and if that’s not shocking enough, billions will die.

  3. #3 Dylan
    October 1, 2009

    “…and if that’s not shocking enough, billions will die.”

    I think that your stratospheric, panic driven numbers are more than a little off, miso. At the outside, I think that we may be looking at a CFR in the range of .14% to .24% on the high end; and I don’t think that we are anywhere near either of those figures, at the present time, actually. The next several months are not likely to prove to be at all pleasant, of course; but I don’t see any reason to expect that they will be entirely catastrophic, either.

  4. #4 Dave
    October 1, 2009

    The “I knew much more about flu 20 years ago than I do now” is a wonderful quote. I actually read it in an article, but I can’t remember where (maybe in a CDC publication?). If any viewers happen to know where it was mentioned, it would be great if they could provide the citation.

    And Revere: The above was fascinating. Thanks for your insights. Presenting complex topics in a readily understandable manner is a challenge and you do it well.

  5. #5 miso
    October 1, 2009

    Dylan,
    I’m reassured to discover that you says billions will not die, and have provided CFR figures to two decimal places to prove it.

  6. #6 Phila
    October 1, 2009

    It’s funny how annoyed some people get when their massive death counts are challenged. It’s almost like they’re rooting for the worst-case scenario.

    I guess it seems like the only way out of our current problems, in some circles. I can sympathize, but I sure wouldn’t want someone with that attitude in charge of anything important.

  7. #7 Flulearner
    October 1, 2009

    Revere,
    Thank you for your great discussion. According to the protein sequences of PB2 in the public domain, since 1997 the K variant has been detected in H5N1 human, cat, and dog isolates in several countries including Hong Kong, Indonesia, and Thailand. But the E variant was detected in all human isolates from the largest H5N1 family cluster reported in Indonesia where six of the seven infected family members died in May 2006.

  8. #8 mark
    October 1, 2009

    Dave (post 4) and Revere,
    I’m reminded of the line that Dylan (Bob, not poster #3) wrote: “I was so much older then…I’m younger than that now.”
    I just never thought of Dylan as a noted flu scientist.

  9. #9 Stan C
    October 2, 2009

    Revere (a little off topic – I’m sorry!) your observation “I knew much more about flu 20 years ago than I do now” is an interesting admission from you (given that you are an expert with some 30-40 years experience) yet on the subject of Global Climate (in which I guess you do not claim any particular expertise) you have criticized those scientists who are skeptical of AGW and claim that the science is beyond dispute! Is climate science so uncomplicated (unlike that of a virus) that all the evidence is indisputable?

  10. #10 Phila
    October 2, 2009

    the subject of Global Climate (in which I guess you do not claim any particular expertise) you have criticized those scientists who are skeptical of AGW and claim that the science is beyond dispute! Is climate science so uncomplicated (unlike that of a virus) that all the evidence is indisputable?

    Posted by: Stan C | October 2, 2009 12:35 AM[kill]‚Äč[hide comment]

    The evidence isn’t indisputable. It’s been disputed for decades. Unfortunately, a few people feel that a “real” debate can’t be said to have taken place until everyone agrees with them.

    To make your analogy accurate, IMO, you’d need to compare climate skeptics to people who claim that flu viruses don’t exist, or don’t make people sick, or were intentionally created by the WHO in order to thin the herd.

  11. #11 K
    October 2, 2009

    Revere, your comment “We will get it eventually” is an article of faith and not provable. Remember science promised we would get cold fusion. We are waiting…..

  12. #12 mk
    October 2, 2009

    K,

    “Science” didn’t promise us anything. Certain scientific people may have, but “science” does not speak (much less promise!) with one voice… and never did.

  13. #13 Chris
    October 2, 2009

    Revere,
    Like Dave, I appreciate your uncomplicated explainantion of a very complex issue.
    I think I know the source of your quote. When I met the expert in 2005 the quote was “I knew more about influenza five years ago than now.” I assume your quote from the expert is more recent and the changing time horizon reflects just how much science has learned about influenza in the last five years, invalidating most of what we thought we knew.
    The other quote I like is “influenza is predictably unpredictable.”

  14. #14 magpie
    October 2, 2009

    Phila! Are you feeding the trolls? Smacks for you.

    Hey Miso, can I ask you if you’re holding Biota shares? Or did you sell ‘em?

  15. #15 Phila
    October 2, 2009

    Phila! Are you feeding the trolls? Smacks for you.

    Now that you mention it, I guess I am.

    Smacks duly accepted.

  16. #16 Brendan
    October 2, 2009

    revere: i’m no flu expert, but do you mean “NP” and not “NA” here? “(PB1, PB2 and PA) work together as a team and interact with another protein (NA) that acts as a structural scaffolding for the genetic material itself….”

  17. #17 revere
    October 3, 2009

    Brendan: Of course it should be NP. That was written on an airplane by someone who was a sleepwriting. I will correct it. Thanks for noticing it.

  18. #18 K
    October 3, 2009

    MK, I wasn’t implying that science promises anything. Scientists however often do. They are human.

  19. #19 ciburke
    October 3, 2009

    Revere, Enjoyed the post. This whole swine flu thing has been fascinating in its evolution. What I am now waiting for is the hysteria when the vaccine finally makes it out to the world. People have really been freaking in anticipation.

  20. #20 Phillip Huggan
    October 4, 2009

    2007 state of thought said communicability was almost all about phlegm and/or droplets and or germy hand touching. We know now immunological factors are at least somewhat important because 2007 flu science says this shouldn’t spread. Guess (just a guess) it means if the flu sneaks up on our bodies it is communicable at a lower # of viruses: our bodies only kill the first 10 with Swine Flu vs first 1000 viruses if seasonal flu, before infection.

    You wouldn’t think an upper respiratory adapted virus would be worthless though from a communicability viewpoint, would it? Shouldn’t the lysine strain take over? Or did it originate too late to get the most social pool of people; already infected during Spring and now immune? Makes me wonder if this flip (IDK which way) was the third Spanish Flu wave.
    Vincent’s thread at “flu blog” asserts designer viruses will mutate designer traits anyway. This E to K flip proves that, but how long did it take? If bioterror/bioaccident in 2030, and if you purposely through a feature like the K or E (presumably on some other part of the genome) on your Skynet communicable vaccine, courier it around the world and hold indoor Skynet flu parties, while killing P-2-P travel of the virulent pandemic, would your Skynet virus hold for enough generations of P-to-P transmissions to give immunity from Armageddon for most/some…maybe scenario is impossible (probably civilizations always get tech social distancing solutions or always take it).
    This is a test case if we can learn more about it.

  21. #21 cpg
    October 4, 2009

    LOL Miso

    I think you meant billions of Roche dollars will die.

    I think millions will die because of world governments stockpiling Tamiflu over Relenza. This was a deliberate choice knowing that Tamiflu was nearly 100% resistant to season H1N1.