This passage illustrates both the promise and the peril of simple observation. The promise is that, by watching attentively, one can learn much about life. The peril is that, even if you do look as closely as you can, not everything of importance is visible. The philosopher thought that baby octopuses, because they are so small, are “completely without organization.” Wrong! Nanobots are nothing if not organized. But the organization of nanobots cannot be seen with the naked eye. To unaided vision the intricate but minute machinery looks just like gray goo.
Although a measure of progress was made by Aristotle and other ancient naturalists, their inability to see down to tiny scales often led them astray. Perhaps the most spectacular blunder was committed by the Roman physician Galen.6 Galen knew that the heart was a pump, but what happened to the blood that the heart pumped? Unable to see that large arteries lead to tiny arterioles that lead to microscopic capillaries that lead to minute venules that lead to visible veins and then back to the heart in a closed loop, Galen could only guess that the blood pumped out of the heart drained into the tissues to “irrigate” them. His mistaken idea was taught to medical students for more than a thousand years.
Technical innovations were needed to overcome the limitations of human eyesight, to make the details of life visible. The first major breakthrough was the microscope, initially put to consistent scientific use in the seventeenth century. Based on theoretical considerations,7 blood circulation had first been hypothesized by William Harvey in 1628—the year Marcello Malpighi was born. Among many other discoveries, through a microscope the grown-up Malpighi observed otherwise-invisible capillaries that connected the larger blood vessels. So a technical advance—the microscope—proved that blood circulated and corrected Galen’s thousand-year-old mistake.
As important as was the discovery of the circulation of blood, however, the overarching significance of the microscope lay in its unveiling of a completely unsuspected, invisible level of life—the micro level. Aristotle thought that baby octopuses were formless, yet microscopes revealed their intricate form. Insects were thought to lack internal organs, but microscopes showed them aplenty. With the ability to see more and more detail, a clearer understanding of life was emerging. Sometimes, however, even though they could be seen, the importance of microscopic details remained obscure. Some of the earliest seventeenth-century microscopic work showed that plant tissues were built of little units with distinct borders—cells.8 It wasn’t until the mid nineteenth century, however, that the German scientists Matthias Schleiden and Theodor Schwann hypothesized that the cell was actually the basic unit of life, that it was in some sense an independent system, and that all living things were composed of cells and their secretions. Bingo!
Science had glimpsed the cellular nanobot through a microscope, but still was far from comprehending it. The reason for befuddlement was that, although microscopes can image objects a bit smaller than cells, even microscopes can’t make visible in sufficient detail the molecular machinery of the cell, whose components are very much smaller than the cell itself. To the microscopes of the nineteenth century the cell looked like “a simple little lump of albuminous combination of carbon.”9 In other words, like gray goo. To allow us to understand the complex workings of the cell, techniques had to be developed that could press beyond the micro scale down to the nano scale. That took another hundred years, until the middle of the twentieth century.
Shortly after World War II a new technique allowed science to peer directly into the nanomachinery of the cell. X-ray crystallography involves shining a focused beam of X-rays onto a crystal of a pure molecular substance. The short-wavelength light interacts with the regularly repeating molecules in the crystal in such a way that the diffraction pattern can reveal the exact atomic structure of the repeating molecule. The procedure is always technically challenging. But for molecules containing many thousands of atoms, as molecules from the cell usually do, crystallography at midcentury was horrendously difficult. Nonetheless, after decades of determined effort, in 1959 a small band of scientists correctly deduced the precise structure of one of the simplest molecular machines of the cell—a molecule called myoglobin.
STONE UGLY
“Could the search for ultimate truth really have revealed so hideous and visceral-looking an object?” lamented the Nobel laureate biochemist Max Perutz when he first beheld the irregular, bowel-like structure of myoglobin.11 Yet, like the mechanical innards of a robot, myoglobin is built to do a job, not to look pretty. Myoglobin belongs to the class of biological molecules called proteins.12 With a few exceptions, the machinery of the cell consists of assemblies of proteins or, less frequently, individual proteins. Proteins are quite literally the gears and levers, wires and circuits of the nanobot.
In order to understand what natural selection may or may not be able to do with life, we need to familiarize ourselves with the fascinating machinery of the cell: proteins—what they’re made of, what they look like, and the ways by which they carry out the vital tasks of the cell. Over the next few sections I’ll touch on how proteins work.13 Don’t worry about remembering technical details. There is no exam at the end of the chapter. The point here is just to show you that, like bigger machines, proteins work by mechanical principles.
Although most people think of them just as something you eat—one of the major food groups—when they aren’t being eaten proteins are the machinery of the cell, the tools that allow the cell to perform the work of life. Like a nano–Home Depot, human cells contain thousands of different kinds of protein tools. One example of a protein is collagen, a major component of connective tissue. Three collagen molecules intertwine to form a ropelike structure, which is the basis for much of the mechanical strength of skin. Another protein is rhodopsin, which is found in cells that make up the retina of the eye. Rhodopsin’s job is to capture photons of light in the initial events of vision. A protein called Ras acts as a switch that helps the cell decide whether it’s time to divide or not. When Ras gets damaged, sometimes cancer can develop. Glutamine synthetase is a member of a class of proteins called enzymes, which are chemical catalysts that build and break down the many different chemical compounds the cell requires. As you can see even from this short list, proteins perform an amazing variety of tasks in a cell. However, just as a sewing machine can’t be used as a food processor and vice versa, collagen can’t be used in vision, and rhodopsin can’t strengthen skin. Just like the tools at Home Depot, a given protein is only good for a certain, narrow task.
All proteins are chains that are constructed from a set of just twenty different kinds of small molecules called amino acids (the “building blocks” of proteins) linked together. The difference between two proteins is just the difference between the number and arrangement of the links in the chain—the different kinds of amino acids making them up. A good analogy is to the alphabet and words. (In fact, in scientific communications amino acids are often abbreviated as single letters.) The English alphabet has just 26 letters, but the letters can be put together in a very large number of ways to generate many different words. For example, the word “goo” is made of just three letters. The word “antidisestablishmentarianism” is made of 28 letters. A typical protein “word” has anywhere from fifty to a thousand amino acid “letters” in it. For example, human myoglobin has 153 amino acids while albumin has 609. The first five amino acids in human myoglobin are G-L-S-D-G, while the first five in albumin are D-A-H-K-S.
Where does DNA fit into this picture? DNA carries the information that tells the cell how to build each and every protein it contains. Like proteins, DNA is a linear chain of a limited number of “building blocks,” but in the case of DNA there are only four kinds of building blocks (called “nucleotides”). The sequence of nucleotides in DNA directly determines (“codes for”) the sequence of amino acids in a protein. Generally a DNA chain in the cell is very long—much, much longer than protein chains.14 The long DNA chain contains many discrete regions, called genes, eac
h of which codes for a different protein. So one DNA chain can code for many protein chains; in other words, one DNA chain contains many genes. In order for a protein to mutate—that is, in order for the protein to have an altered amino acid sequence—the DNA coding for that particular protein has to change. Mutations, therefore, are fundamentally changes in the DNA sequence coding for a protein; the change in the DNA then causes the cell to produce a changed protein. Here’s an analogy. DNA is like a set of instructions to build a machine; a protein is the machine. If the instructions are altered, then an altered machine is produced.
Analogies only take you so far. Although we often rightly speak of the power of words, proteins have abilities that words lack. Unlike words, proteins are physically active—they have palpable powers that can affect their environment. The physical prowess of a protein results from two features: the chemical properties of the twenty different kinds of amino acids it contains, and the exact three-dimensional arrangement of the amino acids of the protein. We should pay special attention to the latter feature—a protein’s 3D shape. Just as in our everyday world the shape of a machine part critically affects its ability to perform its job, so, too, for protein machines. Metal forged into a gear of the right size can help a clock to work; a shapeless blob of metal can’t. A chain of amino acids—a protein—that folds into the right shape can be part of a molecular machine; with the wrong shape it can’t. But what makes a protein fold into the correct shape?
The twenty amino acids can be categorized into several different groups. Some amino acids are oily (“hydrophobic”—water-fearing) and tend to try to avoid water, while others are like sugar and prefer to be dissolved in close contact with water (“hydrophilic”—water-loving). Some amino acids are negatively charged while others are positively charged. These different chemical properties cause different regions of a chain of amino acids—a protein—to attract or repel each other, somewhat like the north and south poles of many tiny magnets. The oily parts huddle together to shield each other from water, water-loving groups strive to stay in touch with water, negative charges attract positive charges, and like charges push away like charges.
The chains of amino acids found in cells—that is, natural proteins—are quite special. If you just randomly linked amino acids into a chain, the result of all these different forces—the pushing and pulling—would very likely be a mess.15 That is, no particular shape or properties would likely result. In order to form a precisely defined shape that allows a given protein to do a cellular task, the amino acids in biological proteins are arranged so that the attractive and repulsive forces bring together parts of the protein chain that need to be together and push apart regions that need to be apart. Rather than a floppy chain, a protein in the cell folds itself into a compact, active shape. An analogy might be made to a chain of differently shaped magnetic blocks that automatically folds itself into a correctly solved Rubik’s cube, and in doing so gains the power to do something special (say, to fit into a larger, more intricate puzzle). If something goes wrong with the folding process, if by accident the protein does not achieve the shape that it’s supposed to, then usually it loses all of its special activity. A melted gear can no longer help a clock to tick. A misfolded protein chain has no more power than do, say, the proteins of a fried egg, which can no longer help build a chick. It is the exact shape of each kind of protein, plus the chemical features of their amino acids, that allow proteins to do the marvels they do.
MYOGLOBIN UP CLOSE
To illustrate how one protein works, let’s look up close and personal at myoglobin, the first protein whose exact structure was determined. Myoglobin binds oxygen and stores it in muscles; it’s especially abundant in the muscles of diving animals such as whales that have to endure long times between breaths. The protein chain of human myoglobin has 153 amino acids, 22 of which are positively charged, 22 negatively charged, 32 water-loving, and 57 water-fearing.16 In eight segments of the protein chain, the amino acids are arranged so that roughly several oily ones are followed by a few water-loving ones, which are followed by several more oily ones, and so on. This arrangement allows the segment to wrap into a spiral in which one side of the helix has mostly oily amino acids and the other side mostly water-loving ones. The helical segments are stiff but the portions of the chain between the helical segments are rather flexible, allowing the helical segments to fold toward each other. Happily, separate segments can now interact and press their oily sides against each other in the interior of the now compactly folded protein, shielding them from water. Their water-loving, hydrophilic sides face outward to contact water. When all is said and done, the myoglobin chain has folded itself into the exquisitely precise form shown in Figure A.1.
FIGURE A.1
A drawing of myoglobin by the late scientific illustrator Irving Geis. The numbered balls (encased in gray shading) connected by rods are the amino acid positions of the protein. (For clarity, details of the structure of the amino acids are not shown.) The flat structure in the middle is the heme. The sphere in the center of the heme is an iron atom. The letters mark different helices and turns in the protein. The folded shape of the protein is required for it to work. (Illustration by Irving Geis. Rights owned by Howard Hughes Medical Institute. Reproduced by permission.)
The shape of the folded myoglobin allows it to bind tightly to a small, rather flat molecule with a hole in its center. The molecule is called “heme” (let’s not worry about where heme comes from). The heme itself is rather oily and fits into an oily pocket formed by the folded myoglobin, like a hand fits into a glove. Now, the heme is also the right size, and has the right chemical groups, to tightly bind one iron atom in its central hole. When the heme fits into the myoglobin pocket, a particular amino acid (the histidine at the eighty-seventh position in the protein chain; histidine is abbreviated as “H”) from the myoglobin is precisely positioned to hook onto the iron and keep the heme in place. The iron in heme can bind (“coordinate”) to six atoms. Four of those atoms are provided by the heme itself, and one is from the myoglobin’s “H”. That leaves one position of the iron open to bind another atom. The open position can tightly bind oxygen when it’s available. All those features combine to allow myoglobin to fulfill its assumed17 role as an oxygen-storage protein in muscle tissue.
Again, don’t worry about remembering those technical details. As far as this book is concerned, the most important point for us to notice here is that myoglobin does its job entirely through mechanistic forces—through positive charges attracting negative ones, by a pocket in the protein being exactly the right size for the heme to bind, by positioning groups such as “H” in the very place they are needed to do their jobs. Proteins such as myoglobin don’t work through mysterious or novel forces, as they once were thought to do. They work through well-understood ones, like the forces by which machines in our everyday world work, like the forces that will control artificial nanobots, should they ever be built. A crucial conclusion is this: Because biological molecular machines work through forces we understand pretty well, we can judge pretty well which improvements are likely to be able to be made to them by random mutation and natural selection, and which are likely to be unattainable.
BEYOND MYOGLOBIN
Believe it or not, myoglobin is one of the smallest, simplest proteins of the nanobot. What’s more, myoglobin works alone, which is unusual among proteins. Most proteins work in teams where each protein fits together with others in a sort of super Rubik’s cube, and each has its own role to play in the team’s task, much as a particular wire or gear might have its own role to play in, say, a time-keeping mechanism in a robot. To give a taste of such teamwork, in this section I’ll briefly discuss the workings of a protein system that is related to, but somewhat more complicated than, myoglobin.
Myoglobin stores oxygen in muscle, but a different protein, called hemoglobin, transports oxygen in red blood cells from the lungs to the peripheral tissues of the body. Although in many ways it is simil
ar to myoglobin, hemoglobin is more complex and sophisticated. Hemoglobin is a composite of four separate protein chains, each one of which is approximately the same size and shape as myoglobin, each one of which has a heme group that can bind an oxygen molecule as myoglobin does. So hemoglobin is about four times larger than myoglobin. The four chains of hemoglobin consist of two pairs of identical chains: two “alpha” chains and two “beta” chains. (Here’s a point of terminology: When several chains of amino acids come together to do a job, and if they generally stay together for the lifetime of the cell, the whole complex of the several chains is referred to as the protein, and each of the chains alone is called a “subunit.”) The sequence of amino acids in both the alpha and beta subunits is similar to, but not identical with, the sequence of amino acids in myoglobin. When correctly folded, the four subunits of hemoglobin stick together to form a shape like a pyramid. The subunits all have regions that allow them to adhere to each other strongly and precisely, in just the right orientation so that the right amino acids are in the right positions to do the right jobs.
The task hemoglobin has to do is trickier than myoglobin’s. Myoglobin simply stores oxygen in muscles, but hemoglobin transports it from one place to another. To transport oxygen, hemoglobin not only has to bind the gas in the lungs where it is plentiful, it also has to release it to the peripheral tissues where it is needed. So it won’t do for hemoglobin just to bind the oxygen tightly, since it then wouldn’t be able to easily let it go where it was needed. And it won’t do just to bind it loosely, because then it wouldn’t efficiently pick up oxygen in the lungs. Like a Frisbee-playing dog that catches, brings back, and drops the saucer at your feet, hemoglobin has to both bind and release. Hemoglobin can bind oxygen tightly in your lungs and dump it off efficiently in your fingers and toes because of a Rube-Goldberg-like arrangement of the parts of the hemoglobin subunits. Here’s a rough sketch of how it works. Don’t worry about remembering the details—just notice the many precise mechanical steps.
The Edge of Evolution Page 27