Chapter 4
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Chapter 4 EVIDENCE FOR DESIGN: MOLECULAR BIOCHEMISTRY
I. Introduction. When Darwin proposed his theory in the 19th Century, he specified the criterion for its falsification. "If it could be demonstrated," he said, "that any complex organ existed which could not possibly have been formed by numerous, successive, slight modifications, my theory would absolutely break down." Darwin's criterion has been met. At that time, scientists were unable to see inside the cell, because the instruments for doing so had not been invented. It was supposed that each cell was an undifferentiated blob of protoplasm - that is, it was supposed that cells were very simple things, and one cell might be as good as another for any number of necessary purposes, such as carrying oxygen in the bloodstream or reacting to light striking the retina. According to Michael J. Behe, the beginning of modern biochemistry can be dated to 1958, when the structure of a complex protein (myoglobin) was first determined using x-ray crystallography. It has only been in the last 40 years that this and other technological developments, such as the tunneling electron microscope and nuclear magnetic resonance imaging, have revealed the staggering complexity of living cells. Each one is a veritable city of factories, machines, streets and transport vehicles, constantly engaged in the mind-boggling life processes of metabolism, sensation, motor function, circulation and respiration, to name but a few. But it is not merely the degree of complexity which poses a problem for Darwinism; it is the kind of complexity, to which Behe refers as "irreducible complexity." A system is irreducibly complex if there is no simpler version that would have any function at all. Molecular biochemists are finding that all of the proteins comprising many of these molecular machines are indispensable to their functioning: remove any of them, and the machine does not merely function at some reduced level of efficiency - it stops dead. If any simpler form of the machine would not have functioned at all, then without the entire system being in place and fully functioning from the beginning, the creature could not have survived; if it could not have survived, it could not have reproduced; and if it could not have reproduced, there could not have been any succeeding generations upon which the environmental pressures toward natural selection might have operated. If the environmental pressures toward natural selection could not have operated, then according to evolutionary theory itself, the development of one species into another could not have taken place. This is the evidence which has evolutionists completely stymied, and it is perfectly obvious why: anyone considering the degree and quality of the complexity found in biological systems will recognize, based on logic and unvarying experience, that such complexity cannot and does not arise accidentally. Nor have scientists suggested how it could have happened. "[N]one of the papers published in JME [the Journal of Molecular Evolution] over the entire course of its life as a journal," says Behe, "has ever proposed a detailed model by which a complex biochemical system might have been produced in a gradual, step-by-step Darwinian fashion." Behe lists several biochemical systems which might be candidates for such studies; then he continues: The very fact that none of these problems is even addressed, let alone solved, is a very strong indication that Darwinism is an inadequate framework for understanding the origin of complex biochemical systems. . . . The reason for this appears to be similar to the reason for the failure to explain the origin of life: a choking complexity strangles all such attempts."1 The magnitude of the complexity of living things is difficult to convey in simple, short sentences. Perhaps it may merely be said that living things are typified by a chain of complexity within complexity, almost endlessly, beyond this observer's capacity for amazement. There can be no substitute for a more detailed description. II. Levels of Complexity. There are many amino acids of many different kinds; but there are 20 of them which combine in various ways to form proteins, much as letters of the alphabet are combined to form words. Each amino acid is itself a complex structure. (1) On the left side of the molecule is a nitrogen-containing group called an amine, consisting of one atom of nitrogen and three of hydrogen. Proteins do not float around like floppy chains. Once a protein is fabricated in the cell, it folds into itself in a specific way, depending on the particular sequence of the various types of amino acids. Electrically charged particles attract opposite charges, hydrophobic side chains group together to squeeze out water, and large side chains are excluded from small spaces. This folding process may take anywhere from a fraction of a second to a minute, depending on the complexity of the protein. In this way, each protein takes on a very specific structure; and the shape of each protein is essential to its function. . . . [A] given protein has only one or a few uses: rhodopsin cannot form skin, and collagen cannot interact usefully with light. Therefore a typical cell contains thousands and thousands of different kinds of proteins to perform the many tasks of life.3 All eukaryotic cells (which include the cells of all organisms except bacteria) contain a membrane, a nucleus (containing the cell's DNA), a number of mitochondria (energy-producing structures), the endoplasmic reticulum (ER)(for protein synthesis), the Golgi apparatus (for modifying proteins made by the ER), and lysosomes (for breaking down used-up molecules).6 Behe maintains that the human body is comprised of hundreds of trillions of cells7; but Newsweek Magazine puts the number at only 100 billion cells.8 Behe says that the simplest self-sufficient, replicating cell has the capacity to produce thousands of different proteins and other molecules, at different times and under variable conditions. Synthesis, degradation, energy generation, replication, maintenance of cell architecture, mobility, regulation, repair, communication - all of these functions take place in virtually every cell, and each function itself requires the interaction of numerous parts.9 We know, of course, that the foregoing sketch is not at all an exhaustive description of the many levels of complexity in biological systems. We barely touched on the atomic elements contained in each protein, and the element required at each position is specific. Atoms themselves are exceedingly complex, with protons, neutrons and electrons in specific configurations, and we have recently learned that protons and neutrons are composed of a half-dozen particles which are smaller yet. The forces binding these particles together are poorly understood. And proceeding in the other direction, toward larger scales, we have not even begun to describe how the molecular machines made of these proteins are themselves parts of systems within systems within systems within the human body, which itself must, of course, live in a certain harmony with the biosphere, which, in turn, is part of a highly specified, interacting solar system, and so on, right on up to the level of the cosmos, which, as we shall see in Chapter 5, is a closely calibrated, finely-tuned system on which all of the subsystems below it are strictly dependent. III. Specific Examples. Behe examines several biochemical systems to illustrate his argument: 1. The blood clotting process in humans; 2. The motion of the cilium; 3. The propulsion of the flagellum; 4. Eyesight: the process whereby a chemical signal is caused to cross the membrane of the human retina when the retina is struck by a photon; 5. Intra-cellular transport of glucose molecules in humans; 6. The development of the human immune response; and 7. AMP synthesis. A. Blood clotting: "Rube Goldberg in the Blood". Foghorn Leghorn, a loudmouth rooster, was a character in the Bugs Bunny cartoon show. Behe tells of an episode in which a baby chick sets a trap for Leghorn as revenge for certain abuse. The chick places a dollar bill in Leghorn's path. The dollar bill is tied by a string to a stick propped against a ball. When Leghorn picks up the dollar bill, the string pulls the stick away from the ball, allowing the ball to roll away and over a cliff, falling on the end of a seesaw, sending a rock into the air. As the rock ascends, a piece of sandpaper attached to the rock strikes a match, which lites a cannon, which fires its cannonball into a funnel. The cannonball rolls down the funnel and out the bottom, hitting a lever that starts a circular saw. The saw cuts a rope holding up a telephone pole, which then falls on Leghorn, pounding him into the ground. Such contrivances were first popularized by a gentleman by the name of Rube Goldberg, and have been known ever since as "Rube Goldberg contraptions" - needlessly complex machines designed to accomplish trivial tasks. The title of the chapter is "Rube Goldberg in the Blood." Behe uses the cartoon episode as an illustration for blood clotting partly because, as he notes, "the Rube Goldberg machine is irreducibly complex. It is a single system composed of several interacting parts that contribute to the basic function, and where the removal of any one of the parts causes the system to cease functioning." What follows is Behe's description of the "cascade" of molecular processes which results in the stanching of the flow of blood from a wound. PATCHWORK About 2 to 3 percent of the protein in blood plasma (the part that's left after the red blood cells are removed) consists of a protein complex called fibrinogen. The name fibrinogen is easy to remember because the protein makes "fibers" that form the clot. Yet fibrinogen is only the potential clot material. Like the telephone pole before it is felled in the story about Foghorn Leghorn, fibrinogen is a weapon waiting to be unleashed. Almost all of the other proteins involved in blood clotting control the timing and placement of the clot. This too is similar to our cartoon example: all components except the telephone pole were required to control the pole's fall. Fibrinogen is a composite of six protein chains, containing twin pairs of three different proteins. Electron microscopy has shown that fibrinogen is a rod-shaped molecule, with two round bumps on each end of the rod and a single round bump in the middle. So fibrinogen resembles a set of barbells with an extra set of weights in the middle of the bar. Normally fibrinogen is dissolved in plasma, like salt is dissolved in ocean water. It floats around, peacefully minding its own business, until a cut or injury causes bleeding. Then another protein, called thrombin, slices off several small pieces from two of the three pairs of protein chains in fibrinogen. The trimmed protein - now called fibrin2 - has sticky patches exposed on its surface that had been covered by the pieces that were cut off. The sticky patches are precisely complementary to portions of other fibrin molecules. The complementary shapes allow large numbers of fibrins to aggregate with each other, like the tubulin tuna cans from Chapter 3. Just as tubulin does not aggregate to form a random glob but forms a smokestack, however, neither do fibrins stick randomly. Because of the shape of the fibrin molecule, long threads form, cross over each other, and (much as a fisherman's net traps fish) make a pretty protein meshwork that entraps blood cells. This is the initial clot (Figure 4 2). The meshwork covers a large area with a minimum of protein; if it simply formed a lump, much more protein would be required to clog up an area. Thrombin, which cuts off the pieces from fibrinogen, is like the circular saw from the Foghorn Leghorn cartoon. Like the saw, thrombin sets in motion the final step of a controlled process. But what if the circular saw ran continuously, without needing the other steps to turn it on? In that case the saw would immediately cut the rope holding up the telephone pole, well before Foghorn moseyed into the vicinity. Similarly, if the only proteins involved in blood coagulation were thrombin and fibrinogen, the process would be uncontrolled. Thrombin would quickly clip all of the fibrinogen to make fibrin; a massive clot would form throughout the animal's circulatory system, solidifying it. Unlike cartoon characters, real animals would rapidly perish. To avoid such an unhappy ending an organism must control the activity of thrombin.11 THE CASCADE The body commonly stores enzymes (proteins that catalyze a chemical reaction, like the cleavage of fibrinogen) in an inactive form for later use. The inactive forms are called proenzymes. When a signal is received that a certain enzyme is needed, the corresponding proenzyme is activated to give the mature enzyme. As with the conversion of fibrinogen to fibrin, proenzymes are often activated by cutting off a piece of the proenzyme that is blocking a critical area. The strategy is commonly used with digestive enzymes. Large quantities can be stored as inactive proenzymes, then quickly activated when the next good meal comes along. Thrombin initially exists as the inactive form, prothrombin. Because it is inactive, prothrombin can t cleave fibrinogen, and the animal is saved from death by massive, inappropriate clotting. Still, the dilemma of control remains. If the cartoon saw were inactivated, the telephone pole would not fall at the wrong time. If nothing switches on the saw . . . it would never cut the rope; the pole wouldn t fall even at the right time. If fibrinogen and prothrombin were the only proteins in the blood-clotting pathway, again our animal would be in bad shape. When the animal was cut, prothrombin would just float helplessly by the fibrinogen as the animal bled to death. Because prothrombin cannot cleave fibrinogen to fibrin, something is needed to activate prothrombin. Perhaps the reader can see why the blood-clotting system is called a cascade - a system where one component activates another component, which activates a third component, and so on. Since things are beginning to get complicated, it will help a lot to keep track of the discussion with Figure 4-3. A protein called Stuart factor cleaves prothrombin, turning it into active thrombin that can then cleave fibrinogen to fibrin to form the blood clot. Unfortunately, as you may have guessed, if Stuart factor, prothrombin, and fibrinogen were the only blood-clotting proteins, then Stuart factor would rapidly trigger the cascade, congealing all the blood of the organism. So Stuart factor also exists in an inactive form that must first be activated. At this point there's a little twist to our developing chicken-and-egg scenario. Even activated Stuart factor can't turn on prothrombin. Stuart factor and prothrombin can be mixed in a test tube for longer than it would take a large animal to bleed to death without any noticeable production of thrombin. It turns out that another protein, called accelerin, is needed to increase the activity of Stuart factor. The dynamic duo accelerin and activated Stuart factor cleave prothrombin fast enough to do the bleeding animal some good. So in this step we need two separate proteins to activate one proenzyme. Yes, accelerin also initially exists in an inactive form, called proaccelerin (sigh). And what activates it? Thrombin! But thrombin, as we have seen, is further down the regulatory cascade than proaccelerin. So thrombin regulating the production of accelerin is like having the granddaughter regulate production of the grandmother. Nonetheless, due to a very low rate of cleavage of prothrombin by Stuart factor, it seems there is always a trace of thrombin in the bloodstream. Blood clotting is therefore auto-catalytic, because proteins in the cascade accelerate the production of more of the same proteins. We need to back up a little at this point because, as it turns out, prothrombin as it is initially made by the cell can't be transformed into thrombin, even in the presence of activated Stuart factor and accelerin. Prothrombin must first be modified (not shown in Figure 4 2) by having ten specific amino acid residues, called glutamate (Glu) residues, changed to y-carboxyglutamate (Gla) residues. The modification can be compared to placing a lower jaw onto the upper jaw of a skull. The completed structure can bite and hang on to the bitten object; without the lower jaw, the skull couldn't hang on. In the case of prothrombin, Gla residues "bite" (or bind) calcium, allowing prothrombin to stick to the surfaces of cells. Only the intact, modified calcium-prothrombin complex, bound to a cell membrane, can be cleaved by activated Stuart factor and accelerin to give thrombin. The modification of prothrombin does not happen by accident. Like virtually all biochemical reactions, it requires catalysis by a specific enzyme. In addition to the enzyme, however, the conversion of Glu to Gla needs another component: vitamin K. Vitamin K is not a protein; rather, it is a small molecule, like the 11-cis-retinal (described in Chapter 1) that is necessary for vision. Like a gun that needs bullets, the enzyme that changes Glu to Gla needs vitamin K to work. One type of rat poison is based on the role that vitamin K plays in blood coagulation. The synthetic poison, called "warfarin" (for the Wisconsin Alumni Research Fund, which receives a cut of the profits from its sale), was made to look like vitamin K to the enzyme that uses it. In the presence of warfarin the enzyme is unable to modify prothrombin. When rats eat food poisoned with warfarin, prothrombin is neither modified nor cleaved, and the poisoned animals bleed to death. But it still seems we haven't made much progress - now we have to go back and ask what activates Stuart factor. It turns out that it can be activated by two different routes, called the intrinsic and the extrinsic pathways. In the intrinsic pathway, all the proteins required for clotting are contained in the blood plasma; in the extrinsic pathway, some clotting proteins occur on cells. Let's first examine the intrinsic pathway. (Please follow along using Figure 4-3.) When an animal is cut, a protein called Hageman factor sticks to the surface of cells near the wound. Bound Hageman factor is then cleaved by a protein called HMK to yield activated Hageman factor. Immediately the activated Hageman factor converts another protein, called prekallicrein, to its active form, kallikrein. Kallikrein helps HMK speed up the conversion of more Hageman factor to its active form. Activated Hageman factor and HMK then together transform another protein, called PTA, to its active form. Activated PTA in turn, together with the activated form of another protein (discussed below) called convertin, switch a protein called Christmas factor to its active form. Finally, activated Christmas factor, together with antihemophilic factor (which is itself activated by thrombin in a manner similar to that of proaccelerin) changes Stuart factor to its active form. Like the intrinsic pathway, the extrinsic pathway is also a cascade. The extrinsic pathway begins when a protein called proconvertin is turned into convertin by activated Hageman factor and thrombin. In the presence of another protein, tissue factor, convertin changes Stuart factor to its active form. Tissue factor, however, only appears on the outside of cells that are usually not in contact with blood. Therefore, only when an injury brings tissue into contact with blood will the extrinsic pathway be initiated. (A cut plays a role similar to that of Foghorn Leghorn picking up the dollar. It is the initiating event - something outside of the cascade mechanism itself.) The intrinsic and extrinsic pathways cross over at several points. Hageman factor, activated by the intrinsic pathway, can switch on proconvertin of the extrinsic pathway. Convertin can then feed back into the intrinsic pathway to help activated PTA activate Christmas factor. Thrombin itself can trigger both branches of the clotting cascade by activating antihemophilic factor, which is required to help activated Christmas factor in the conversion of Smart factor to its active form, and also by activating proconvertin. Slogging through a description of the blood-clotting system makes a fellow yearn for the simplicity of a cartoon Rube Goldberg machine.12 . . . [T]he clotting cascade depends critically on the timing and speed at which the different reactions occur. An animal could solidify if thrombin activated proconvertin at the wrong time; it could bleed to death if proaccelerin or antihemophilic factor were activated too slowly. An organism would fade into history if thrombin activated protein C much faster than it activated proaccelerin, or if antithrombin inactivated Stuart factor as fast as it was formed. If plasminogen was activated immediately upon clot formation, then it would quickly dissolve the clot, frustrating the pathway. . . . The lack of some blood clotting factors, or the production of defective factors, often results in serious health problems or death. The most common form of hemophilia arises from a deficiency of antihemophilic factor, which helps activated Christmas factor in the conversion of Stuart factor to its active form. Lack of Christmas factor is the second most common form of hemophilia. Severe health problems can also result if other proteins of the clotting pathway are defective, although these are less common. . . . Additionally, lack of protein C causes death in infancy due to the occurrence of numerous, inappropriate clots.13 Such an event would not be expected to happen even if the universe's ten-billion year life were compressed into a single second and relived every second for ten billion years. . . . The fact is, no one on earth has the vaguest idea how the coagulation cascade came to be. . . . Blood coagulation is a paradigm of the staggering complexity that underlies even apparently simple bodily processes. Faced with such complexity beneath even simple phenomena, Darwinian theory falls silent.15 . . . Just as a mousetrap does not work unless all of its constituent parts are present, ciliary motion simply does not exist in the absence of microtubules, connectors, and motors. Therefore we can conclude that the cilium is irreducibly complex - an enormous monkey wrench thrown into its presumed gradual, Darwinian evolution.17 . . . [A] cilium contains over two hundred different kinds of proteins. . . . All of the reasons for such complexity are not yet clear and await further experimental investigation. Other tasks for which the proteins might be required, however, include attachment of the cilium to a base structure inside the cell; modification of the elasticity of the cilium; control of the timing of the beating; and strengthening of the ciliary membrane.18 C. The Bacterial Flagellum. In summary, as biochemists have begun to examine apparently simple structures like cilia and flagella, they have discovered staggering complexity, with dozens or even hundreds of precisely tailored parts. . . . Darwinian theory has given no explanation for the cilium or the flagellum. The overwhelming complexity of the swimming systems push us to think it may never give an explanation.21 11-cis-retinal E. Intracellular transport. 1) a tag for identifying the proteins as authorized to enter the vehicle; 2) a vehicle; 3) a scanner on the vehicle for recognizing the tags; 4) a tag for identifying the vehicle; 5) a scanner for identifying the vehicle as authorized to enter the destination structure; and 6) a gate in the destination structure capable of opening and closing.23 A single flaw in the cell's labyrinthine protein-transport pathway is fatal. Unless the entire system were immediately in place, our ancestors would have suffered a similar fate. Attempts at a gradual evolution of the protein transport system are a recipe for extinction.25 The evidence for design is beginning to pile up. G. Synthesizing AMP. AMP is composed of 10 carbon atoms, eleven hydrogens, seven oxygens, four nitrogens and one phosphorus. The mechanism for synthesizing AMP must be automated. It takes place in 13 steps involving twelve enzymes, one molecule of carbon dioxide, two of glutamine, one of glycine, two formyl groups, two molecules of asparic acid, and five molecules of the energy-provider ATP to drive the chemical reactions at certain steps, all to produce just one kind of molecule. This process is ongoing in every cell of the body, continuously, automatically, every hour of our lives. Yet it produces only one of the approximately 10,000 proteins our bodies need to live, each one of which our bodies produce continuously, automatically, every hour, or we die. Behe asks, "[I]f only the end product of a complicated biosynthetic pathway is used in the cell, how did the pathway evolve in steps? . . . On their face, metabolic pathways where intermediates are not useful present severe challenges to a Darwinian scheme of evolution. This goes in spades for something like AMP, because the cell has no choice: AMP is required for life. Either it immediately has a way to produce or obtain AMP, or the cell is dead."26 Actually the synthesis of AMP is even more complicated, because the process must be regulated - accelerated or decelerated, depending on the cell's needs at any given time. Behe describes the cell's method of regulating the production of AMP. Then he describes several diseases which result from defects in the regulatory process, including diabetes and Lesch-Nyhan syndrome. In the latter, an accumulation of uric acid produces mental retardation and a compulsion toward self-mutilation. IV. Summary. Modern biochemistry has shown a complexity in living things of such a degree and kind that it does not seem possible that they could have developed by a process in which parts were added one at a time and in which each successive stage conferred an added survival advantage on the organism. Instead, living things, even at the simplest level, are, as Michael Behe makes clear, irreducibly complex - composed of subsystems so intricate and interdependent that in order to function at any level at all - that is, in order for the organism to survive - it was necessary for each subsystem to be present fully formed from the beginning. Whether evolutionary biologists will ever provide a convincing answer to irreducible complexity remains to be seen. To date, they have not, and the response to Behe will be discussed in Chapter 6. If it should appear that evolutionary theorists' attempts to answer Behe are unconvincing, the investigator will be more confident that Behe's observations are important. Before proceeding to critiques of Behe, however, it should be noted that if design theory is plausible insofar as living systems are concerned, then it is only natural to ask whether some of the other things we find in the universe do not also bear the marks of design: non-living things - rocks, planets, stars, and galaxies, for instance. If we should also discover compelling evidence of design in non-living systems, it could strengthen the inference to design in living systems. Endnotes 1Michael J. Behe, Darwin's Black Box: The Biochemical Challenge to Evolution, (New York: Simon & Schuster, 1996), pp. 176-177. |
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