The Edge of Evolution Page 3

  FIGURE 2.1

  Invasion of red blood cells by malaria parasites.(Reprinted from Cowman, A.F. and Crabb, B. S. 2006. Invasion of red blood cells by malaria parasites. Cell 124:755–66. Courtesy of Elsevier.)

  Over the centuries, the human genome has tried many different defenses against malaria. In the light of modern science we now understand a great deal about each defense—not only its genetic blueprint, but often its geographical location (where on earth it has appeared) and its success at spreading through the human population. The lessons of these studies are profound and unexpected: 1) Darwinian processes are incoherent and highly constrained; and 2) the battle of predator and prey (or parasite and host), which has often been portrayed by Darwinist writers as a productive arms-race cycle of improvements on each side, is in fact a destructive cycle, more like trench warfare, where conditions deteriorate. The changes in the malaria genome are even more highly instructive, simply because of the sheer numbers of parasites involved. From them we see: 3) Like a staggering, blindfolded drunk who falls after a step or two, when more than a single tiny step is needed for an evolutionary improvement, blind random mutation is very unlikely to find it. And 4) extrapolating from the data on an enormous number of malaria parasites allows us to roughly but confidently estimate the limits of Darwinian evolution for all of life on earth over the past several billion years.

  MONKEYWRENCHES

  Cells are robots. Or rather, because they are so small, “nanobots.” They work by unconscious, automatic mechanisms. To perform the routine tasks of their microscopic lives, cellular nanobots need sophisticated molecular machinery that works without conscious guidance. In order to stick to red blood cells, invade them, feed, and perform other essential tasks, malaria has all sorts of complicated molecular gadgets and gizmos. So does the red blood cell, for all its daily tasks.

  Automated machinery of course can be quite fragile. A sophisticated mechanism can be stopped simply by some sand in its gears, or a well-placed monkeywrench. A robot navigation system can be stymied if anticipated landmarks are missing. Automated machinery may perform very well within certain limits, but can easily fail outside its working specifications.

  Whenever two separate, automated mechanisms must interact, there are many opportunities for things to go wrong. Infection of a person by malaria can be pictured as the invasion of an automated city by a robot army. Although conscious humans can improvise, machines can’t. If the robot army is programmed to, say, cross just one particular bridge, the invasion route can be blocked by burning that bridge. If a robot invader has a key to a certain building in the city, it can be stopped by deforming that building’s lock, so the key no longer fits. On the molecular level, human resistance to malaria is much like these destructive examples.

  The life of a malarial cell inside a human body is quite a complicated one. It interacts with many human structures and systems (the liver, red blood cells, walls of veins, skin, muscle, the immune system, and more) and has to perform many tasks (migration from the site of the mosquito bite to the liver, recognition of the liver, replication in the liver, attachment to a red blood cell, and so on) to successfully prepare to be sucked up in a future blood meal by a hungry mosquito. That means that the parasitic nanobot has many vulnerable points where a well-aimed monkeywrench could make the invasion grind to a halt.

  The evolutionary pressure on humanity to come up with some mutational monkeywrench to counteract malaria is about as intense as it can get. If malaria were much more deadly or contagious than it is, there wouldn’t be any humanity left to worry about. Any person who was born in a malarious region of the earth with some genetic change—one that, say, burned a molecular bridge—that made her resistant to the parasite would be able to have children who inherited her immunity. Her children would survive where many other children in the village would perish of the disease. When her children grew up they would be a larger fraction of the population of the village, simply because the disease kills off other children who don’t have the fortunate genetic change. Over time, the descendants of the lucky woman would outnumber everyone else’s descendants. Eventually every person in the village would carry the resistance mutation. Evolution by random mutation and natural selection would have changed the world, at least in that one respect.

  It turns out that the above scenario has been played out hundreds of times in the course of human history. The inventive human genome has “figured out” a number of different ways to frustrate the nefarious intentions of Plasmodium falciparum (the most virulent species of malaria). In this chapter we’ll examine several evolutionary responses to malaria by humans that show the edge of evolution is indeed past the point of many responses to parasites. Again and again, we’ll see cases in which evolution is destructive, not constructive. The overriding lesson of this chapter is that the metaphor so beloved by Darwinists—that evolution is an arms race—is wrong. Evolution is trench warfare. Let’s start by looking at how one well-known antimalarial monkeywrench also gums up the normal workings of the red blood cell.

  HAMMERED BY SICKLE

  A friendly, winsome young woman, Gail C. would stop by my laboratory about every two weeks when I was a graduate student in biochemistry at the University of Pennsylvania in the mid-1970s. Sometimes her mother would come along, too, to help Gail walk. She would step slowly and stiffly over to a table in the lab and sit down. I would draw a couple of small tubes of blood from a vein in her arm and pay her ten dollars (from my research advisor’s grant money). With effort, she’d then get up and leave. I would take a bit of her blood and subject the hemoglobin to a standard laboratory procedure in which an electrical field pulls the protein through a semisolid gel. Alongside Gail’s blood I’d run a drop of my own. Her hemoglobin moved somewhat more slowly through the gel than mine did—more slowly than most Americans’ would—because Gail had sickle cell disease. I don’t know what happened to Gail over the years, but most people with sickle cell disease die young. They suffer much pain in their shortened lives, all because their hemoglobin has a critical change in its structure.

  Hemoglobin was one of the first proteins studied by scientists in modern times since it is easy to obtain (blood is full of it) and it’s easy to see (most proteins are colorless, but hemoglobin is a brilliant red, and it is packed into red blood cells). Hemoglobin is the protein whose job is to carry oxygen. It isn’t easy to carry oxygen—very few proteins can do it. Hemoglobin, however, is a pro. It not only collects oxygen by binding tightly to it in the lungs, but it also dumps off the oxygen in peripheral tissues where it’s needed. Although simple to describe, this little trick requires very precise engineering of the shape and amino acid sequence of hemoglobin. A number of genetic diseases are known where a single amino acid change destroys hemoglobin’s ability to carry oxygen effectively.

  In sickle cell hemoglobin, a single amino acid differs from normal hemoglobin. Hemoglobin has two copies of each of two distinct kinds of chains of amino acids. The four chains, two “alphas” and two “betas,” all precisely stick to each other in order to do their job. In the beta chain, at position number 6 out of 146 amino acids, a single change causes trouble. That one alteration has alternately been a blessing and a curse, poison and cure, for millions of people of African descent. Although it does not significantly alter the ability of the hemoglobin to carry oxygen, it has other profound effects.

  In 1904 Chicago physician James Herrick examined the blood of a young black man from Grenada, Walter Clement Noel, and was startled to see that his red blood cells were distorted.2 Instead of the usual “Lifesaver” (or “doughnut”) shape, Noel’s cells displayed bizarre shapes, including crescents and sickles. The discovery of the reason for the misshapen cells took another forty years. After World War II the eminent scientist Linus Pauling first showed that the hemoglobin from people carrying the sickle cell gene moved more sluggishly than normal hemoglobin in some lab tests.3 He correctly deduced that there was a change in the structure of the hemo
globin itself. It was the first example discovered of a molecular disease—one that is caused by an aberrant biological molecule. It took ten more years for the exact change in a single amino acid to be uncovered.4

  Essentially, that one change causes the molecule to act as if one part were a strong magnet. Moreover, that “magnet” causes one hemoglobin to stick to a second hemoglobin, and in turn to stick to a third, and so on, until pretty much all the hemoglobin in the cell has stuck together. Sickle hemoglobin congeals into a gelatinous mess inside each red blood cell. This only happens after it has deposited its oxygen and is heading back to the heart in the veins.

  FIGURE 2.2

  Normal (left) and sickled (right) red blood cells.(Drawing by Celeste Behe.)

  Exactly how this leads to the symptoms of the disease, including episodes of sharp pain and the death of some tissues, is still not fully understood. The most popular hypothesis has been that the stiffened cells might get stuck where the bloodstream narrows—inside tiny capillaries, whose size is often smaller than the width of a typical red blood cell. (Normal red blood cells are very flexible and easily squeeze through the capillaries.) The cells stuck at the narrows would cause a traffic jam, stopping flow through a blood vessel, which might kill cells and tissues due to lack of oxygen. That idea, however, has been disputed. We do know that the distorted shape of sickled cells is recognized as abnormal by the spleen, and the cells are destroyed more quickly than usual, leading to anemia. It’s a sobering thought that, although sickle cell disease was the first molecular disorder discovered, nearly sixty years have passed and there is still virtually nothing science can do to cure it.

  We also know that for people who carry the disease, having inherited the gene for it from only one parent but not both, there are nonfatal effects in the blood. About half of the hemoglobin in each of their red blood cells is the sickle form and half isn’t. Usually such people have few or no health problems. It is only when two carriers mate that their children have about a one in four chance of getting the sickle cell gene from each parent, and thus inheriting the full disease. In the United States about one in ten African Americans carry the sickle trait and about a hundred thousand have the disease. In some regions of Africa close to half of the population has the trait; many have the disease.

  The preceding discussion makes sickle hemoglobin sound just awful, a thoroughgoing disaster. And for many people it certainly is exactly that. But if the downside were the whole story, we’d have a real puzzle on our hands: Why has sickle cell disease persisted? Why is it so widespread? Why doesn’t it disappear? Darwin’s theory of evolution says that, other things being equal, those with the fittest genes will survive. But if the sickle cell gene leads to illness and death in those with two copies, why hasn’t natural selection remorselessly weeded it out until none is left? The answer, of course, is that not all other things are equal. In the United States the gene is pretty much an unadulterated bane, but in Africa it can be a blessing. The sickle cell gene confers resistance to malaria.

  SICK LEAVE

  Thousands of years ago in malaria-ridden Africa, in a human community where many women suffered miscarriages or saw their babies die of fever, one child stayed healthy. Like the other kids, she was bitten again and again by mosquitoes, and sometimes got sick. But the illness was never severe and she quickly got back on her feet. When she grew up, she had children. Some of her children could shrug off the insect bites, too, although some couldn’t, and they died. Her robust children grew up, married, and had kids of their own. As generations passed, more and more people in the region traced their ancestry back to that first healthy little girl. Let’s call that first thriving child “Sickle Eve,” because she became the mother of all the living who have genes for sickle hemoglobin. We should pronounce her name “Sick Leave,” however, because she granted to her descendants a leave from the lethal sickness of malaria.

  In one of Sickle Eve’s parents, neither of whom had any special resistance to malaria, a tiny mistake happened when either the sperm or egg was made. The machinery for faithfully copying the parent’s DNA, which does an almost flawless job, slipped. Instead of an exact copy, one (one!) of the billions of nucleotide components of the DNA was changed. The DNA in that reproductive cell, which would provide half of Sickle Eve’s genetic information, now coded for a different amino acid (valine) at the sixth position of the second chain of hemoglobin, instead of the usual one (glutamic acid). The other half of Sickle Eve’s genetic information came from her other parent, who bequeathed to her an unchanged copy of hemoglobin.

  No human at the time knew why little Sickle Eve could work and play and live while other children were dying or languishing in sickbeds. But the malarial parasite knew—or found out. When a malarial cell was duly injected into Sickle Eve by the bite of a mosquito, it blithely made its usual journey to her liver and routinely changed its form. The nanobot had all its standard machinery on hand to leave the liver, recognize and stick to Sickle Eve’s red blood cells, invade, feed, and reproduce. The predator docked to a red blood cell, oriented itself, released a fusillade of enzymes and proteins to prepare a tight junction, reformed its skeleton, and glided into the blood cell.

  But then, from the predator’s vantage point, something went terribly wrong. As the parasite fed, the inside of Sickle Eve’s red blood cell changed. Random molecular motions always cause individual hemoglobins to bump into each other. But this time, instead of bouncing off as usual, they stuck together. More and more proteins clung to each other, and soon the whole liquid hemoglobin solution of the red cell began to gel. The spreading, gelatinous, semisolid mass pressed against the invader and against the red blood cell membrane, distorting its shape. As it was swept along in the bloodstream, before the parasite had time to anchor to the walls of a vein, the infected cell passed through the spleen. Ever alert to rid the body of old, damaged blood cells, the spleen grabbed the warped cell and destroyed it, along with the killer hidden inside. Sickle Eve survived, utterly oblivious to the battle her hemoglobin had fought.

  TROUBLES AND TINKERING

  The invisible mutation in hemoglobin, which first emerged in Sickle Eve, bestowed health upon many of her children and grandchildren. But as generations passed and her posterity grew more numerous, some descendants married other descendants. One particular husband and wife both had a copy of the sickle gene they had inherited from their ancestor. Their children suffered a variety of fates. Two of the couple’s eight children were sickly from birth, with distended bones and spleen; they died before the age of ten. Instead of just one copy of the sickle gene, by a roll of the genetic dice these two wretched children inherited two copies. As we now know, when only half of a person’s hemoglobin takes the sickle form, it won’t solidify on its own. It needs a further push to make it gel. That push is supplied by the invasion of the malarial parasite. The parasite’s metabolic activity raises the amount of acid in the blood cell, triggering the aggregation of the hemoglobin. For those lucky Sickle Eve descendants, only the infected cells are destroyed. But when all of the hemoglobin in a red blood cell is sickle hemoglobin, it needs no extra push. These children have full-fledged sickle cell disease, as opposed to the half-gene version known as “sickle trait.”

  Sickle cell disease is a genetic death sentence, especially in areas without access to modern medicine. But malaria is often a death sentence, too. Continuing our story from above, although two of the couple’s eight children died of sickle cell disease, two others also left no descendants. One of them died of malaria and the other, crippled by the disease, never married. Those two had inherited no copies of the sickle gene, and they missed out on Sickle Eve’s advantage. The four surviving children who left progeny had “sickle trait”—one copy each of normal and sickle hemoglobin genes. Over time, as the robust children married and begot their own offspring, and as other carriers of the sickle gene did likewise, “sickle trait” people flourished. This is a Darwinian success story, but it’s the success of a
trench-war standoff. Natural selection balanced heartbreak against heartbreak, as an equilibrium was negotiated between the plague of malaria and the curse of sickle cell disease.

  How often does random mutation produce a “beneficial” change like sickle trait? By studying the DNA of many human populations, scientists have concluded that this particular mutation has arisen independently no more than a few times in the past ten thousand years—possibly only once.5

  In evolution, equilibria are made to be broken. If, by tinkering with the machinery of life, a further mutation were able to alleviate the waste of lives from sickle cell disease without decreasing protection against malaria, then natural selection could grab hold of the variation and run with it. Over the generations that process has happened in populations of African descent, numerous times. The results can be broken down into two categories. I’ll discuss the less numerous but more elegant category second, and start with the more frequent but less adroit one, something called “hereditary persistence of fetal hemoglobin,” or HPFH.

  As I briefly noted earlier, hemoglobin is actually made of four amino acid chains stuck together. There are two copies of one kind of chain (the alpha chain) and two copies of a similar but distinct chain (the beta chain). At least, that’s the way it is in people after birth. Before birth, however, there is another kind of hemoglobin. Postnatal hemoglobin allows us to use our lungs for oxygen. But an unborn baby has to get her oxygen from her mother, through the umbilical cord. Fetal hemoglobin has a slightly different shape that allows it to pull oxygen away from Mom’s hemoglobin, sort of like using a stronger magnet to pull a paperclip away from someone else’s magnet. Fetal hemoglobin has two alpha chains and two gamma chains (no beta chains). While they are pretty similar to beta chains, gamma chains also have a number of differences, making the protein a stronger oxygen magnet.