The Edge of Evolution Read online

  Shortly before birth our bodies automatically switch from making fetal hemoglobin to making “adult” hemoglobin. But some people continue to make a noticeable amount of fetal hemoglobin throughout their lives. Their children often do the same, which is the “hereditary persistence” part of HPFH. HPFH helps sickle disease sufferers, apparently by diluting the sickle hemoglobin in their red blood cells. So instead of 100 percent sickle, folks with HPFH might have only 90 percent sickle and 10 percent fetal hemoglobin. People who have sickle cell disease but who also have HPFH often have much milder clinical symptoms than do those without HPFH. Their anemia is much less; they live longer, they can have children, so they can pass on their genes. With HPFH the execution date is often postponed, or even canceled altogether.

  What causes HPFH? The DNA of a human cell codes for tens of thousands of different kinds of proteins. However, not all proteins are needed at the same time. In fact, some proteins work at cross purposes and have to be kept separate from each other. For example, after a person eats a big meal his body will normally take some of the excess sugar and turn it into starch, to be stored until energy is needed at a later time. When that time arrives, the body will break down the starch to sugar, and burn the sugar for energy. These opposing chemical processes are all catalyzed by enzymes in the cell. If all the enzymes were around and active all the time, then after a big meal the cell would be trying both to store and to burn the extra sugar, spinning its wheels. To make sure that the right proteins are made at the right times in the right order and in the right amounts, DNA contains complex “control elements”—switches that turn genes on and off. In the case of HPFH some of these control elements are broken.6 Again, this is trench warfare. The problem (although minor) for adults with HPFH is that their hemoglobin gives them less oxygen from the air compared to normal hemoglobin. Fetal hemoglobin is not meant for adults, but if we have to break a lock or blow up a bridge to save the city, so be it.

  Evolution may be trench warfare, but the armies on both sides are survivors. If a cheaper sacrifice can save a battalion, it will be more widely used because these battalions won’t be as weak. A more elegant solution to the problem of the lethality of sickle cell disease is found in something called hemoglobin C-Harlem. As its name implies, C-Harlem was first discovered in a resident of New York City.7 C-Harlem has much in common with sickle hemoglobin—both have two regular alpha chains as well as two beta chains that have the same substitute amino acid at position number 6. But the beta chains of C-Harlem also have a second mutation. Position number 73 has changed as well. That second mutation leads to surprising behavior. Half-and-half mixtures of C-Harlem with normal hemoglobin gel about as easily as the fifty-fifty mixtures of normal and sickle hemoglobin found in people with sickle cell trait. Pure sickle hemoglobin gels more strongly but pure hemoglobin C-Harlem doesn’t gel at all!8 The important practical effect is that people with one normal hemoglobin gene and one C-Harlem gene have almost all the protection against malaria that Sickle Eve had. But those with two copies of C-Harlem don’t have the devastating problems that people with sickle cell disease have. So C-Harlem has the advantages but not the drawbacks of sickle.

  So far, the C-Harlem gene doesn’t seem to have spread much. Its antimalarial properties aren’t much help in contemporary New York. Its only advantage there is that it doesn’t lead to sickle cell disease, but the same is true of normal hemoglobin. In Africa the C-Harlem gene would be a boon,9 but the C-Harlem mutation apparently hasn’t turned up there yet.

  WHAT’S WRONG WITH THIS PICTURE?

  It is crystal clear that the spread of the sickle gene is the result of Darwinian evolution—natural selection acting on random mutation. In fact, it’s so transparent that the example of the sickle gene is nearly always used to teach biology students about evolution. Even in the professional literature sickle cell disease is still called, along with other mutations related to malaria, “one of the best examples of natural selection acting on the human genome.”10 No wonder—all the basic elements are there to see: the selective pressure from malaria, the single small change from the ancestral hemoglobin gene. What’s more, we see additional mutations building on and modifying the first. Hereditary persistence of fetal hemoglobin (HPFH) is already widespread in Africa, ameliorating the problems of the sickle gene. The C-Harlem gene, which builds directly on the foundation of the sickle gene and would entirely eliminate the drawbacks of the sickle mutation, has not yet turned up in Africa, where it would do the most good, but there’s little doubt that over time it, or something like it, will appear. Perhaps, as advocates of Darwinian evolution argue, we can jump directly from this pristine example to the conclusion that all of life—the complex machinery of the cell, the human mind, and everything in between—can be explained the same way.

  But can we? The defense of vertebrates from invasion by microscopic predators is the job of the immune system, yet hemoglobin is not part of the immune system. Hemoglobin’s main job is as part of the respiratory system, to carry oxygen to tissues. Using hemoglobin to fight off malaria is an act of utter desperation, like using a TV set to plug a hole in the Hoover Dam. Even leaving aside the question of where the dam and TV set came from—which is no small question—it must be conceded that this Darwinian process is a tradeoff of least-bad alternatives. The army in its trenches is suffering loss upon loss. No matter which way it turns, in this war fought by random mutation and natural selection, it is losing function, not gaining.

  Sickle hemoglobin is not the only change that malaria has wrought in the human genome. Let’s explore a handful of others—changes that have literally been written in the blood of many humans—some of which have arisen independently hundreds of times over the past ten thousand years. Let’s see if the picture of random mutation we get from sickle hemoglobin is an exception or the rule.

  SIEVE

  Since the primary target of malaria is the red blood cell, it’s not surprising that hemoglobin has endured a number of evolutionary changes. Besides the sickle cell mutation, other changes to hemoglobin have also arisen that slow the parasite’s progress. One change that’s similar to sickle hemoglobin—but with illuminating differences—is something called hemoglobin C.11 Confusingly, hemoglobin C isn’t the same thing as hemoglobin C-Harlem. Like sickle cell hemoglobin, hemoglobin C (abbreviated HbC) has just one difference from normal hemoglobin in its amino acid sequence. Again like sickle cell hemoglobin, the change occurs in the sixth position of the beta chain. But in the case of hemoglobin C the substitution is of a close relative. Like the amino acid it replaces, the new one is electrically charged. The difference between them is that the new one is positively charged, whereas its predecessor is negatively charged.

  Hemoglobin C is not as widespread as sickle hemoglobin, but it does occur frequently in some regions of west Africa. Unlike sickle hemoglobin, HbC does not solidify, so it doesn’t seem to cause any major problems itself, certainly none as severe as sickle cell disease. Nonetheless, it seems to help people fight malaria. We aren’t quite sure why, but experiments indicate that HbC is less sturdy than normal hemoglobin. When the malarial parasite enters the red blood cell, the increased stress inside the cell apparently causes the mutant hemoglobin to unfold more readily, exposing the parasite to reactive oxygen molecules that may damage it. The unfolded hemoglobin may also indirectly cause the cell to be destroyed by the spleen.

  HbC gives protection from malaria and doesn’t cause nearly as many problems as sickle does. Yet HbC hasn’t spread throughout Africa, replacing sickle hemoglobin. Why not? The answer lies with the folks who get one gene for hemoglobin C from one parent, but a normal gene for regular hemoglobin from the other parent—the “heterozygotes.” Although only one sickle gene gives excellent protection against malaria, one hemoglobin C gene gives only a small amount of protection. To get a full dose of protective power, a person has to have two copies of the C gene12; in other words, she has to inherit one from each parent. Ironically, while two co
pies of the sickle gene kill, a double dose of the C gene cures. On the other hand, while a single sickle gene cures, a single C gene doesn’t do much.

  To see why hemoglobin C is limited to a few regions of Africa, let’s contrast the fates of Sickle Eve, the first person to have the mutant sickle gene, and another little girl I’ll call, inelegantly, “C-Eve,” who was the first to have the mutant C gene. If Sickle Eve is pronounced “Sick Leave,” let’s stretch a bit and pronounce C-Eve as “Sieve,” because all too often protection from malaria trickles through her grasp.

  When Sickle Eve was born she flourished, shrugging off the mosquito bites that sickened and killed other children in her village. About half of her own children inherited her immunity, and their progeny quickly became more numerous than that of other villagers. Only later, when the sickle gene became common enough for a husband and wife to each have a copy, did problems arise, as some children inherited two sickle genes and thus sickle cell disease. In contrast, when C-Eve was born in a neighboring village she was no better off than most other kids in the region. As a toddler she was constantly being bitten by malarious mosquitoes. Like many other kids, she developed fever and was often desperately sick. But, as luck would have it, she was part of the fraction of children who survived up to age five or so, where the threat of death from malaria greatly diminishes.13 C-Eve grew up, married, and watched in helpless agony as half of her children died, either through miscarriage or by fever, as infants and toddlers.

  But the other half of C-Eve’s children survived, grew up, and had kids of their own. When some of these descendants moved to Sickle Eve’s ancestral village and took spouses there, their children were much worse off from malaria than many other children in the village—all descendants of Sickle Eve—so their line quickly died out in that village. However, the descendants who stayed in C-Eve’s ancestral village became somewhat more numerous than the descendants of others in that village. One-half of C-Eve’s children carried the mutation (to little effect), and when the right descendants had children, one-quarter of those kids both had mutations and were much more likely to survive. Still, when their kids grew up and married, often their children would not have nearly as much resistance as their mother, unlike the children of Sickle Eve. Over time, though, more and more lucky babies were born in the village, some of whom married each other, and their children always had strong resistance. But there was a catch. When C-Eve’s offspring moved to a different village and married a local boy or girl, their children lost resistance. So for C-Eve’s progeny to prosper, they had to stay close to home and, like Charles Darwin, marry their kissing cousins.14 (Meanwhile, Sickle Eve’s children could spread their advantage far and wide.)

  With the advance of science we can now understand the reasons behind these seemingly arbitrary twists of fate, which would certainly have baffled C-Eve and her descendants. Since the sickle gene gives resistance to malaria with just one copy, Sickle Eve prospered from the beginning, as did many of her descendants until they married each other and some children inherited two copies of the sickle gene. However, since the hemoglobin C gene needs two copies to be effective, and gives only a small amount or malaria resistance in single copy, then C-Eve was no better off than her fellow villagers. As C-Eve’s progeny increased—initially just by luck—as a percentage of the population of the village, then the small amount of protection from a single copy of the C gene started to give them a statistically better chance of surviving than those with no copy, so the C-gene started to take hold.

  As more villagers had the C gene, there was a better chance that two of them would marry, and have at least a few children who had two copies, and thus full protection against malaria. When those healthy kids grew up and married another villager, it was still rather likely that most or all of their children would have only a single C gene. But if those fortunate children moved to another village that had no one with a C gene, then the children of the intervillage marriage would necessarily have only a single C gene, and so lose almost all the protection from malaria their parent had.15 So to prosper, the children had to stay close to home and preferably marry close relatives.

  The good part of hemoglobin C is that people with two mutant genes have few health problems, unlike either people with two sickle genes (who have sickle disease) or people with two normal hemoglobin genes (who are vulnerable to malaria). The downside is that the C gene spreads only very slowly. In a head-to-head contest the C gene should replace the sickle gene in endemic malarial regions over enough time, all other things being equal, because at C’s best it does as well as the sickle gene at resisting malaria, without the severe collateral damage. However, since all things are rarely ever equal, the prediction is far from certain.16

  TAKE-HOME LESSONS

  Let’s pause here for a moment to consider several simple points about the sickle and HbC mutations. The first point is that both sickle and HbC are quintessentially hurtful mutations because they diminish the functioning of the human body. Both induce anemia and other detrimental effects. In happier times they would never gain a foothold in human populations. But in desperate times, when an invasion threatens the city, it can be better in the short run to burn a bridge to keep the enemy out.

  A second point is that the mutations are not in the process of joining to build a more complex, interactive biochemical system. The sickle and C mutations are mutually exclusive, vying for the same site on hemoglobin—the sixth position of the beta chain. They do not fit together to do something. A related point is that neither hemoglobin mutation occurs in the immune system, the system that is generally responsible for defending the body from microscopic predators. So the mutations are neither making a new system nor even adding to an established one. In this book we are concerned with how machinery can be built. To build a complex machine many different pieces have to be brought together and fitted to one another.

  A final, important point is that even with just those two simple mutations the process is convoluted almost to the point of incoherence.17 Even with just the sickle and C genes—with heterozygote versus homozygote advantage and with varying detrimental effects—the interplay of the mutant and normal genes is chaotic and tangled. Sickle is better in the beginning but C is better in the end; sickle spreads quickly, establishing itself as king of the hill before C can get started; sickle trait carriers are better off marrying someone outside the clan, but C carriers do better by marrying relatives; and so on. It’s not hard to imagine a few more mutations popping up in hemoglobin or other genes to make the process truly Byzantine in its intricacy and cross-purposedness. The chaotic interplay of genes is not constructive at all. In the everyday world of our experience, when many unrelated threads get tangled together, the result is not a pretty tapestry—it’s a Gordian knot. Is that where Darwinian evolution also leads?

  MAN OVERBOARD

  The mutations that yield sickle hemoglobin and HbC are both subtle. In each case a single alteration in a specific nucleotide—one of the building blocks of DNA—altered the gene for the beta chain of hemoglobin so that only one amino acid was different in the mutant proteins. There are, however, cruder, more drastic mutations that also aid in the war with malaria. In this set of mutations a whole gene is tossed out—either accidentally deleted or altered so that it no longer produces any working protein. When that protein is hemoglobin, the resultant class of conditions is called “thalassemia,” from the Greek word for the sea, because it was first noticed in people who lived by the Mediterranean Sea. In fact, thalassemia is widespread in Africa, the Middle East, and Asia.

  Healthy hemoglobins have four chains—two alpha chains and two beta chains. In a person with thalassemia, however, a copy of a gene for one of the kinds of chains of hemoglobin is either deleted or switched off. This causes an imbalance in the total amount of chains that are made by the cell. In some thalassemias there is an excess of beta chains; in others there is an excess of alpha chains. Thalassemias in which the alpha chain is in short supply usu
ally lead to less severe anemia than when the amount of beta chain is deficient. In most alpha thalassemias, a whole gene is deleted. The effects of the deletion can vary considerably. Normal persons have four alpha genes, inheriting two from each parent. Alpha-thalassemic children of alpha-thalassemic parents can be missing one, two, three, or all four alpha genes. If only one or two alpha genes are missing, the remaining two or three alpha genes apparently make enough of the alpha chain to supply the red blood cell with enough working hemoglobin to get by. If no alpha genes are present, the child dies before birth.

  Sickle hemoglobin and hemoglobin C are very specific mutations, each caused by one particular amino acid. In contrast, many—about a hundred—different kinds of mutations halt production of the beta chain, resulting in thalassemias.18 Sometimes a whole beta gene is deleted. Other times the mutant gene has lost important processing signals, which leads either to a malformed beta chain or to a decrease in the amount of beta chain the gene can make. In other cases a few or even just a single nucleotide is changed in the beta gene, rendering it completely nonfunctional. Because there are so many different mutations that can cause thalassemia versus just one that can make sickle or hemoglobin C, thalassemias originate by chance much more frequently. They spread quickly in malarious areas before particular mutations like sickle have a chance to even get started.

  Thalassemia is another detrimental mutation, like sickle hemoglobin or HbC. Even in its mildest form, it is a diminishment of the functioning of the system that supplies oxygen to the tissues. But thalassemia is useful in slowing a malarial invasion. Studies have shown that, although thalassemia doesn’t protect nearly as well as one copy of a sickle cell gene, it still gives about 50 percent protection against malaria (at least for one type of thalassemia), probably by making the red cell more fragile.19 It’s a bridge that can be burned to thwart malarial attack.