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How far off is such an ability? Steps have been taken, but much work remains to be done. Biochemists have already mapped the structures of many proteins. With gene machines to help write DNA tapes, they can direct cells to build any protein they can design. But they still don't know how to design chains that will fold up to make proteins of the right shape and function. The forces that fold proteins are weak, and the number of plausible ways a protein might fold is astronomical, so designing a large protein from scratch isn't easy. The forces that stick proteins together to form complex machines are the same ones that fold the protein chains in the first place. The differing shapes and kinds of stickiness of amino acids - the lumpy molecular "beads" forming protein chains - make each protein chain fold up in a specific way to form an object of a particular shape. Biochemists have learned rules that suggest how an amino acid chain might fold, but the rules aren't very firm. Trying to predict how a chain will fold is like trying to work a jigsaw puzzle, but a puzzle with no pattern printed on its pieces to show when the fit is correct, and with pieces that seem to fit together about as well (or as badly) in many different ways, all but one of them wrong. False starts could consume many lifetimes, and a correct answer might not even be recognized. Biochemists using the best computer programs now available still cannot predict how a long, natural protein chain will actually fold, and some of them have despaired of designing protein molecules soon. Yet most biochemists work as scientists, not as engineers. They work at predicting how natural proteins will fold, not at designing proteins that will fold predictably. These tasks may sound similar, but they differ greatly: the first is a scientific challenge, the second is an engineering challenge. Why should natural proteins fold in a way that scientists will find easy to predict? All that nature requires is that they in fact fold correctly, not that they fold in a way obvious to people. Proteins could be designed from the start with the goal of making their folding more predictable. Carl Pabo, writing in the journal Nature, has suggested a design strategy based on this insight, and some biochemical engineers have designed and built short chains of a few dozen pieces that fold and nestle onto the surfaces of other molecules as planned. They have designed from scratch a protein with properties like those of melittin, a toxin in bee venom. They have modified existing enzymes, changing their behaviors in predictable ways. Our understanding of proteins is growing daily. In 1959, according to biologist Garrett Hardin, some geneticists called genetic engineering impossible; today, it is an industry. Biochemistry and computer-aided design are now exploding fields, and as Frederick Blattner wrote in the journal Science, "computer chess programs have already reached the level below the grand master. Perhaps the solution to the protein-folding problem is nearer than we think." William Rastetter of Genentech, writing in Applied Biochemistry and Biotechnology asks, "How far off is de novo enzyme design and synthesis? Ten, fifteen years?" He answers, "Perhaps not that long." Forrest Carter of the U.S. Naval Research Laboratory, Ari Aviram and Philip Seiden of IBM, Kevin Ulmer of Genex Corporation, and other researchers in university and industrial laboratories around the globe have already begun theoretical work and experiments aimed at developing molecular switches, memory devices, and other structures that could be incorporated into a protein-based computer. The U.S. Naval Research Laboratory has held two international workshops on molecular electronic devices, and a meeting sponsored by the U.S. National Science Foundation has recommended support for basic research aimed at developing molecular computers. Japan has reportedly begun a multimillion-dollar program aimed at developing self-assembling molecular motors and computers, and VLSI Research Inc., of San Jose, reports that "It looks like the race to bio-chips [another term for molecular electronic systems] has already started. NEC, Hitachi, Toshiba, Matsushita, Fujitsu, Sanyo-Denki and Sharp have commenced full-scale research efforts on bio-chips for bio-computers." Biochemists have other reasons to want to learn the art of protein design. New enzymes promise to perform dirty, expensive chemical processes more cheaply and cleanly, and novel proteins will offer a whole new spectrum of tools to biotechnologists. We are already on the road to protein engineering, and as Kevin Ulmer notes in the quote from Science that heads this chapter, this road leads "toward a more general capability for molecular engineering which would allow us to structure matter atom by atom."

Second-Generation Nanotechnology

Despite its versatility, protein has shortcomings as an engineering material. Protein machines quit when dried, freeze when chilled, and cook when heated. We do not build machines of flesh, hair, and gelatin; over the centuries, we have learned to use our hands of flesh and bone to build machines of wood, ceramic, steel, and plastic. We will do likewise in the future. We will use protein machines to build nanomachines of tougher stuff than protein. As nanotechnology moves beyond reliance on proteins, it will grow more ordinary from an engineer's point of view. Molecules will be assembled like the components of an erector set, and well-bonded parts will stay put. Just as ordinary tools can build ordinary machines from parts, so molecular tools will bond molecules together to make tiny gears, motors, levers, and casings, and assemble them to make complex machines. Parts containing only a few atoms will be lumpy, but engineers can work with lumpy parts if they have smooth bearings to support them. Conveniently enough, some bonds between atoms make fine bearings; a part can be mounted by means of a single chemical bond that will let it turn freely and smoothly. Since a bearing can be made using only two atoms (and since moving parts need have only a few atoms), nanomachines can indeed have mechanical components of molecular size. How will these better machines be built? Over the years, engineers have used technology to improve technology. They have used metal tools to shape metal into better tools, and computers to design and program better computers. They will likewise use protein nanomachines to build better nanomachines. Enzymes show the way: they assemble large molecules by "grabbing" small molecules from the water around them, then holding them together so that a bond forms. Enzymes assemble DNA, RNA, proteins, fats, hormones, and chlorophyll in this way - indeed, virtually the whole range of molecules found in living things. Biochemical engineers, then, will construct new enzymes to assemble new patterns of atoms. For example, they might make an enzyme-like machine which will add carbon atoms to a small spot, layer on layer. If bonded correctly, the atoms will build up to form a fine, flexible diamond fiber having over fifty times as much strength as the same weight of aluminum. Aerospace companies will line up to buy such fibers by the ton to make advanced composites. (This shows one small reason why military competition will drive molecular technology forward, as it has driven so many fields in the past.) But the great advance will come when protein machines are able to make structures more complex than mere fibers. These programmable protein machines will resemble ribosomes programmed by RNA, or the older generation of automated machine tools programmed by punched tapes. They will open a new world of possibilities, letting engineers escape the limitations of proteins to build rugged, compact machines with straightforward designs. Engineered proteins will split and join molecules as enzymes do. Existing proteins bind a variety of smaller molecules, using them as chemical tools; newly engineered proteins will use all these tools and more. Further, organic chemists have shown that chemical reactions can produce remarkable results even without nanomachines to guide the molecules. Chemists have no direct control over the tumbling motions of molecules in a liquid, and so the molecules are free to react in any way they can, depending on how they bump together. Yet chemists nonetheless coax reacting molecules to form regular structures such as cubic and dodecahedral molecules, and to form unlikely-seeming structures such as molecular rings with highly strained bonds. Molecular machines will have still greater versatility in bondmaking, because they can use similar molecular motions to make bonds, but can guide these motions in ways that chemists cannot. Indeed, because chemists cannot yet direct molecular motions, they can seldom assemble complex molecules according to specific plans. The largest molecules they can make with specific, complex patterns are all linear chains. Chemists form these patterns (as in gene machines) by adding molecules in sequence, one at a time, to a growing chain. With only one possible bonding site per chain, they can be sure to add the next piece in the right place. But if a rounded, lumpy molecule has (say) a hundred hydrogen atoms on its surface, how can chemists split off just one particular atom (the one five up and three across from the bump on the front) to add something in its place? Stirring simple chemicals together will seldom do the job, because small molecules can seldom select specific places to react with a large molecule. But protein machines will be more choosy. A flexible, programmable protein machine will grasp a large molecule (the workpiece) while bringing a small molecule up against it in just the right place. Like an enzyme, it will then bond the molecules together. By bonding molecule after molecule to the workpiece, the machine will assemble a larger and larger structure while keeping complete control of how its atoms are arranged. This is the key ability that chemists have lacked. Like ribosomes, such nanomachines can work under the direction of molecular tapes. Unlike ribosomes, they will handle a wide variety of small molecules (not just amino acids) and will join them to the workpiece anywhere desired, not just to the end of a chain. Protein machines will thus combine the splitting and joining abilities of enzymes with the programmability of ribosomes. But whereas ribosomes can build only the loose folds of a protein, these protein machines will build small, solid objects of metal, ceramic, or diamond - invisibly small, but rugged. Where our fingers of flesh are likely to bruise or burn, we turn to steel tongs. Where protein machines are likely to crush or disintegrate, we will turn to nanomachines made of tougher stuff.

Universal Assemblers

These second-generation nanomachines - built of more than just proteins - will do all that proteins can do, and more. In particular, some will serve as improved devices for assembling molecular structures. Able to tolerate acid or vacuum, freezing or baking, depending on design, enzyme-like second-generation machines will be able to use as "tools" almost any of the reactive molecules used by chemists - but they will wield them with the precision of programmed machines. They will be able to bond atoms together in virtually any stable pattern, adding a few at a time to the surface of a workpiece until a complex structure is complete. Think of such nanomachines as assemblers. Because assemblers will let us place atoms in almost any reasonable arrangement (as discussed in the Notes), they will let us build almost anything that the laws of nature allow to exist. In particular, they will let us build almost anything we can design - including more assemblers. The consequences of this will be profound, because our crude tools have let us explore only a small part of the range of possibilities that natural law permits. Assemblers will open a world of new technologies. Advances in the technologies of medicine, space, computation, and production - and warfare - all depend on our ability to arrange atoms. With assemblers, we will be able to remake our world or destroy it. So at this point it seems wise to step back and look at the prospect as clearly as we can, so we can be sure that assemblers and nanotechnology are not a mere futurological mirage.

Nailing Down Conclusions

In everything I have been describing, I have stuck closely to the demonstrated facts of chemistry and molecular biology. Still, people regularly raise certain questions rooted in physics and biology. These deserve more direct answers. ° Will the uncertainty principle of quantum physics make molecular machines unworkable? This principle states (among other things) that particles can't be pinned down in an exact location for any length of time. It limits what molecular machines can do, just as it limits what anything else can do. Nonetheless, calculations show that the uncertainty principle places few important limits on how well atoms can be held in place, at least for the purposes outlined here. The uncertainty principle makes electron positions quite fuzzy, and in fact this fuzziness determines the very size and structure of atoms. An atom as a whole, however, has a comparatively definite position set by its comparatively massive nucleus. If atoms didn't stay put fairly well, molecules would not exist. One needn't study quantum mechanics to trust these conclusions, because molecular machines in the cell demonstrate that molecular machines work. Will the molecular vibrations of heat make molecular machines unworkable or too unreliable for use? Thermal vibrations will cause greater problems than will the uncertainty principle, yet here again existing molecular machines directly demonstrate that molecular machines can work at ordinary temperatures. Despite thermal vibrations, the DNA-copying machinery in some cells makes less than one error in 100,000,000,000 operations. To achieve this accuracy, however, cells use machines (such as the enzyme DNA polymerase I) that proofread the copy and correct errors. Assemblers may well need similar error-checking and error-correcting abilities, if they are to produce reliable results. ° Will radiation disrupt molecular machines and render them unusable? High-energy radiation can break chemical bonds and disrupt molecular machines. Living cells once again show that solutions exist: they operate for years by repairing and replacing radiation-damaged parts. Because individual machines are so tiny, however, they present small targets for radiation and are seldom hit. Still, if a system of nanomachines must be reliable, then it will have to tolerate a certain amount of damage, and damaged parts must regularly be repaired or replaced. This approach to reliability is well known to designers of aircraft and spacecraft. ° Since evolution has failed to produce assemblers, does this show that they are either impossible or useless? The earlier questions were answered in part by pointing to the working molecular machinery of cells. This makes a simple and powerful case that natural law permits small clusters of atoms to behave as controlled machines, able to build other nanomachines. Yet despite their basic resemblance to ribosomes, assemblers will differ from anything found in cells; the things they do - while consisting of ordinary molecular motions and reactions - will have novel results. No cell, for example, makes diamond fiber. The idea that new kinds of nanomachinery will bring new, useful abilities may seem startling: in all its billions of years of evolution, life has never abandoned its basic reliance on protein machines. Does this suggest that improvements are impossible, though? Evolution progresses through small changes, and evolution of DNA cannot easily replace DNA. Since the DNA/RNA/ribosome system is specialized to make proteins, life has had no real opportunity to evolve an alternative. Any production manager can well appreciate the reasons; even more than a factory, life cannot afford to shut down to replace its old systems. Improved molecular machinery should no more surprise us than alloy steel being ten times stronger than bone, or copper wires transmitting signals a million times faster than nerves. Cars outspeed cheetahs, jets outfly falcons, and computers already outcalculate head-scratching humans. The future will bring further examples of improvements on biological evolution, of which second-generation nanomachines will be but one. In physical terms, it is clear enough why advanced assemblers will be able to do more than existing protein machines. They will be programmable like ribosomes, but they will be able to use a wider range of tools than all the enzymes in a cell put together. Because they will be made of materials far more strong, stiff, and stable than proteins, they will be able to exert greater forces, move with greater precision, and endure harsher conditions. Like an industrial robot arm - but unlike anything in a living cell - they will be able to rotate and move molecules in three dimensions under programmed control, making possible the precise assembly of complex objects. These advantages will enable them to assemble a far wider range of molecular structures than living cells have done. ° Is there some special magic about life, essential to making molecular machinery work? One might doubt that artificial nanomachines could even equal the abilities of nanomachines in the cell, if there were reason to think that cells contained some special magic that makes them work. This idea is called "vitalism." Biologists have abandoned it because they have found chemical and physical explanations for every aspect of living cells yet studied, including their motion, growth, and reproduction. Indeed, this knowledge is the very foundation of biotechnology. Nanomachines floating in sterile test tubes, free of cells, have been made to perform all the basic sorts of activities that they perform inside living cells. Starting with chemicals that can be made from smoggy air, biochemists have built working protein machines without help from cells. R. B. Merrifield, for example, used chemical techniques to assemble simple amino acids to make bovine pancreatic ribonuclease, an enzymatic device that disassembles RNA molecules. Life is special in structure, in behavior, and in what it feels like from the inside to be alive, yet the laws of nature that govern the machinery of life also govern the rest of the universe. ° The case for the feasibility of assemblers and other nanomachines may sound firm, but why not just wait and see whether they can be developed? Sheer curiosity seems reason enough to examine the possibilities opened by nanotechnology, but there are stronger reasons. These developments will sweep the world within ten to fifty years - that is, within the expected lifetimes of ourselves or our families. What is more, the conclusions of the following chapters suggest that a wait-and-see policy would be very expensive - that it would cost many millions of lives, and perhaps end life on Earth. Is the case for the feasibility of nanotechnology and assemblers firm enough that they should be taken seriously? It seems so, because the heart of the case rests on two well-established facts of science and engineering. These are (1) that existing molecular machines serve a range of basic functions, and (2) that parts serving these basic functions can be combined to build complex machines. Since chemical reactions can bond atoms together in diverse ways, and since molecular machines can direct chemical reactions according to programmed instructions, assemblers definitely are feasible.

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