The Loom

Malaria For Brains

malaria cross-section.jpg

The red blob in this picture is a human red blood cell, and the green blob in the middle of it is a pack of the malaria-causing parasites Plasmodium falciparum. Other species of the single-celled Plasmodium can give you malaria, but if you’re looking for a real knock-down punch, P. falciparum is the parasite for you. It alone is responsible for almost all of the million-plus deaths due to malaria.

How did this scourge come to plague us? In a paper to be published this week in the Proceedings of the National Academy of Sciences, scientists have reconstructed a series of molecular events three million years ago that allowed Plasmodium falciparum to make us its host. They argue that a change in the receptors on the cells of hominids was the key. Ironically, this same change of receptors may have also allowed our ancestors to evolve big brains. Malaria may simply be the price we pay for our gray matter.

To uncover this ancient history, the researchers compared the malaria humans get to the malaria of our closeest relatives, chimpanzees. In 1917, scientists discovered Plasmodium parasites in chimpanzees that looked identical to human Plasmodium falciparum. But when some ethically challenged doctors tried to infect people with the chimpanzee parasites, the subjects didn’t get sick. Likewise, chimpanzees have never been known to get sick with Plasmodium falciparum from humans. In the end, scientists recognized that chimpanzees carry a separate species of Plasmodium, known today as Plasmodium reichenowi. Studies on DNA show that Plasmodium rechnowi is the closest living relative to Plasmodium falciparum–just as chimpanzees are the closest living relatives of humans.

The authors of the new study set out to find the difference between these parasitic cousins. They focused on how each species of Plasmodium gets into red blood cells. Every Plasmodium species uses special molecular hooks on its surface to latch onto receptors on the cell, and then noses its way through the membrane to get inside. The parasite has a number of hooks, each of which is adapted to latch onto particular kinds of receptors. One of the most important groups of receptors that Plasmodium needs to latch onto are sugars known as sialic acids, which are found on all mammal cells.

These sugars play a crucial but mysterious role in human evolution. As I’ve written here (and here), almost all mammals carry a form of the sugar called Neu5Ac on their cells, as well as a modified version of it, known as Neu5Gc. In most mammals, this modified form, Neu5Gc is very common. In humans, it’s nowhere to be found. That’s because the enzyme that converts the precursor Neu5Ac into Neu5Gc doesn’t work. We still carry the gene for the enzyme, but it became mutated about three million years ago and stopped working.

Since chimpanzees make Neu5Gc and we don’t, the researchers hypothesized that the two Plasmodium species must use different strategies to latch onto red blood cells. To test their hypothesis, they genetically engineered cells to produce the molecular hooks used by human Plasmodium falciparum, and other cells to produce the chimp parasite hooks. The researchers then mixed the engineered cells with red blood cells from humans and chimpanzees to see how well they attached. In another set of experiments, they made human blood cells more chimpanzee-like by adding Neu5Gc sugars to them, to see if the change helped the chimpanzee parasites attack them, or if it impaired the attacks of human parasites.

Their results show that humans are uniquely vulnerable to Plasmodium falciparum because our ancestors lost the Neu5Gc sugar. Plasmodium falciparum prefers to bind to Neu5Ac, the sugar we still carry. At the same time, the sugar we lost somehow blocks Plasmodium falciparum’s hooks from latching onto Neu5Ac. That’s why chimpanzees don’t get sick with Plasmodium falciparum, despite carrying both kinds of sugars. On the other hand, we don’t get sick with chimpanzee malaria, because Plasmodium reichenowi prefers attaching to Neu5Gc, the sugar we lost.

The scientists argue that some seven million years ago the common ancestor of chimpanzees and humans carried both kinds of sugars on their cells. This ancient ape would sometimes get sick with malaria, caused by the common ancestor of today’s P. rechnowi and P. falciparum. This ancient parasite preferred to latch onto Neu5Gc to get into its host’s blood cells.

Hominids then branched off from other apes, walking upright and moving out of the jungle into open woodlands. They still got sick with the old malaria, because they still produced both kinds of sugars. But then, about three million years ago, our ancestors lost the ability to make Neu5Gc. Initially this was a great relief, because the malaria parasites had a much harder time gaining entry into our cells.

But this relief did not last, the scientists argue. Sometimes mutant parasites emerged that did a better job of latching onto the one sugar hominids still made, Neu5Ac. They now could get into hominid red blood cells, while other Plasmodium parasites were still making do with the other apes. Over time these parasites evolved a better ability to infect hominids. But at the same time, they surrendered the ability to infect other apes, such as chimpanzees. Thus Plasmodium falciparum was born.

This new research is yet another example of how studying evolution yields new insights into medicine. (I’ve blogged before about similar examples with tuberculosis and HIV.) And it may also reveal something about the downside of our unique intelligence. Our ancestors lost Neu5Gc around the time that the hominid brain began to get significantly bigger than a chimp’s.

In other animals, Neu5Gc is abundant on the cells of most organs, but exceedingly rare in the brain. It is very peculiar for a gene to be silenced in the brain, which suggests that it might have some sort of harmful effect. Once a mutation knocked out the gene altogether, hominids didn’t have to suffer with any Neu5Gc in the brain at all.

Perhaps Neu5Gc limited brain expansion in other mammals, but once it was gone from our ancestors, our brains exploded. Along with a big brain, however, came our very own form of malaria.

Comments

  1. #1 Dave
    August 23, 2005

    Dolphins have relatively large brains in comparison to body mass. Is it known if their cells express as much Neu5Gc as other mammals?

  2. #2 Doug
    August 23, 2005

    In this scenario, Carl has pointed out the following two genetic changes as the cause of Malaria’s success against humans. First human ancestors lose the Neu5Gc sugar.

    …because the enzyme that converts the precursor Neu5Ac into Neu5Gc doesn’t work. We still carry the gene for the enzyme, but it became mutated…

    This change is a result of a loss of function. This is an example of a mutation that provides a benefit, at least initially, but does nothing to suggest that new function is evolving, only “disolving”.

    Carl goes on to say:

    But this relief did not last, the scientists argue. Sometimes mutant parasites emerged that did a better job of latching onto the one sugar hominids still made, Neu5Ac…But at the same time, they surrendered the ability to infect other apes, such as chimpanzees.

    This event is not quite as specific as the previous one but it may share a similar problem. The change resulted in some of the parasites having a greater affinity for the Neu5Ac sugar but it came at a cost. The net result is that it is better at doing something that it already did which doesn’t suggest the emergence of a new ability only the honing of a skill which came at the cost of losing function.

    Carl writes, “This new research is yet another example of how studying evolution yields new insights into medicine.”

    This is an excellent example of the vague use of the term evolution. In saying “evolution” the audience generaly assumes a molecules-to-man or common descent definition. The truth is, in the first event, this is merely an instance of a loss of genetic information through mutation. While less is described about the second event it appears to be the result of natural selection selecting genes with greater affinity for Neu5Ac. Similar to the “unnatural” selection of farmers when attempting to increase the sugar content of the sugar beet. The genetic information already existed. It is therefore not evidence for common descent. If the research were conducted under a creationist methodology the result would be the same.

    For a short article summarizing the creationist view on genetics I encourage you to read this article by Dr Lane P. Lester. He is a graduate of the University of Florida and holds a Ph.D. in genetics from Purdue University, and M.S. in ecology.

    Genetics: No Friend of Evolution

    Incidently, I hope you don’t mind me referring to you as Carl instead of the more formal Mr Zimmer. It should not be regarded as a lack of respect. Your style strikes me as someone laid back enough not to care. There certainly are those that would take it as being condescending in nature. They would be wrong, but I’m happy to address you however you prefer.

  3. #3 John S Bolton
    August 23, 2005

    This information fits with the idea that escape from malaria correlates positively with evolution of greater brain capacities. The spread of falciparum malaria, in its more modern and virulent form, into subtropical regions in classical antiquity, is associated with cultural and even population decline. Sallares and Coluzzi say that Rome suffered irreparably from this. Perhaps the intelligent design believers will explain that this was a delayed punishment of the ancients for their impiety.

  4. #4 Richard Dietzel
    August 23, 2005

    So if we engineered Neu5Gc out of Chimps they might develop bigger brains? Cool.

  5. #5 Nick (Matzke)
    August 23, 2005

    Creationists/IDers couldn’t come up with a rigorous definition of “information increase” vs. “information decrease” if their life depended on it. They employ these terms in contradictory, arbitrary ways to discount any proposed example, and their arguments rely on a vague colloquial definition of “information” rather than anything resembling real information theory, which is entirely about the transmission and storing of messages, and not at all about “meaning”. See:

    Information Theory and Creationism
    http://www.talkorigins.org/faqs/information/infotheory.html

    For examples of the evolution of new genes with new functions, which should count as “new genetic information” in anybody’s book, see:

    Evolution of new information
    http://www.evowiki.org/index.php/Evolution_of_new_information

    And don’t give us any rubbish about these just being examples of mere “reshuffling”. If you end up with two different genes with different functions, where you originally had one, you’ve got more “information”, using any reasonable definition.

    Note to creationists: Not every writing on evolution is an attempt to your peculiar half-baked argument and quarter-baked definitions. In this post, was Zimmer trying to show how “new information”, whatever the creationists mean by that slogan, arises? Clearly not.

    PS: On a completely different topic: The loss of Neu5Gc in the brains of hominids could simply be another step in malaria avoidance. Malaria gets particularly deadly when it gets into the brain.

  6. #6 Dan S.
    August 23, 2005

    Doug, you’re missing the point again, I think. The entire scenario is based on chimps and humans evolving from a common ancestor; likewise with P. rechnowi and P. falciparum.

    Frankly, I can’t understand what you’re saying. People have used genetics to study the relationship between different varieties and species of brassicas (although it gets a little hinky what with hybridization and weird plant stuff). They’re descended from a common ancestor, although in this case many of the changes result from artificial selection. Sugar and table beets are related to swiss chard, they’re related to spinach, and they’re related to lambquarters (Chenopodium spp.) (I may be garbling the details here, but this is the general idea). Common descent. What’s the problem?

    In regard to the use of the word “evolution,” remember that for science, beet to sugar beet and goo* to you (I do love that phrase, although adding in ‘zoo’ makes it too unwieldy, methinks) is essentially the same thing.

    * living goo, though. Evolution doesn’t deal with how life started, just what it did once it showed up.
    ___________

    Something Carl is very good at is conveying the excitement – both of pure discovery and practical knowledge – of such research. Creationism, for its adherents, surely offers a kind of satisfaction, but it is of a very different nature. The scientific-wonder-and-productive-usefulness content of creationism seems to me to be essentially nil.

    “So if we engineered Neu5Gc out of Chimps they might develop bigger brains? Cool.”
    Great, just what we need, intelligent poop-flingers . . .

    . . . wait. Don’t we have those already . . .?

    Carl, any chance you’d toss something off here about recent work using genetic material extracted from ancient bones to work out evolutionary relationships, etc? Besides the thing with the horses, there was something cool released earlier this month about cougars, cheetahs, Miracinonyx and sabretooths . . . (oh my!)

  7. #7 Dan S.
    August 23, 2005

    To be fair, the moral and ethical values content of evolutionary theory is likewise basically nonexistant.* Of course, nobody expects science to provide such things (unless they’re very, very, very silly people . . .

    * Of course, other (mainstream) religious interpretations and traditions, as well as many non-religious systems, offer these values, often without pretending to be science out of some strange sense of aggrieved inferiority.

    Now back to the science . . .

  8. #8 João Carlos
    August 24, 2005

    An interesting issue here is that is possible say that Plasmodium falciparum speciated 3 million years ago. When Plasmodium falciparum get stuck inside hominid red blobs it lost the hability to infect other primates red blobs. A reprodutive barrier was formed when that happened.

    So, the data give us information about a speciation event. But creationists will lie and say that there is no proof that evolution will give speciation.

    Creationists are liars, they forget that there is a Commandement to not lie inside the Bible. They will go to Hell. :p

    João Carlos

    Sorry the bad english, my native language is portuguese.

  9. #9 Juan
    August 24, 2005

    Just curious:
    Doug wrote:”If the research were conducted under a creationist methodology the result would be the same.” Isn’t this a self contradictory sentence or oxymoron.
    I always thought that creationism is faith based: you belief in it or not. Period. Ergo, there can not be any methodology or research in creationism as they are mutually exclusive.

  10. #10 ruidh
    August 24, 2005

    Doug,

    Any mutation *increases* the information content of the species genome. The assertion that the mutution reduces information content of the genome is contrafactual.

    Natural selection then operates to reduce that information content over long periods of time by selecting for strongly advantageous mutations and selecting against strongly disadvantageous mutations.

    This ebb and flow of information over time is how evolution works. The net result is a tendancy to increase the information content of all genomes summed across all species corresponding to biological diversity.

  11. #11 John S Bolton
    August 24, 2005

    Deletion mutants decrease information content. Mutations are randomization and thus destruction of genetic information, except for the very rare ones which actually improve the informational content functionally. If not so, then why would lethal mutagenesis be lethal, rather than an enrichment of genetic informational diversity?

  12. #12 Dan S.
    August 25, 2005

    “Deletion mutants decrease information content. Mutations are randomization and thus destruction of genetic information”

    I’m not a scientist, and don’t even have much informal education about this, besides some pop science stuff. But as far as I can understand, this is missing the point that DNA isn’t a book (although spoken and written language is so redundant that up to a a point even extensive garbage, duplications, etc, won’t effect the the abilty to ndrstnd wht s bng sd dnt you gurble agree?). It’s sort of a like a house blueprint that actually makes a house. If some of the details get changed, there might be a big problem – uh oh, no outside door! toliet draining into bedroom! loss of structural support!- it might not make a difference (unseen supporting beams are a different color), it might be an improvement – hey, a window there? I like that! There might be minute changes in insulation thickness, pipe material, wiring that might be improvements, problems, etc., depending on living conditions (thicker insulation in Alaska? Good. In Brazil? Maybe not?) But a lot more complex.

    I don’t get ID creationism. It insists that things are very complex, yet very simple. Doesn’t seem interested in actually appreciating how cool thing are.

  13. #13 John S Bolton
    August 25, 2005

    There is a huge disproportion between the chances for a good versus a bad mutation. If this is not so, why are we wasting so much time and money on protecting people from mutagenic radiation? Why aren’t the bold seekers of new possibilities exposing their germline cells to radiation, if the chances for a good mutation are within range of what some might try? A deletion mutant which disbles part of the deliberate design, so to speak, only to frustrate a parasite, looks like natural selection, not like the intelligent way to make man.

  14. #14 Homer
    August 29, 2005

    It would be interesting to see if there were any connection between this shift of sugar hooks and autism, which might be a mutation of human brain development processes. Might chimpanzee malaria be able to attach to the blood of autistic individuals?