Subtleties of Sickle-Cell

Sickle-cell is a standard textbook example, but there are subtleties that those texts never mention. Not just the point about the advantage of early lethality in homozygotes.

Ask yourself why, over thousands of years, falciparum malaria never became resistant to this genetic defense.

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43 Responses to Subtleties of Sickle-Cell

  1. Jerome says:

    Oh, for the same reason we still get colds. Sometimes it’s just hard to develop a trait when it would come in handy. Billions of years of evolution, and humans still can’t fly. .

    • gcochran9 says:

      Chloroquine used to work well, but now falciparum is often resistant.

      Wrong about colds and wrong about falciparum vs sickle cell.

      • Jerome says:

        Hmmm… But right about flying?

        Don’t get me wrong, I think evolution is a beautiful theory. But I don’t think it is falsifiable. No True Evolutionist ever says, “I can’t think of any possible evolutionary explanation for this observed fact, so evolution must be false.” They just keep thinking ….

        • No true physicist ever says “I don’t understand the physics here, so physics is bunk.”

          Yet any given bit of physics is falsifiable. Hmmm.

          Vertebrates showing up in the pre-Cambrian fossil record would sure falsify a thing or two. Cut a squirrel’s tail off and it produces tailless descendants, that’d falsify some stuff. But those are absurdities, you say. Indeed, anything that would falsify anything major about evolution would pretty much have to be an absurdity. This does not help your case, however.

          • Jerome says:

            Thinks which cannot survive don’t. There are lots of copies of things which are good at reproducing. Those statements are essentially tautologies. Definitions. The rest is just working out the details, right? Why things that can survive suddenly can’t, and things that are good at reproducing suddenly aren’t. Details.

          • Jerome says:

            Indeed. As a lifelong student of science, and its history, I think that puts me in pretty good company. Almost everyone was almost always wrong about almost everything. You could even take away any two of those “almosts”, and the statement would still be true. How fortunate we are, to live in the very first era in which everything we know is true.

          • James Baird says:

            OT, but I think you should rename your blog this.

        • Carl Popper wrote that evolution is not a theory but a framework in which falsifiable theories might be made.

          • DJohn1 says:

            For most of history science has been about Verificationism.

            Someone performs an experiment and discovers a finding. Everyone else replicates the experiment and verifies the finding.

            Popper’s thesis of falsifiability is a precise inversion of why science works, and is not productive.

        • Frau Katze says:

          No recent human ancestor has been remotely capable of flying. In fact, you have to go a LONG way back. I wouldn’t expect flying.

          True, bats can fly and they’re closer to us than birds, but still. Our relation to bats isn’t very close at all.

        • Michel Rouzic says:

          “But I don’t think it is falsifiable”
          Then you simply don’t understand what falsifiable means. If cats and dogs didn’t share a common ancestor then they wouldn’t have so much DNA in common and so much of their insides and how it all works in common too. Falsifiability means “if this theory was wrong then you’d expect things to be different in this or that way”, like in the case of evolution if it was wrong the tree of life would have to be broken up into unrelated pieces instead of every living creature sharing a common ancestor, and unfalsifiability means “if this theory is wrong then it would change literally nothing to anything we could possibly verify” like parallel universes or “the universe is a computer simulation”.

          “Almost everyone was almost always wrong about almost everything”
          You don’t even understand the basics of what you’re talking about. There’s being Newton-wrong on gravity in which case you’re still mostly right, that means what you figure out is useful and gets you somewhere, and there’s being really wrong when you’re just going the wrong way and have no useful insights.

          “Billions of years of evolution, and humans still can’t fly.”
          See, once again you have no understanding of what you’re talking about. Different species have different strategies to thrive. Ours is to have big brains, fancy hands that are perfect for tooling and being good at walking/running long distance. What great advantage would flying offer to us when it would make it difficult to have big heavy heads and would require a pretty different morphology?

          You should comment less and learn more.

          • Jerome says:

            You confuse the “Theory of Evolution” with the descent of species. If you go to a junk yard, you will see that each year’s vehicles are slight modifications of the precious years. That does not prove that they evolved.

            • catte says:

              What an asinine comparison. Vehicles don’t reproduce, for one thing.

            • JP says:

              Vehicles absolutely evolve. All vehicle share a common ancestor with the Yamnaya wheeled vehicle, and most share a common ancestor from the offspring of the the Daimler ICE and the horse carriage. Convergent evolution is the name of the game today, in most cases, vehicles conform to a fairly narrow economic niche given by the collective will of the consumer.

            • amac78 says:

              Jerome, you should comment less and learn more.

      • teageegeepea says:

        He’s wrong about colds because colds keep evolving along with our natural defenses. The difference is that our defenses against cold aren’t anywhere near as costly as sickle-cell, so their frequency is high and acts as a stronger pressure on colds. The lower/bounded frequency of sickle cell means that malaria variants deterred by it still have plenty of other hosts to infect.

    • Ursiform says:

      I’ve flown many times. Just not by sprouting wings. Other tool users built them for me.

  2. HI says:

    Let’s say a strain of falciparum emerged that’s not affected by the sickled cell gene. Your post suggests there’s a reason why the original, tamer strain would outcompete the new, more savage strain. I could see that happen for example if the savage strain were to completely wipe out its host population. But that’s only one possible outcome, depending on a number of factors. It’s not a given. So what’s the answer?

    • West Anon says:

      Parasite variants compete against each other. The population’s genome occupies a region around a local competitive optimum. Effectiveness of resistance suggests that overcoming resistance means leaving that region, i.e. gaining the ability to infect heterozygotes loses competitive edge against non-mutant parasites in non-carriers.

      The problem now is that the new mutation can’t just stay in their niche. The parasites doesn’t control who they’re going to infect next, so in between getting into a happy place now and then, they must spend multiple generations in non-carriers, that non-niche place where they are handily outcompeted by their former buddies.

  3. HI says:

    Let me rephrase. Yes, a good parasite doesn’t kill the host. But why is a strain that responds to the sickle cell gene necessarily better than a strain that doesn’t? What am I missing?

    • Frau Katze says:

      Some things are different: it’s a more complex disease. The plasmodium has to survive in the mosquito too. It can’t evolve something that wouldn’t kill humans if it was bad for the mosquito.

      Plus, plasmodia are more than just one cell.

      I’m just starting a book on autoimmune diseases that may, might, possibly be connected to disappearance of diseases like malaria.

      So far, the author has gone into detail about an evolved defence found in Sardinia. Because the island is low altitude it was always a very malaria prone area, so invaders didn’t find it attractive. Corsica and Sicily have a lot more mountains. Sardinians are quite distinct from other Europeans genetically.

      That defence is also like sickle cell: only those with one copy benefit. Two copies kills in childhood.

      I wonder what the situation with other primates is?

    • Ursiform says:

      A successful parasite doesn’t kill its hosts at a rate that causes it to run our of hosts.

  4. Smithie says:

    How old is Plasmodium infection in humans, anyway? Isn’t there some genetic clock theory that humans had a lucky mutation that kept them from being infected for a long time? Possibly a great aid to early expansion.

    That one was a real head scratcher for me. Assuming the theory is right, numbers probably have something to do with reinfection, but it is still hard to believe that a long reproductive cycle species had the edge on a short reproductive cycle organism for such a long time. And one with a good vector and a real bag tricks.

    • gcochran9 says:

      Because of its negative effects in homozygotes, the frequency of HbS never gets too high – so there are always more people without it than with it. You get rare-gene advantage, and it lasts.

      It got to the point where the big majority of people in central Africa had chloroquine in their blood stream, partly because it lingers. If only a few people had used it, resistance would never have become common. That’s why quinine worked well for a long time (centuries): only Europeans could afford it.

  5. Maybe for a similar reason resistance to vaccines is quite rare but resistance to antiobiotics is quite common?

    Part of the idea, from what I understand, is that pathogen population never gets large in a vaccinated individual– which means there usually isn’t a large pool of a pathogens exposed to a selection pressure of the specific immunological targets a given person’s immune system.

    Antiobiotics, by contrast, are usually given after symptoms arise, which implies an already extant large pathogen population within the individual exposed to some selection pressure.

    So maybe in individuals heterozygous with sickle cell plasmodium populations never get too large, so there isn’t a large population subject to that Selection pressure.

    But that seems like not the story.

    Maybe because it’s just not physiologically ‘easy’ to develop resistance to the sickle cell defense? It’s a pretty crude defense– but maybe because of that, it’s harder to develop resistance to than a more finely tuned immunological response.

  6. Yudi says:

    Cool stuff. You’ve convinced me to put Ewald’s book on my wishlist. Possible review material for you?

  7. another fred says:

    My first thought was that sickle cell might just confer protection while those protected were still carriers and still passed the disease on. Admittedly, I know squat about this, but do we know that sickle cell kills all the parasites?

    Biochemical and immunological mechanisms by which sickle cell trait protects against malaria
    “Abstract

    Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.”

    https://malariajournal.biomedcentral.com/articles/10.1186/1475-2875-12-317

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