The Edge of Evolution Read online

  OTHER RED CELL GENES

  Hemoglobin is a good protein to alter in the fight against malaria because it’s the most abundant protein in the red blood cell. If hemoglobin isn’t working just right—if it gels or is unstable—then the red cell in which malaria travels will not be as strong, and will have a shortened lifespan. Any additional stress on the fragile cell from the malarial parasite might quickly push it over the edge, causing it and the parasite to be destroyed by the spleen. It’s not surprising that so many different mutations to hemoglobin have prospered in malarious areas, since there are many different ways to foul up the workings of a machine.

  But although hemoglobin is the most abundant protein in the red blood cell, it certainly isn’t the only one. When some of the other red blood cell proteins mutate, a person acquires some resistance to malaria. In this section I’ll briefly mention several of those proteins. The point to keep in mind is this: As with hemoglobin, the mutations all involve diminishing the function of a protein, or jettisoning it altogether. Readers who do not feel it necessary to pay close attention to the technical details may prefer to skip the rest of this section.

  One useful gadget of the red blood cell nanobot is a protein called “glucose-6-phosphate dehydrogenase,” which (mercifully) can be abbreviated as G6PD. G6PD is responsible for generating “reducing power” in the cell, which can be thought of as something akin to antacid. The red blood cell has a dangerous job. A cell carrying a lot of oxygen can be likened to a person carrying glass bottles of acid. Once in a while one of those bottles is going to accidentally drop and break, and the person will be splashed and burned. In the red blood cell the oxygen is like the acid and the hemoglobin like the glass bottles. Although hemoglobin does a good job, even in the best of circumstances, occasionally a hemoglobin molecule “breaks,” the oxygen (or chemically related material) escapes, and the cell can be burned. To deal with the anticipated breakage, G6PD leads to a chemical (called glutathione) that, under the guidance of other repair machinery, sops up the spilled oxygen, limiting the damage as much as possible.

  Junking G6PD makes the red blood cell more fragile, which as we have seen can be a net plus during an invasion by malaria.20 Infected, more-fragile cells may be spotted more easily by the spleen and destroyed. Hundreds of mutations are known that alter the amino acid sequence of G6PD, and either destroy or greatly diminish its effectiveness. Depending on the nature of the mutation, and on whether it occurs in a man or woman,21 it can lead to anemia. Because so many different mutations can break the G6PD gene, the rate of their appearance is much, much higher than the rate of appearance of the mutation for sickle hemoglobin. G6PD mutations are widespread in malarious regions around the world, from Africa to Asia. Studies have indicated they can give roughly the same degree of protection against malaria as thalassemia.22

  Another protein machine that normally helps keep the red blood cell nanobot humming is called “band 3” protein. Band 3 protein is situated in the membrane of the red blood cell. Its job is to be a supply-exchange portal, allowing some kinds of needed materials to come into the cell, and to pump out waste products.23 In some malarious regions, particularly in Melanesia, the population contains a high percentage of people with defective band 3 genes, which again seems to confer some resistance to malaria.24 How it does so is not clear. Perhaps it, too, works by increasing the fragility of the red blood cell. Alternatively, it may work by forming clumps more easily than usual. Clumped band 3 proteins are normally a sign that a cell is aging, and the body targets those cells for destruction.25 In some regions the percentage of the population with one copy of a defective band 3 gene is quite high (about 20 percent) but no people have been found there who have two defective copies. The grim implication is that inheriting two broken copies kills a child before birth. A high price for a population to pay, but apparently less than enduring the full brunt of malaria.

  Malaria grabs onto red blood cells by seizing on certain proteins that are akin to antennas on the outside of the cells. One “antenna” protein sticking out from the surface of the red blood cell is called “Duffy antigen.” A species of malarial parasite called P. vivax (a milder cousin of the vicious P. falciparum) specifically grabs hold of it as a prelude to invasion. However, almost all people in west and central Africa are completely immune to P. vivax malaria because their red blood cells no longer make Duffy antigen. A single nucleotide change in DNA does the trick.26 Like HbC, the mutated gene has to be present in two copies to have much of a benefit against malaria. Turning off Duffy antigen in red cells has little noticeable ill effect, although it may be associated with an increased risk of prostate cancer.

  Some other mutations are also known to help in the fight against malaria, but the ones discussed so far are the best characterized. Here’s the bottom line: They are all damaging. Some are worse than others, but all are diminishments; none are constructive. Like sickle hemoglobin, they are all acts of desperation to stave off an invader.

  BACK TO THE STONE AGE

  Over much of the second half of the twentieth century the United States and Soviet Union engaged in mutual saber-rattling of the most unnerving sort. Verbal threats were backed up by a terrifying arms race. The United States developed nuclear weapons, then so did the U.S.S.R. One side made larger weapons; the other improved the accuracy of theirs. One side placed weapons in countries close to the other; the other side put them in submarines. One side developed an antimissile system; the other invented sophisticated evasion equipment. By some miracle the weapons haven’t been used yet, but there are no guarantees for the future.

  The arms race in ballistic missiles and related technology between the human superpowers was of course carried out by intelligent agents acting purposefully to achieve a goal (however misconceived). That is pretty much the absolute opposite of Darwinian evolution, which posits only blind, purposeless genetic accidents, some of which might be favored by the automatic effects of natural selection. Nonetheless, some Darwinists have professed to see in human arms races a good analogy for blind evolution. For example: Suppose that in the distant past the ancestor of a modern cheetah started hunting the ancestor of a modern gazelle. At that time both were relatively slow compared to their descendants, but even then some of the faster cheetahs caught some of the slower gazelles. After dinner, pairs of faster, better-fed cheetahs repaired to the brush to produce more offspring than hungry, slower cheetahs; laggard gazelles simply disappeared into cheetah stomachs while the speedier ones survived. Natural selection in action.

  The occasional random mutation that made a cheetah or a gazelle a bit faster would favor its descendants, so, the story continues, speedier cheetahs would set the stage for the evolution of speedier gazelles, and vice versa. Over many generations both cheetahs and gazelles would get faster, even though the average number of gazelles consumed by cheetahs might stay roughly constant. So by competing against each other, the two species would both get better, although neither would entirely surpass the other. Another label that has been pasted on this concept is the “Red Queen effect,” after the silly statement by the Red Queen to Alice that in Wonderland you have to run as fast as you can just to stay in the same place. The idea is that in evolution, a species and its enemies all have to keep getting better just to keep surviving.

  At first blush the idea of an arms race sounds plausible, and some ardent Darwinists have proclaimed it to be perhaps the most important factor in progressive evolution—the building of coherent, complex systems. In his classic book defending Darwin, The Blind Watchmaker, Oxford biologist Richard Dawkins announced:

  I regard arms races as of the utmost importance because it is largely arms races that have injected such “progressiveness” as there is in evolution. For, contrary to earlier prejudices, there is nothing inherently progressive about evolution.27

  And:

  The arms-race idea remains by far the most satisfactory explanation for the existence of the advanced and complex machinery that animals and
plants possess.28

  Dawkins’s deduction of the importance of arms races in evolution is wishful thinking. To play along, let’s consider the illustration of the cheetah and gazelle, but a bit more skeptically. How could a gazelle better avoid a faster cheetah? One way, as the standard story has it, is to become faster itself. But another way might be to become better at making quick turns, in order to dodge the predator in a chase. Or to develop stronger horns for defense. Or tougher skin. Or grow bigger. Or develop camouflage. Or graze where cheetahs aren’t. Or when cheetahs are asleep. Or close to a forest in which to hide. Or any of a hundred other strategies. Or all of the above. Like the many different ways human genes can change to help fend off malaria, gazelles could change in numerous, unconnected ways.

  The Just-So story seems plausible at first only because it doggedly focuses its gaze on just one trait—speed—ignoring the rest of the universe of possibilities. But in the real world Darwinian evolution has no gaze to focus; it is blind. In a blind process, there can be no intentional building on a single trait, continually improving a discrete feature. Anything that works at the moment, for the moment, will be selected whether it is “progressive” or not—to hell with the future. The descendants of a slightly faster gazelle might go on to develop slightly better camouflage or slightly different feeding strategies or to slightly change any of innumerable other traits, eliminating the need for speed. If that were the case, gazelles would not keep getting faster. They would change over time in myriad, disjointed, jumbled ways. There is no reason to expect the coherent development of a single trait in a Darwinian arms race.

  You may be wondering whom to believe at this point, since I am just countering Dawkins’s suppositions with my own. But consider this. Although there have been some studies showing modest arms races with smaller animals—ants, other invertebrates, and microorganisms—there have been absolutely no studies that document that large animals change in the way Dawkins supposes. We know the most about “arms races” between parasites and hosts. Far and away the most extensive relevant data we have on the subject of evolution’s effects on competing organisms is that accumulated on interactions between humans and our parasites. As with the example of malaria, the data show trench warfare, with acts of desperate destruction, not arms races, with mutual improvements.

  The thrust and parry of human-malaria evolution did not build anything—it only destroyed things. Jettisoning G6PD wrecks, it does not construct. Throwing away band 3 protein does likewise. Sickle hemoglobin itself is not an advancement of the immune system; it’s a regression of the red blood cell. Even the breaking of the normal controls in HPFH doesn’t build a new system; it’s just plugging another hole in the dike.

  The arms race metaphor itself is misconceived. The relationship between malaria and humans is nature red in tooth and claw. Real arms races are run by highly intelligent, bespectacled engineers in glass offices thoughtfully designing shiny weapons on modern computers. But there’s no thinking in the mud and cold of nature’s trenches. At best, weapons thrown together amidst the explosions and confusion of smoky battlefields are tiny variations on old ones, held together by chewing gum. If they don’t work, then something else is thrown at the enemy, including the kitchen sink—there’s nothing “progressive” about that. At its usual worst, trench warfare is fought by attrition. If the enemy can be stopped or slowed by burning your own bridges and bombing your own radio towers and oil refineries, then away they go. Darwinian trench warfare does not lead to progress—it leads back to the Stone Age.

  In a real war, everything relentlessly gets worse. In its real war with malaria, the human genome has only diminished.

  THE MORE THE MERRIER

  Vain creatures that we are, no topic holds our interest more than ourselves. Yet perhaps a focus on us humans distorts the picture. Although our cities seem crowded, the number of humans on earth is actually minuscule compared to the numbers of microscopic creatures. For each human sick with malaria in the world, there are roughly a trillion parasites. The more individuals of a species there are, and the shorter the life span of each generation, the more opportunities for beneficial mutations pop up. To get a better idea of what random mutation and natural selection—Darwinian evolution—can do, let’s consider that far more numerous species, Plasmodium falciparum itself. How has the million-murdering death evolved during its encounter with humans?

  3

  THE MATHEMATICAL LIMITS OF DARWINISM

  For millennia humans struggled with malaria in an unconscious war, where the only defense was by attrition in the evolutionary process of random mutation and natural selection envisioned by Charles Darwin. But in the past five hundred years a radically different factor has transformed the war. Using our ability to reason, over time we humans have learned much about the world that was hidden from our ancestors. In particular, the discovery of microscopic predators has allowed us to take the fight to the enemy. Rather than waiting for a lucky mutation to come along, medicines have been both discovered and invented that can kill malaria. At first the new, rational phase of the war was restricted to the use of plants that nature herself provided. But in the past three-quarters of a century advances in chemistry, medicine, and basic biology have led to new drugs that nature never thought of.

  The initial glorious result was sweeping victory wherever the battle was joined. The cruel malarial parasites perished by the uncounted trillions. In the giddy days of the 1950s there was much talk of totally eradicating malaria. Humanity would soon live in a world free of its ancient nemesis. Optimism was cheap. Around the same time it was thought that other tiny scourges—virulent bacteria, viruses, and even agricultural insect pests—could be fended off by drugs and insecticides. Early victories on those fronts were also easy to come by.

  But the mood these days is somber. The miracle drugs are in retreat or have failed. The title of a recent article in the journal Science, “A Requiem for Chloroquine,”1 refers to the medicine that was for decades the standard treatment for malaria. Gone is talk of a final victory over malaria, replaced by modest hopes that maybe it at least can be contained. Malaria seems actually to be on the increase in Africa.2 Although it does not yet look as if we’re headed back to the bad old days, the war between humanity and P. falciparum has reached an uneasy stalemate. To our chagrin, the unexpected stubbornness of the parasite proves that evolution is powerful for foes and friends alike. Sickle Eve isn’t the only one to benefit from a fortunate mutation. P. falciparum knows that trick, too. Here, too, lies some of the best available evidence for Darwinism—as well as clear evidence of its limits.

  A NATURAL CURE

  For centuries of recorded history, even while entire civilizations were obliterated by it, humanity remained helpless in the face of malaria. Hippocrates—the Father of Medicine himself—ascribed its periodic fevers to an imbalance in the body’s four “humors” (blood, phlegm, and black and yellow bile). Medieval men of medicine thought that the fevers were caused by bad air (mal’aria is Italian for bad air) rising from fetid swamps in the summer. Treatments included bleeding with leeches—in retrospect not a good idea for people suffering from malaria-induced anemia.

  The modern fight against malaria began with the discovery that powder made from the bark of the cinchona tree in the South American Andes was useful for treating fever. Although it probably wasn’t used for malaria by the local natives, in the seventeenth century European settlers brought it back across the Atlantic, where it was first used unwittingly on malarial patients. When a few members of royalty were cured by cinchona bark, demand soared. The cinchona tree was cultivated for export by the Dutch on their Indonesian colonial plantations. The bark became widely available and literally changed the world. With quinine from cinchona bark, Europeans could colonize and operate commercial ventures in tropical climates, usually with the help of African or Indian workers who, because of sickle trait or thalassemia, had a measure of natural resistance to malaria.

  Quinine, t
he active ingredient, was first isolated from cinchona bark by French chemists in the early nineteenth century. It was not until the 1940s, however, that the eminent organic chemist Robert Woodward synthesized the compound in his laboratory at Harvard. In the 1930s a synthetic antimalarial drug similar to quinine was developed by a German pharmaceutical firm. During World War II a cache of the drug was captured by the American army, which reformulated it as chloroquine. Like quinine, chloroquine is a rather small molecule (not a big, “macro” molecule) and has a core structure called a “quinoline.” Chloroquine is a simpler molecule than quinine and thus is much easier to synthesize in the lab. Because of its effectiveness and cheap production cost, chloroquine became the drug of choice for the treatment of malaria for decades.

  Yet within a few years after the introduction of chloroquine, reports popped up of its failure to cure some patients. As time passed, the reports became more frequent, and by the 1980s chloroquine was ineffective against the majority of cases of P. falciparum. To understand how chloroquine once worked and why it has failed, let’s look at some of the nuts and bolts of the malarial nanobot.

  TOXIC WASTE

  P. falciparum feeds on the hemoglobin inside a human red blood cell. But there’s a hitch. Although the parasite can digest the protein part of hemoglobin—breaking it down to amino acids which it reuses to help construct copies of itself—it can’t use the heme part of hemoglobin. Heme, which gives blood its red color, is a small molecule (roughly the same size as chloroquine, and about one-thirtieth the size of one of the four protein chains of hemoglobin) that sticks to the protein, but heme is not made of amino acids. It is an indigestible and poisonous waste product that the parasite urgently has to neutralize. If heme accumulates in the parasite’s digestive compartment—its “stomach”—the bug dies. Normally, P. falciparum ties together the waste heme to form something called hemozoin, which is harmless. But chloroquine interferes with waste removal, so that the toxic heme remains free. Exactly how heme kills the parasite isn’t quite clear. But the fate of drowning in its own waste is a fitting end for the agent of such human misery.