Blood Simple: Mammoths, mice, malaria and hemoglobin

Oh, the allure of a misleading headline. When I saw this story on BBC news, “Mammoths had 'anti-freeze blood', gene study finds,” I thought for a moment that scientists had discovered those Ice Age behemoths had secreted some glycerol-like compound into their tissues to prevent freezing. Such a finding would have been genuinely astounding because, as far as I know, that trick is seen only among certain polar fish and overwintering insects; it would have been a first among mammals. In reality, the surprise is not that the mammoths’ blood resisted freezing but rather that it cleverly continued to do what blood vitally must do: transport oxygen to needy tissues, even at low temperatures. Kevin L. Campbell of the University of Manitoba and his colleagues reached this conclusion through a nifty piece of paleogenomic molecular biology, as they reported in Nature Genetics. Their technique’s fascinating potential to help biologists learn about the physiologies of extinct creatures has already drawn considerable attention, but the mechanism of the hardiness of the mammoths’ blood also helps to highlight a common way in which evolution innovates.

Mammoths display obvious features that must have helped them stay warm in the brutal subzero temperatures of the Pleistocene ice ages, such as long, shaggy coats and small ears. They may well also have had less obvious ones, too, like the arrangement of blood vessels in the legs of caribou that allows countercurrent exchange to minimize the loss of body heat from their legs while they stand in snow. Nevertheless, Campbell had wondered about whether the mammoths’ blood might have been adapted, too, because of hemoglobin releases oxygen into tissues only sluggishly at low temperatures.

By extracting the hemoglobin gene from DNA in well-preserved mammoth remains and inserting it into bacteria, Campbell and Alan Cooper of the University of Adelaide were able to replicate samples of the mammoth’s hemoglobin. And sure enough, in subsequent tests, the resurrected hemoglobin proved to release oxygen much more consistently across a wide range of temperatures—even glacially low ones.

Perhaps it sounds surprising that something so fundamental to mammalian physiology as its hemoglobin chemistry would be subject to evolutionary revision. Surely the mammoths might have survived the cold just as well by evolving more hair or thicker insulation. Yet hemoglobin chemistry is actually a feature particularly well suited to modification—and that has been modified many times throughout evolutionary history. The key is that the genes making the globin proteins have leant themselves to frequent duplication throughout evolutionary history, which opens up the opportunity of variation among the copies and specialization in their activities.

Humans, for example, have several different types of globin genes (designated alpha, beta, gamma and so on) on chromosomes 11 and 16 that may be used in various combinations to manufacture variant forms of the tetrameric (four-chain) oxygen-transport protein in red blood cells. For our first 12 weeks or so in utero, our bodies make embryonic hemoglobin, then switch to fetal hemoglobin, which can continue to be a major component of newborn babies for six months. Mammalian fetuses need hemoglobin that takes up oxygen very avidly because they need to steal it away from their mothers’ blood as it circulates through the placenta (see graph). So fetal hemoglobin does not respond to a chemical (2,3-bisphosphoglycerate) that reduces the oxygen affinity of adult hemoglobin.

Fetal hemoglobin has actually been the salvation of many adults who suffer from sickle-cell anemia. These people make a defective form of adult hemoglobin that distorts their red blood cells into the elongated, sickle shape that gives their condition its name; these sickle cells can clump together and block blood vessels, leading to painful and frequently fatal complications. A treatment for sickle-cell anemia, however, is to give a patient hydroxyurea and recombinant erythropoietin, which stimulate the body to begin making fetal hemoglobin again, alleviating some of the problems.

Of course, sickle-cell anemia is itself the result of a mutant variation in the copies of the genes that make the beta subunit of hemoglobin. As is well known today, the genetic trait for sickle cell seems to have originally taken root in populations in sub-Saharan Africa and other parts of the world where mosquito-borne malaria is endemic: people who are carriers of the trait are somewhat more resistant to malaria infection. The prevalence of sickle-cell genes in those populations therefore may represent an adaptive, evolved response—albeit it a cruel one—to the harsh burden of malaria. Indeed, the genetic blood disorders called thalassemias, which are prevalent in many Mediterranean ethnic groups, may similarly represent the result of natural selection for improved survival against malaria (although unlike sickle-cell anemia, which involves an abnormal hemoglobin, thalassemias are caused by underproduction of a normal hemoglobin).

Looking outside the human species, one finds that the globin proteins have a staggeringly wide range of forms and chemistries, representing an incredible amount of evolutionary experimentation that long preceded the development of our species’ own tidy system. Horseshoe crabs aren’t aristocrats but they are literally blue bloods, with a blood pigment that carries copper instead of iron. Sea squirts have a green blood pigment based on vanadium.

Many animals (including humans), in addition to some form of hemoglobin, also have myoglobin, a large globular protein that helps muscle tissue hang onto the oxygen it needs while working. (Myoglobin is the reason that meat is red, my fellow steak lovers.) Some dopaminergic neurons and glia in the brain also seem to contain hemoglobin, possibly to insure the brain’s own access to oxygen under suffocating conditions. And hemoglobin itself also seems to have functions quite apart from oxygen transport: its antioxidant properties and interactions with iron seem to be used by cells in the kidneys and immune system.

All this variation suggests that hemoglobin genetics might not have been such an odd target for natural selection in the evolution of mammoths: it is an extremely malleable protein with diverse capabilities, and because organisms often contain multiple copies of it, variants can creep into a population and survive long enough to be tested by selection.

In fact, another example not unlike the mammoths was reported in the scientific literature last year. Jay Storz of the University of Nebraska-Lincoln and an international team of collaborators reported last August in the Proceedings of the National Academy of Sciences on their genetic comparison of deer mice living in lowland prairies and in the mountains. The mice were identical in every respect except for just four genes—all of which boosted the oxygen capacity of the mountain mice’s hemoglobin.

Mammoths and deer mice may be at opposite ends of the spectrum for mammalian size, but similar principles of evolution applies at all scales.

Energetically Batty

A recent discovery about the evolutionary origins of bats relates, at least indirectly, to a problem causing the extinction of many bat species throughout North America.

As they reported in the Proceedings of the National Academy of Sciences, Ya-Ping Zhang of the Kunming Institute of Zoology and colleagues have found evidence that mitochondrial genes in bats, which are responsible for their metabolic use of energy, have been under heavy selection pressure since early in their evolutionary history. Such a conclusion makes considerable sense on its face because bats’ way of life is highly energy intensive.

Nevertheless, the finding also helps to sketch in some of the mysteries of the evolution of bats. Bats are hard to look at in fossil record because they don’t fossilize well; they suddenly appeared in Eocene strata from about 50 million years ago looking fairly much as they do now, which left cryptic some of the steps up to that point.

Over the past decade, several discoveries have helped to firm up the view that the ancestors of bats spent their lives leaping and hopping through vegetation before they could fly; that the evolution of their wings seemed associated with key changes in certain genes for digits; that their ability to echolocate seems to have emerged after their capacity for flight; that the larger bats called Megachiroptera are indeed descendants of the smaller Microchiroptera and not the convergently evolved cousins of primates. The place of the metabolic changes in that scheme, though, were largely speculative. The demands on bats’ mitochondria could have emerged only once they started flying, but instead it seems that their ancestors made a living as an extra hyperkinetic group of insectivores leaping through the trees and shrubs.

All that energy expenditure comes at some cost to the bats, however. Most obviously, they need to eat colossal numbers of insects to satisfy their energy needs. During the cold winter months when insects become more sparse, bat species that don’t migrate to warmer climes must overwinter in caves, suspended in a state of torpor with their metabolisms at a crawl.

Unexpectedly, those energy demands may also figure into the catastrophic epidemic of white nose syndrome that has been killing bats in North America in recent years. The bodies of the dead bats studied by researchers have commonly been marked by heavy accumulations of this fungal infection, which in severe cases can damage the overwintering animals' skin and wings, leaving them unfit. Yet the observed level of infection and the timing of the bats' deaths suggest that this obvious explanation isn't adequate: in many cases, the fungus should have been only about enough to pose an itchy nuisance, maybe akin to aggressive athlete’s foot in humans.

That benign comparison may break down when applied to bats in torpor, however. Bats going into hibernation carry stockpiles of fat to sustain them, but those stockpiles are often just sufficient to get them through the winter season. Moreover, the bats do not consume those fat reserves at a consistently slow pace: every two or three weeks throughout their hibernation, the bats wake out of torpor, excrete, groom themselves, settle into genuine sleep for a while, then slow down their metabolisms again. These periods of activity seem to be essential to hibernating mammals, perhaps because they help to reinvigorate their immune systems. Eighty percent or more of the energy that the bats consume during their hibernation is spent during these brief intervals.

One theory therefore being investigated by researchers such as Craig Willis at the University of Winnipeg is that the fungus makes the animals rouse from torpor more often to groom themselves, and in the process makes them burn through their crucial fat reserves too quickly. Long before winter is over and insects are plentiful again, the bats starve.

North American bat species may be more vulnerable to white nose fungus than their European counterparts are because they roost in far larger colonies and so may transmit the fungus more widely throughout their population. It’s entirely possible, however, that the smaller European colonies are in fact an evolutionary consequence of white nose fungus (or some equivalent affliction) selecting against larger gatherings in the distant past.

This is only my own speculation, but if a highly amped metabolism has long been an adaptive feature of bats and their immediate ancestors, then perhaps for as long as these creatures have been using torpor to survive the cold months, something like white nose fungus has been cropping back colony sizes periodically. Unfortunately, given the difficulty of finding good bat fossils, verifying such a hypothesis may never really be feasible. But who’s to say what other deductions might yet be possible from the DNA record?

(For the information about white nose syndrome and its possible mechanisms, I'm indebted to science writer Erik Ortlip, now of Environmental Health News, who wrote about this subject while he was my student in the Science, Health and Environmental Reporting Program at the Arthur L. Carter Journalism Institute of New York University. Thanks, Erik!)

Putting the "CT" back in "Creationist"

Smack your heads in shame, my fellow intellectual snobs of the Northeastern elite. We're used to sneering at the creationist follies playing out in Kentucky, Pennsylvania, Texas and elsewhere—benighted hellholes where they wouldn't know a decent bagel, a proper chowder or the correct pronunciation of "Worcester" if it were served up alongside their customary daily ration of cheese grits. But now the same buffoonery is occurring in (bless my nutmeg!) Connecticut. In short, the administration of the Weston Intermediate School has twice rejected a proposal for students in the third, fourth and fifth grade Talented and Gifted program to study the work of Charles Darwin. Such a plan seems to be completely in keeping with Connecticut's standards for science education. Mark Ribbens, the principal who first denied the plan, apparently left the school earlier this year, but a subsequent resubmission for the curriculum fared no better.

Brandon Keim at Wired Science has more details, but I'm struck by the proposition (which may not originate with Brandon) that this antievolution development in Weston is somehow different in kind from what we've seen before:

Evolution education is under attack in Weston, Connecticut, but not from the usual direction.

Nobody is promoting intelligent design in the curriculum, or asking schools to teach evolution’s “strengths and weaknesses.” There’s just an administration afraid that teaching third graders too much about Charles Darwin will cause trouble.

How does this genuinely differ in essence from the reasons usually given by evolution's opponents in education? No matter whether they attack evolution's merits directly or insist that intelligent design should be taught as a valid alternative, the antievolutionists nearly always say that "forcing" evolution on students would intrude on parents' rights to raise their children as they see fit. In other words, they are saying not to create controversy and upset the parents. And just as seems to be the case here in Connecticut, the antievolutionists often make these arguments preemptively, long before any actual outrage from parents appears.

Moreover, look at the reasons that Ribbens gave for his decision (emphasis added):

“While evolution is a robust scientific theory, it is a philosophically unsatisfactory explanation for the diversity of life. I could anticipate that a number of our parents might object to this topic,” wrote Ribbens. “It is not appropriate to have [Darwin's] work or the theory part of the TAG program since the topic is not age appropriate.”

Ribbens explained further, “Evolution touches on a core belief — Do we share common ancestry with other living organisms? What does it mean to be a human being? I don’t believe that this core belief is one in which you want to debate with children or their parents, and I know personally that I would be challenged in leading a 10-year-old through this sort of discussion while maintaining the appropriate sensitivity to a family’s religious beliefs or traditions.”

A "philosophically unsatisfactory explanation for the diversity of life"? What exactly does that mean? If the idea is scientifically robust, how does that leave it philosophically wanting? And what other ideas are more satisfying as explanations for the diversity of life? Ribbens' words sound like the rhetorical tap dancing that creationists use to say, "yes, evolution is good science, but...."

As for the argument that evolution might intrude on some families' core beliefs: either you teach evolution or you don't. Common ancestry and kinship with other organisms are central to the theory. Lots of ideas in higher education step on various core beliefs; that confrontation is part of what real education involves. Would Ribbens have quailed at teaching about the big bang and the eons-old earth because those, too, touched on core beliefs? Or on racial and religious equality? With all due respect for the staggeringly tough demands of teaching, when you aren't willing to have those fights, it's time to get out of the profession.

Moreover, is a "debate" really necessary? If any children or parents question how to reconcile evolution with their beliefs, tell them that they will need to work that out for themselves; that your job as a teacher is simply to make sure students know what the scientific answers are.

Ribbens, of course, is now gone, and I don't know whether whoever is responsible for rejecting the Darwin proposal the second time would cling to the same excuses. But if so, it's deplorable because the argument that we shouldn't do what's right because other people would think it's wrong is cowardly, dishonest or both. Maybe it sounds more familiar when phrased this way:

"Personally, I think it would be great to have a black family in the neighborhood, but a lot of people around here are still pretty racist, so maybe you should sell the house to somebody else."

Or:

"Not that I have anything against gays, but many of the parents would be very uncomfortable with having one teaching the kids, so...."

Or:

"She's perfectly qualified, but I really don't think the other men in the company would give her enough respect for her to handle the job."

Own your arguments. If you aren't for teaching the most powerful idea in science, then you're against it.