Existing Protein Machines

These protein hormones and enzymes selectively stick to other molecules. An enzyme changes its target's structure, then moves on; a hormone affects its target's behavior only so long as both remain stuck together. Enzymes and hormones can be described in mechanical terms, but their behavior is more often described in chemical terms. But other proteins serve basic mechanical functions. Some push and pull, some act as cords or struts, and parts of some molecules make excellent bearings. The machinery of muscle, for instance, has gangs of proteins that reach, grab a "rope" (also made of protein), pull it, then reach out again for a fresh grip; whenever you move, you use these machines. Amoebas and human cells move and change shape by using fibers and rods that act as molecular muscles and bones.

A reversible, variable-speed motor drives bacteria through water by turning a corkscrew-shaped propeller. If a hobbyist could build tiny cars around such motors, several billions of billions would fit in a pocket, and 150-lane freeways could be built through your finest capillaries. Simple molecular devices combine to form systems resembling industrial machines. In the 1950s engineers developed machine tools that cut metal under the control of a punched paper tape. A century and a half earlier, Joseph-Marie Jacquard had built a loom that wove complex patterns under the control of a chain of punched cards. Yet over three billion years before Jacquard, cells had developed the machinery of the ribosome. Ribosomes are proof that nanomachines built of protein and RNA can be programmed to build complex molecules. Then consider viruses. One kind, the T4 phage, acts like a spring-loaded syringe and looks like something out of an industrial parts catalog. It can stick to a bacterium, punch a hole, and inject viral DNA (yes, even bacteria suffer infections). Like a conqueror seizing factories to build more tanks, this DNA then directs the cell's machines to build more viral DNA and syringes. Like all organisms, these viruses exist because they are fairly stable and are good at getting copies of themselves made. Whether in cells or not, nanomachines obey the universal laws of nature. Ordinary chemical bonds hold their atoms together, and ordinary chemical reactions (guided by other nanomachines) assemble them. Protein molecules can even join to form machines without special help, driven only by thermal agitation and chemical forces. By mixing viral proteins (and the DNA they serve) in a test tube, molecular biologists have assembled working T4 viruses. This ability is surprising: imagine putting automotive parts in a large box, shaking it, and finding an assembled car when you look inside! Yet the T4 virus is but one of many self-assembling structures. Molecular biologists have taken the machinery of the ribosome apart into over fifty separate protein and RNA molecules, and then combined them in test tubes to form working ribosomes again. To see how this happens, imagine different T4 protein chains floating around in water. Each kind folds up to form a lump with distinctive bumps and hollows, covered by distinctive patterns of oiliness, wetness, and electric charge.

Picture them wandering and tumbling, jostled by the thermal vibrations of the surrounding water molecules. From time to time two bounce together, then bounce apart. Sometimes, though, two bounce together and fit, bumps in hollows, with sticky patches matching; they then pull together and stick. In this way protein adds to protein to make sections of the virus, and sections assemble to form the whole. Protein engineers will not need nanoarms and nanohands to assemble complex nanomachines. Still, tiny manipulators will be useful and they will be built. Just as today's engineers build machinery as complex as player pianos and robot arms from ordinary motors, bearings, and moving parts, so tomorrow's biochemists will be able to use protein molecules as motors, bearings, and moving parts to build robot arms which will themselves be able to handle individual molecules.

Designing with Protein

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.

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