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Unbounding the Future:

the Nanotechnology Revolution

Chapter 4

Paths, Pioneers, and Progress

A basic question about nanotechnology is, "When will it be achieved?" The answer is simple: No one knows. How molecular machines will behave is a matter for calculation, but how long it will take us to develop them is a separate issue. Technology timetables can't be calculated from the laws of nature, they can only be guessed at. In this chapter, we examine different paths to nanotechnology, hear what some of the pioneers have to say, and describe the progress already made. This will not answer our basic question, but it will educate our guesses.

Molecular nanotechnology could be developed in any of several basically different ways. Each of these basic alternatives itself includes further alternatives. Researchers will be asking, "How can we make the fastest progress?" To understand the answers they may come to, we need to ask the same question here, adopting (for the moment) a gung-ho, let's-go, how-do-we-get-the-job-done? attitude. We give some of the researchers' answers in their own words.

Will It Ever Be Achieved?

Like "When will it be achieved?", this is a basic question with an answer beyond calculation. Here, though, the answer seems fairly clear. Throughout history, people have worked to achieve better control of matter, to convince atoms to do what we want them to do. This has gone on since before people learned that atoms exist, and has accelerated ever since. Although different industries use different materials and different tools and methods, the basic aim is always the same. They seek to make better things, and make them more consistently, and that means better control of the structure of matter. From this perspective, nanotechnology is just the next, natural step in a progression that has been under way for millennia.

Consider the compact discs now replacing older stereo records: both the old and the new technologies stamp patterns into plastic, but for CDs, the bumps on the stamping surface are only about 130 by 600 nanometers in size, versus 100,000 nanometers or so for the width of the groove on an old-style record. Or look at a personal computer. John Foster, a physicist at IBM's Almaden Research Center, points to a hard disk and says that "inside that box are a bunch of whirring disks, and every one of those disks has got a metal layer where the information is stored. The last thing on top of the metal layer is a monolayer that's the lubricant between the disk and the head that flies over it. The monolayer is not fifteen angstroms [15 angstroms = 1.5 nanometers] and it's not three, because fifteen won't work and neither will three. So it has to be ten plus or minus a few angstroms. This is definitely working in the nanometer regime. We're at that level: We ship it every day and make money on it every day."

The transistors on computer chips are heading down in size on an exponential curve. Foster's colleague at IBM, Patrick Arnett, expects the trend to continue: "If you stay on that curve, then you end up at the atomic scale at 2020 or so. That's the nature of technology now. You expect to follow that curve as far as you can go." The trend is clear, and at least some of the results can be foreseen, but the precise path and timetable for the development of nanotechnology is unpredictable. This unpredictability goes to the heart of important questions: "How will this technology be developed? Who will do it? Where? When? In ten years? Fifty? A hundred? Will this happen in my lifetime?" The answers will depend on what people do with their time and resources, which in turn will depend on what goals they think are most promising. Human attitudes, understanding, and goals will make all the difference.

What Decisions Most Affect the Rate of Advance?

Decisions about research directions are central. Researchers are already pouring effort into chemical synthesis, molecular engineering, and related fields. The same amount of effort could produce more impressive results in molecular nanotechnology if a fraction of it were differently directed. The research funders—corporate executives, and decision makers in science funding agencies like the National Science Foundation in the United States and Japan's Ministry of International Trade and Industry—all have a large influence on research directions, but so do the researchers working in the labs. They submit proposals to potential funders (and often spend time on personally chosen projects, regardless of funding), so their opinions also shape what happens. Where public money is involved, politicians' impressions of public opinion can have a huge influence, and public opinion depends on what all of us think and say..

Still, researchers play a central role. They tend to work on what they think is interesting, which depends on what they think is possible, which depends on the tools they have or—among the most creative researchers—on the tools they can see how to make. Our tools shape how we think: as the saying goes, when all you have is a hammer, everything looks like a nail. New tools encourage new thoughts and enable new achievements, and decisions about tool development will pace advances in nanotechnology. To understand the challenges ahead, we need to take a look at ideas about the tools that will be needed.

Why Are Tools So Important?

Throughout history, limited tools have limited achievement. Leonardo da Vinci's sixteenth century chain drives and ball bearings were theoretically workable, yet never worked in their inventor's lifetime. Charles Babbage's nineteenth century mechanical computer suffered the same fate. The problem? Both inventors needed precisely machined parts that (though readily available today) were beyond the manufacturing technology of their times. Physicist David Miller recounts how a sophisticated integrated circuit design project at TRW hit similar limits in the early 1980s: "It all came down to whether a German company could cool their glass lenses slowly enough to give us the accuracy we needed. They couldn't."

In the molecular world, tool development again paces progress, and new tools can bring breathtaking advances. Mark Pearson, director of molecular biology for Du Pont, has observed this in action: "When I was a graduate student back in the 1950s, it was a multiyear problem to determine the molecular structure of a single protein. We used to say, 'one protein, one career.' Yet now the time has shrunk from a career to a decade to a year—and in optimal cases to a few months." Protein structures can be mapped atom by atom by studying X-ray reflections from layers in protein crystals. Pearson observes that "Characterizing a protein was a career-long endeavor in part because it was so difficult to get crystals, and just getting the material was a big constraint. With new technologies, we can get our hands on the material now—that may sound mundane, but it's a great advance. To the people in the field, it makes all the difference in the world." Improved tools for making and studying proteins are of special importance because proteins are promising building blocks for first-generation molecular machines.

But Isn't Science About Discoveries, Not Tools?

Nobel Prizes are more often awarded for discoveries than for the tools (including instruments and techniques) that made them possible. If the goal is to spur scientific progress, this is a shame. This pattern of reward extends throughout science, leading to a chronic underinvestment in developing new tools. Philip Abelson, an editor of the journal Science, points out that the United States suffers from "a lack of support for development of new instrumentation. At one time, we had a virtual monopoly in pioneering advances in instrumentation. Now practically no federal funds are available to universities for the purpose." It's easier and less risky to squeeze one more piece of data out of an existing tool than to pioneer the development of a new one, and it takes less imagination.

But new tools emerge anyway, often from sources in other fields. The study of protein crystals, for example, can benefit from new X-ray sources developed by physicists, and techniques from chemistry can help make new proteins. Because they can't anticipate tools resulting from innovations in other fields, scientists and engineers are often too pessimistic about what can be achieved in their own fields. Nanotechnology will join several fields, and yield tools useful in many others. We should expect surprising results.

What Tools Do Researchers Use to Build Small Devices?

Today's tools for making small-scale structures are of two kinds: molecular-processing tools and bulk-processing tools. For decades, chemists and molecular biologists have been using better and better molecular-processing tools to make and manipulate precise, molecular structures. These tools are of obvious use. Physicists, as we will see, have recently developed tools that can also manipulate molecules. Combined with techniques from chemistry and molecular biology, these physicist's tools promise great advances.

Microtechnologists have applied chip-making techniques to the manufacture of microscopic machines. These technologies—the main approach to miniaturization in recent decades—can play at most a supporting role in the development of nanotechnology. Despite appearances, it seems that microtechnology cannot be refined into nanotechnology.

But Isn't Nanotechnology Just Very Small Microtechnology?

For many years, it was conventional to assume that the road to very small devices led through smaller and smaller devices: a top-down path. On this path, progress is measured by miniaturization: How small a transistor can we build? How small a motor? How thin a line can we draw on the surface of a crystal? Miniaturization focuses on scale and has paid off well, spawning industries ranging from watchmaking to microelectronics.

Researchers at AT&T Bell Labs, the University of California at Berkeley, and other laboratories in the United States have used micromachining (based on microelectronic technologies) to make tiny gears and even electric motors. Micromachining is also being pursued successfully in Japan and Germany. These microgears and micromotors are, however, enormous by nanotechnological standards: a typical device is measured in tens of micrometers, billions of times the volume of comparable nanogears and nanomotors. (In our simulated molecular world, ten microns is the size of a small town.) In size, confusing microtechnology with molecular nanotechnology is like confusing an elephant with a ladybug.

The differences run deeper, though. Microtechnology dumps atoms on surfaces and digs them away again in bulk, with no regard for which atom goes where. Its methods are inherently crude. Molecular nanotechnology, in contrast, positions each atom with care. As Bill DeGrado, a protein chemist at Du Pont, says, "The essence of nanotechnology is that people have worked for years making things smaller and smaller until we're approaching molecular dimensions. At that point, one can't make smaller things except by starting with molecules and building them up into assemblies." The difference is basic: In microtechnology, the challenge is to build smaller; in nanotechnology, the challenge is to build bigger—we can already make small molecules.

(A language warning: in recent years, nanotechnology has indeed been used to mean "very small microtechnology"; for this usage, the answer to the above question is yes, by definition. This use of a new word for a mere extension of an old technology will produce considerable confusion, particularly in light of the widespread use of nanotechnology in the sense found here. Nanolithography, nanoelectronics, nanocomposites, nanofabrication: not all that is nano- is molecular, or very relevant to the concerns raised in this book. The terms molecular nanotechnology and molecular manufacturing are more awkward but avoid this confusion.)

Will Microtechnology Lead to Nanotechnology?

Can bulldozers can be used to make wristwatches? At most, they can help to build factories in which watches are made. Though there could be surprises, the relevance of microtechnology to molecular nanotechnology seems similar. Instead, a bottom-up approach is needed to accomplish engineering goals on the molecular scale.

What Are the Main Tools Used for Molecular Engineering?

Almost by definition, the path to molecular nanotechnology must lead through molecular engineering. Working in different disciplines, driven by different goals, researchers are making progress in this field. Chemists are developing techniques able to build precise molecular structures of sorts never before seen. Biochemists are learning to build structures of familiar kinds, such as proteins, to make new molecular objects.

In a visible sense, most of the tools used by chemists and biochemists are rather unimpressive. They work on countertops cluttered with dishes, bottles, tubes, and the like, mixing, stirring, heating, and pouring liquids—in biochemistry, the liquid is usually water with a trace of material dissolved in it. Periodically, a bit of liquid is put into a larger machine and a strip of paper comes out with a graph printed on it. As one might guess from this description, research in the molecular sciences is usually much less expensive than research in high-energy physics (with its multibillion-dollar particle accelerators) or research in space (with its multibillion-dollar spacecraft). Chemistry has been called "small science," and not because of the size of the molecules.

Chemists and biochemists advance their field chiefly by developing new molecules that can serve as tools, helping to build or study other molecules. Further advances come from new instrumentation, new ways to examine molecules and determine their structures and behaviors. Yet more advances come from new software tools, new computer-based techniques for predicting how a molecule with a particular structure will behave. Many of these software tools let researchers peer through a screen into simulated molecular worlds much like those toured in the last two chapters.

Of these fields, it is biomolecular science that is most obviously developing tools that can build nanotechnology, because biomolecules already form molecular machines, including devices resembling crude assemblers. This path is easiest to picture, and can surely work, yet there is no guarantee that it will be fastest: research groups following another path may well win. Each of these paths is being pursued worldwide, and on each, progress is accelerating.

Physicists have recently contributed new tools of great promise for molecular engineering. These are the proximal probes, including the scanning tunneling microscope (STM) and the atomic force microscope (AFM). A proximal-probe device places a sharp tip in proximity to a surface and uses it to probe (and sometimes modify) the surface and any molecules that may be stuck to it.

Figure 4: STM/AFM

The scanning tunneling microscope (STM, on the left) images surfaces well enough to show individual atoms, sensing surface contours by monitoring the current jumping the gap between tip and surface. The atomic force microscope (AFM, on the right) senses surface contours by mechanical contact, drawing a tip over the surface and optically sensing its motion as it passes over single-atom bumps.

How Does an STM Work?

An STM brings a sharp, electrically conducting needle up to an electrically-conducting surface, almost touching it. The needle and surface are electrically connected (see the left-hand side of Figure 4), so that a current will flow if they touch, like closing a switch. But at just what point do soft, fuzzy atoms "touch"? It turns out that a detectable current flows when just two atoms are in tenuous contact—fuzzy fringes barely overlapping—one on the surface and one on the tip of the needle. By delicately maneuvering the needle around over the surface, keeping the current flowing at a tiny, constant rate, the STM can map shape of the surface with great precision. Indeed, to keep the current constant, the needle has to go up and down as it passes over individual atoms.

The STM was invented by Gerd Binnig and Heinrich Rohrer, research physicists studying surface phenomena at IBM's research labs in Zurich, Switzerland. After working through the 1970s, Rohrer and Binnig submitted their first patent disclosure on an STM in mid-1979. In 1982, they produced images of a silicon surface, showing individual atoms. Ironically, the importance of their work was not immediately recognized: Rohrer and Binnig's first scientific paper on the new tool was rejected for publication on the grounds that it was "not interesting enough." Today, STM conferences draw interested researchers by the hundreds from around the world.

In 1986—quite promptly as these things go—Binnig and Rohrer were awarded a Nobel Prize. The Swedish Academy explained its reasoning: "The scanning tunneling microscope is completely new and we have so far seen only the beginning of its development. It is, however, clear that entirely new fields are opening up for the study of matter." STMs are no longer exotic: Digital Instruments of Santa Barbara, California, sells its system (the NanoscopeŽ) by mail with an atomic-resolution-or-your-money-back guarantee. Within three years of their commercial introduction, hundreds of STMs had been purchased.

How Does an AFM Work?

The related atomic force microscope (on the right side of Figure 4) is even simpler in concept: A sharp probe is dragged over the surface, pressed down gently by a straight spring. The instrument senses motions in the spring (usually optically), and the spring moves up and down whenever the tip is dragged over an atom on the surface. The tip "feels" the surface just like a fingertip in the simulated molecular world. The AFM was invented by Binnig, Quate, and Gerber at Stanford University and IBM San Jose in 1985. After the success of the STM, the importance of the AFM was immediately recognized. Among other advantages, it works with nonconducting materials. The next chapter will describe how AFM-based devices might be used as molecular manipulators in developing molecular nanotechnology. As this is written, AFMs have just become commercially available.

(Note that that AFMs and STMs are not quite as easy to use as these descriptions might suggest. For example, a bad tip or a bad surface can prevent atomic resolution, and pounding on the table is not recommended when such sensitive instruments are in operation. Further, scientists often have trouble deciding just what they're seeing, even when they get a good image.)

Can Proximal Probes Move Atoms?

To those thinking in terms of nanotechnology, STMs immediately looked promising not only for seeing atoms and molecules but for manipulating them. This idea soon became widespread among physicists. As Calvin Quate stated in Physics Today in 1986, "Some of us believe that the scanning tunneling microscope will evolve . . . that one day [it] will be used to write and read patterns of molecular size." This approach was suggested as a path to molecular nanotechnology in Engines of Creation, again in 1986.

By now, whole stacks of scientific papers document the use of STM and AFM tips to scratch, melt, erode, indent, and otherwise modify surfaces on a nanometer scale. These operations move atoms around, but with little control. They amount to bulk operations on a tiny scale— one fine scratch a few dozen atoms wide, instead of the billions that result from conventional polishing operations.

Can Proximal Probes Move Atoms More Precisely?

In 1987, R. S. Becker, J. A. Golovchenko, and B. S. Swartzentruber at AT&T Bell Laboratories announced that they had used an STM to deposit small blobs on a germanium surface. Each blob was thought to consist of one or a few germanium atoms. Shortly thereafter, IBM Almaden researchers John Foster, Jane Frommer, and Patrick Arnett achieved a milestone in STM-based molecular manipulation. Of this team, Foster and Arnett attended the First Foresight Conference on Nanotechnology, where they told us the motivations behind their work.

Foster came to IBM from Stanford University, where he had completed a doctorate in physics and taught at graduate school. The STM work was one of his first projects in the corporate world. He describes his colleague Arnett as a former "semiconductor jock" involved in chip creation at IBM's Burlington and Yorktown locations. Besides his doctorate in physics, Arnett brought mechanical-engineering training to the effort.

Arnett explains what they were trying to do: "We wanted to see if you could do something on an atomic scale, to create a mechanism for storing information and getting it back reliably." The answer was yes. In January 1988, the journal Nature carried their letter reporting success in pinning an organic molecule to a particular location on a surface, using an STM to form a chemical bond by applying an electrical pulse through the tip. They found that having created and sensed the feature, they could go back and use another voltage pulse from the tip to change the feature again: enlarging it, partly erasing it, or completely removing it.

IBM quickly saw a commercial use, as explained by Paul M. Horn, acting director of physical sciences at the Thomas J. Watson Research Center: "This means you can create a storage element the size of an atom. Ultimately, the ability to do that could lead to storage that is ten million times more dense than anything we have today." A broader vision was given by another researcher, J. B. Pethica, in the issue of Nature in which the work appeared: "The partial erasure reported by Foster et al. implies that molecules may have pieces deliberately removed, and in principle be atomically 'edited,' thereby demonstrating one of the ideals of nanotechnology."

Can Proximal Probes Move Atoms With Complete Precision?

Foster's group succeeded in pinning single molecules to a surface, but they couldn't control the results—the position and orientation—precisely. In April 1990, however, another group at the same laboratory carried the manipulation of atoms even further, bringing a splash of publicity. Admittedly, the story must have been hard to resist: it was accompanied by an STM picture of the name IBM," spelled out with thirty-five precisely placed atoms (Figure 5). The precision here is complete, like the precision of molecular assembly: each atom sits in a dimple on the surface of a nickel crystal; it can rest either in one dimple or in another, but never somewhere between.

FIGURE 5: WORLD SMALLEST LOGO—35 XENON ATOMS (Courtesy of IBM Research Division)

Donald Eigler, the lead author on the Nature paper describing this work, sees clearly where all this is leading: "For decades, the electronics industry has been facing the challenge of how to build smaller and smaller structures. For those of us who will now be using individual atoms as building blocks, the challenge will be how to build up structures atom by atom."

How Far Can Proximal Probes Take Us?

Proximal probes have advantages as a tool for developing nanotechnology, but also weaknesses. Today, their working tips are rough and irregular, typically even rougher than shown in Figure 4. To make stable bonds form, John Foster's group used a pulse of electricity, but the results proved hard to control. The "IBM" spelled out by Donald Eigler's group was precise, but stable only at temperatures near absolute zero—such patterns vanish at room temperature because they are not based on stable chemical bonds. Building structures that are both stable and precise is still a challenge. To form stable bonds in precise patterns is the next big challenge.

John Foster says, "We're exploring a concept which we call 'molecular herding,' using the STM to 'herd' molecules the way my Shetland sheep dog would herd sheep . . . Our ultimate goal with molecular herding is to make one particular molecule move to another particular one, and then essentially force them together. If you could put two molecules that might be small parts of a nanomachine on the surface, then this kind of herding would allow you to haul one of them up to the other. Instead of requiring random motion of a liquid and specific chemical lock-and-key interactions to give you exactly what you want in bringing two molecules together [as in chemical and biochemical approaches], you could drive that reaction on a local level with the STM. You could use the STM to put things where you want them to be." The next chapter will discuss additional ideas for using proximal probes in early nanotechnology.

Proximal-probe instruments may be a big help in building the first generation of nanomachines, but they have a basic limit: Each instrument is huge on a molecular scale, and each could bond only one molecular piece at a time. To make anything large—say, large enough to see with the naked eye—would take an absurdly long time. A device of this sort could add one piece per second, but even a pinhead contains more atoms than the number of seconds since the formation of Earth. Building a Pocket Library this way would be a long-term project.

How Can Such Slow Systems Ever Build Anything Big?

Rabbits and dandelions contain structures put together one molecular piece at a time, yet they grow and reproduce quickly. How? They build in parallel, with many billions of molecular machines working at once. To gain the benefits of such enormous parallelism, researchers can either 1) use proximal probes to build a better, next-generation technology, or 2) use a different approach from the start.

The techniques of chemistry and biomolecular engineering already have enormous parallelism, and already build precise molecular structures. Their methods, however, are less direct than the still hypothetical proximal probe-based molecule-positioners. They use molecular building blocks shaped to fit together spontaneously, in a process of self-assembly.

David Biegelsen, a physicist who works with STMs at the Xerox Palo Alto Research Center, put it this way at the nanotechnology conference: "Clearly, assembly using STMs and other variants will have to be tried. But biological systems are an existence proof that assembly and self-assembly can be done. I don't see why one should try to deviate from something that already exists.

What Are the Main Advantages of Molecular Building Blocks?

A huge technology base for molecular construction already exists. Tools originally developed by biochemists and biotechnologists to deal with molecular machines found in nature can be redirected to make new molecular machines. The expertise built up by chemists in more than a century of steady progress will be crucial in molecular design and construction. Both disciplines routinely handle molecules by the billions and get them to form patterns by self-assembly. Biochemists, in particular, can begin by copying designs from nature.

Molecular building-block strategies could work together with proximal probe strategies, or could replace them, jumping directly to the construction of large numbers of molecular machines. Either way, protein molecules are likely to play a central role, as they do in nature.

How Can Protein Engineering Build Molecular Machines?

Proteins can self assemble into working molecular machines, objects that do something, such as cutting and splicing other molecules or making muscles contract. They also join with other molecules to form huge assemblies like the ribosome (about the size of a washing machine, in our simulation view). Ribosomes—programmable machines for manufacturing proteins—are nature's closest approach to a molecular assembler. The genetic-engineering industry is chiefly in the business of reprogramming natural nanomachines, the ribosomes, to make new proteins or to make familiar proteins more cheaply. Designing new proteins is termed protein engineering. Since biomolecules already form such complex devices, it's easy to see that advanced protein engineering could be used to build first-generation nanomachines.

If We Can Make Proteins, Why Aren't We Building Fancy Molecular Machines?

Making proteins is easier than designing them. Protein chemists began by studying proteins found in nature, but have only recently moved on to the problem of engineering new ones. These are called de novo proteins, meaning completely new, made from scratch. Designing proteins is difficult because of the way they are constructed. As Bill DeGrado, a protein chemist at Du Pont, explains: "A characteristic of proteins is that their activities depend on their three-dimensional structures. These activities may range from hormonal action to a function in digestion or in metabolism. Whatever their function, it's always essential to have a definite three-dimensional shape or structure." This three-dimensional structure forms when a chain folds to form a compact molecular object. To get a feel for how tough it is to predict the natural folding of a protein chain, picture a straight piece of cord with hundreds of magnets and sticky knots along its length. In this state, it's easy to make and easy to understand. Now pick it up, put it in a glass jar, and shake it for a long time. Could you predict its final shape? Certainly not: it's a tangled mess. One might call this effort at prediction "the sticky-cord-folding problem"; protein chemists call theirs "the protein-folding problem."

Given the correct conditions, a protein chain always folds into one special shape, but that shape is hard to predict from just the straightened structure. Protein designers, though, face the different job of first determining a desired final shape, and then figuring out what linear sequence of amino acids to use to make that shape. Without solving the classic protein-folding problem, they have begun to solve the protein-design problem.

What Has Been Accomplished So Far?

Bill DeGrado and his colleagues at Du Pont had one of the first successes: "We've been able to use basic principles to design and build a simple molecule that folds up the way we want it to. This is really the first real example of a designed protein structure, designed from scratch, not by taking an already existing structure and tinkering with it."

Although scientists do the work, the work itself is really a form of engineering, as shown by the title of the field's journal, Protein Engineering. Bill DeGrado's description of the process makes this clear: "After you've made it, the next step is to find out whether your protein did what you expected it to do. Did it fold? Did it pass ions across bilayers [such as cell membranes]? Does it have a catalytic function [speeding specific chemical reactions]? And that's tested using the appropriate experiment. More than likely, it won't have done what you wanted it to do, so you have to find out why. Now, a good design has in it a contingency plan for failure and helps you learn from mistakes. Rather than designing a structure that would take a year or more to analyze, you design it so that it can be assayed for given function or structure in a matter of days."

Many groups are pursuing protein design today, including academic researchers like Jane and Dave Richardson at Duke University, Bruce Erickson at the University of North Carolina, and Tom Blundell, Robin Leatherbarrow, and Alan Fersht in Britain. The successes have started to roll in. Japan, however, is unique in having an organization devoted exclusively to such projects: the Protein Engineering Research Institute (PERI) in Osaka. In 1990, PERI announced the successful design and construction of a de novo protein several times larger than any built before.

Is There Anything Special About Proteins?

The main advantage of proteins is that they are familiar: a lot is known about them, and many tools exist for working with them. Yet proteins have disadvantages as well. Just because this design work is starting with proteins—soft, squishy molecules that are only marginally suitable for nanotechnology—doesn't mean it will stay within those limits. De Grado points out "The fundamental goal of our work in de novo design is to be able to take the next step and get entirely away from protein systems." An early example is the work of Wallace Carothers of Du Pont, who used a de novo approach to studying the nature of proteins: Rather than trying to cut up proteins, he tried to build up things starting with amino acids and other similar monomers. In 1935, he succeeded in making nylon.

DeGrado explains "There is a deep philosophical belief at Du Pont in the ability of people to make molecules de novo that will do useful things. And there is a fair degree of commitment from the management that following that path will lead to products: not directly, and not always predictably, but they know that they need to support the basic science.

"I think ultimately we have a better chance at doing some really exciting things by de novo design, because our repertory should be much greater than that of nature. Think about the ability to fly: One could breed better carrier pigeons or one could design airplanes." The biology community, however, leans more toward ornithology than toward aerospace engineering. DeGrado's experience is that "a lot of biologists feel that if you aren't working with the real thing [natural proteins], you aren't studying biology, so they don't totally accept what we're doing. On the other hand, they recognize it as good chemistry."

Where Is Protein Engineering Headed?

Like the IBM physicists, protein designers are moved by a vision of molecular engineering. In 1989, Bill DeGrado predicted, "I think we'll be able to make catalysts or enzymelike molecules, possibly ones that catalyze reactions not catalyzed in nature." Catalysts are molecular machines that speed up chemical reactions: they form a shape for the two reacting molecules to fit into and thereby help the reaction move faster, up to a million reactions per second. New ones, for reactions that now go slowly, will give enormous cost savings to the chemical industry.

This prediction was borne out just a few months later, when Denver researchers John Stewart, Karl Hahn, and Wieslaw Klis announced their new enzyme, designed from scratch over a period of two years and built successfully on the first try. It's a catalyst, making some reactions go about 100,000 times faster. Nobel Prize-winning biochemist Bruce Merrifield believes that "if others can reproduce and expand on this work, it will be one of the most important achievements in biology or chemistry."

DeGrado also has longer term plans for protein design, beyond making new catalysts: "It will allow us to think about designing molecular devices in the next five to ten years. It should be possible ultimately to specify a particular design and build it. Then you'll have, say, proteinlike molecules that self-assemble into complex molecular objects, which can serve as machinery. But there's a limit to how small you can make devices. You'll shrink things down so far and then you won't be able to go any further, because you've reached molecular dimensions."

Mark Pearson shows that management at Du Pont also has this vision. Regarding the prospects for nanotechnology and assemblers, he remarked, "You know, it'll take money and effort and good ideas for sure. But to my way of thinking, there is no absolute fundamental limitation to preclude us from doing this kind of thing." He didn't say his company plans to develop nanotechnology, but such plans aren't really necessary. Du Pont is already on the nanotechnology path, for other—shorter-term, commercial—reasons. Like IBM, if they do decide to move quickly, they have the resources and forward-looking people needed to succeed.

Who Else Builds Molecular Objects?

Chemists, most of whom do not work on proteins, are the traditional experts in building molecular objects. As a group they've been building molecules for over a century, with ever increasing ability and confidence. Their methods are all indirect: They work with billions of atoms at a time—massive parallelism—but without control of the positions of their workpieces. The molecules typically tumble randomly in a liquid or gas, like pieces of a puzzle that may or may not fit together correctly when shaken together in a box. With clever design and planning, most pieces will join properly.

Chemists mix molecules on a huge scale (in our simulation view, a test tube holds a churning molecular swarm with the volume of an inland sea), yet they still achieve precise molecular transformations. Given that they work so indirectly, their achievements are astounding. This is, in part, the result of the enormous amount of work poured into the field for many decades. Thousands of chemists are working on molecular construction in the United States alone; add to that the chemists in Europe, in Japan, and in the rest of the world, and you have a huge community of researchers making great strides. Though it publishes only a one-paragraph summary of each research report, a guide to the chemical literature—Chemical Abstracts—covers several library walls and grows by many feet of shelf space every year.

How Can Mixing Chemicals Build Molecular Objects?

An engineer would say that chemists (at least those specializing in synthesis) are doing construction work, and would be amazed that they can accomplish anything without being able to grab parts and put them in place. Chemists, in effect, work with their hands tied behind their backs. Molecular manufacturing can be termed "positional chemistry" or "positional synthesis," and will give chemists the ability to put molecules where they want them in three-dimensional space. Rather than trying to design puzzle pieces that will stick together properly by themselves when shaken together in a box, chemists will then be able to treat molecules more like bricks to be stacked. The basic principles of chemistry will be the same, but strategies for construction will become far simpler.

Without positional control, chemists face a problem something like this: Picture a giant glass barrel full of tiny battery-powered drills, buzzing away in all directions, vibrating around in the barrel. Your goal is to take a piece of wood and put a hole in just one specific spot. If you simply throw it in the barrel, it will be drilled haphazardly in many places. To control the process, you must protect all the places you don't want drilled—perhaps by gluing protective pieces of metal over most of the wood surface. This problem—how to protect one part of a molecule while altering another part—has forced chemists to develop ever-cleverer ploys to build larger and larger molecules.

If Chemists Can Make Molecules, Why Aren't They Building Fancy Molecular Machines?

Chemists can achieve great things, but have focused much of their effort on duplicating molecules found in nature and then making minor variants. As an example, take palytoxin, a molecule found in a Hawaiian coral. It was so difficult to make in the lab that it has been called "the Mount Everest of synthetic chemistry," and its synthesis was hailed as a triumph. Other efforts are poured into making small molecules with unusual bonding, or molecules of remarkable symmetry, like "cubane" and "dodecahedrane" (shaped like the Platonic solids they are named after).

Chemists, at least in the United States, regard themselves as natural scientists even when their life's work is the construction of molecules by artificial means. Ordinarily, people who build things are called engineers. And indeed, at the University of Tokyo the Department of Synthetic Chemistry is part of the Faculty of Engineering; its chemists are designing molecular switches for storing computer data. Engineering achievements will require work directed at engineering goals.

How Could Chemists Move Toward Building Molecular Machines?

Molecular engineers working toward nanotechnology need a set of molecular building blocks for making large, complex structures. Systematic building-block construction was pioneered by Bruce Merrifield, winner of the 1984 Nobel Prize in Chemistry. His approach, known as "solid phase synthesis," or simply "the Merrifield method," is used to synthesize the long chains of amino acids that form proteins. In the Merrifield method, cycles of chemical reaction each add one molecular building block to the end of a chain anchored to a solid support. This happens in parallel to each of trillions of identical chains, building up trillions of molecular objects with a particular sequence of building blocks. Chemists routinely use the Merrifield method to make molecules larger than palytoxin, and related techniques are used for making DNA in so-called gene machines: an ad from an Alabama company reads, "Custom DNA—Purified and Delivered in 48 hours."

While it's hard to predict how a natural protein chain will fold—they weren't designed to fold predictably—chemists could make building blocks that are larger, more diverse, and more inclined to fold up in a single, obvious, stable pattern. With a set of building blocks like these, and the Merrifield method to string them together, molecular engineers could design and build molecular machines with greater ease.

How Do Researchers Design What They Can't See?

To make a new molecule, both its structure and the procedure to make it must be designed. Compared to gigantic science projects like the Superconducting Supercollider and the Hubble Space Telescope, working with molecules can be done on a shoestring budget. Still, the costs of trying many different procedures add up. To help predict in advance what will work and what won't, designers turn to models.

You may have played with molecular models in chemistry class: colored plastic balls and sticks that fit together like Tinker Toys. Each color represents a different kind of atom: carbon, hydrogen, and so on. Even simple plastic models can give you a feel for how many bonds each kind of atom makes, how long the bonds are, and at what angles they are made. A more sophisticated form of model uses only spheres and partial spheres, without sticks. These colorful, bumpy shapes are called CPK models, and are widely used by professional chemists. Nobel laureate Donald Cram remarks that "We have spent hundreds of hours building CPK models of potential complexes and grading them for desirability as research targets." His research, like that of fellow Nobelists Charles J. Pedersen and Jean-Marie Lehn, has focused on designing and making medium-sized molecules that self assemble.

Although physical models can't give a good description of how molecules bend and move, computer-based molecules can. Computer-based modeling is already playing a key role in molecular engineering. As John Walker (a founder and leader of Autodesk) has remarked, "Unlike all of the industrial revolutions that preceded it, molecular engineering requires, as an essential component, the ability to design, model, and simulate molecular structures using computers."

This has not gone unnoticed in the business community. John Walker's remark was part of a talk on nanotechnology given at Autodesk, a leader in computer-aided design and one of the five largest software firms in the United States. Soon after this talk, the company made its first major investment in the computer-aided design of molecules.

[See Nanotechnology in Manufacturing, by John Walker]

How Does Molecular Design Compare to More Familiar Kinds of Engineering?

Manufacturers and architects know that designs for new products and buildings are best done on a computer, by computer-aided design (CAD). The new molecular design software can be called molecular CAD, and in its forefront are researchers such as Jay Ponder of the Yale University Department of Molecular Biophysics and Biochemistry. Ponder explains that "There's a strong link between what molecular designers are doing and what architects do. Michael Ward of Du Pont is designing a set of building blocks for a Tinker Toy set so that you can build larger structures. That's exactly what we're doing with molecular modeling techniques.

"All the design and mechanical engineering principles that apply to building a skyscraper or a bridge apply to molecular architecture as well. If you're building a bridge, you're going to model it and see how many trucks can be on the bridge at the same time without it collapsing, what kind of forces you're going to apply to it, whether it can stand up to an earthquake.

"And the same process goes on in molecular design: You're designing pieces and then analyzing the stresses and forces and how they will change and perturb the structure. It's exactly the same as designing and building a building, or analyzing the stresses on any macroscale structure. I think it's important to get people to think in those terms.

"The molecular designer has to be creative in the same way that an architect has to be creative in designing a building. When people are looking at the interior of a protein structure and trying to redesign it to create a space that will have a particular function, such as binding to particular molecules, that's like designing a room to use as a dining room—one that will fit certain sizes of tables and certain numbers of guests. It's the same thing in both cases: You have to design a space for a function."

Ponder combines chemistry and computer science with an overall engineering approach: "I'm kind of a hybrid. I spend about half my time doing experiments and about half my time writing computer programs and doing computational work. In the laboratory, I create or design molecules to test some of the computational ideas. So I'm at the interface." The engineering perspective helps in thinking about where molecular research can lead: "Even though with nanotechnology we're at the nanometer scale, the structures are still big enough that an awful lot of things are classical. Again, it's really like building bridges—very small bridges. And so there are many almost standard mechanical-engineering techniques for architecture and building structures, such as stress analysis, that apply."

Doesn't Engineering Require More Teamwork Than Science Does?

Getting to nanotechnology will require the work of experts in differing fields: chemists, who are learning how to make molecular machines; computer scientists, who are building the needed design tools; and perhaps STM and AFM experts, who can provide tools for molecular positioning. To make progress, however, these experts must do more than just work, they must work together. Because nanotechnology is inherently interdisciplinary, countries that draw hard lines between their academic disciplines, as the United States does, will find that their researchers have difficulty communicating and cooperating.

In chemistry today, a half-dozen researchers aided by a few tens of students and technicians is considered a large team. In aerospace engineering, enormous tasks like reaching the Moon or building a new airliner are broken down into tasks that are within the reach of small teams. All these small teams work together, forming a large team that may consist of thousands of engineers aided by many thousands of technicians. If chemistry is to move in the direction of molecular systems engineering, chemists will need to take at least a few steps in this direction.

In engineering, everyone knows that designing a rocket will require skills from many disciplines. Some engineers know structures, others know pumps, combustion, electronics, software, aerodynamics, control theory, and so on and so forth down a long list of disciplines. Engineering managers know how to bring different disciplines together to build systems.

In academic science, interdisciplinary work is productive and praised, but is relatively rare. Scientists don't need to cooperate to have their results fit together: they are all describing different parts of the same thing—nature—so in the long run, their results tend to come together into a single picture. Engineering, however, is different. Because it is more creative (it actually creates complex things), it demands more attention to teamwork. If the finished parts are going to work together, they must be developed by groups that share a common picture of what each part must accomplish. Engineers in different disciplines are forced to communicate; the challenge of management and team-building is to make that communication happen. This will apply to engineering molecular systems as much as it does to engineering computers, cars, aircraft, or factories.

Jay Ponder suggests that it's a question of perspective. "It's all a matter of what's perceived to be important by the different groups that have to come together to make this work: the chemists doing their bit and the computational people doing their bit. People have to come together and see the big picture. There are people who try to bridge the gaps, but they are rare compared to the people who just work in their own specialty." Progress toward nanotechnology will continue, and as it does, researchers trained as chemists, physicists, and the like will learn to talk to one another to solve new problems. They will either learn to think like engineers and work in teams, or they will be eclipsed by colleagues who do.

Are These Problems Preventing Advances?

With all these problems, the advance toward nanotechnology steadily continues. Industry must gain ever-better control of matter to stay competitive in the world marketplace. The STM, protein engineering, and much of chemistry are driven by commercial imperatives. Focused efforts would yield faster advances, yet even without a clear focus, advances in this direction have an air of inevitability. As Bill DeGrado observes, "We really do have the tools. Experience has shown that when you have the analytic and synthetic tools to do things, in the end science goes ahead and does them—because they are doable." Jay Ponder agrees: "Over the next few years, you're going to see slow evolutionary advances coming from people tinkering with molecular structures and figuring out their principles. People are going to work on a particular problem because they see some application for it or because they got grant funding for it. And in the process of doing something like improving a laundry detergent's ability to clean protein stains, Proctor and Gamble is going to help work out the principles for how to increase molecular stability, and to design spaces inside the molecules."

Are the Japanese Bearing Their Share of the Burden in Nanotechnology Research?

For a variety of reasons, Japan's contribution to nanotechnology research promises to be excellent. While the United States has generally pursued researching this area with little sense of long-term direction, it appears that Japan has begun to take a more focused approach. Researchers there already have clear ideas about molecular machines—about what might work and what probably won't. Japanese researchers are accustomed to a higher level of interdisciplinary contact and engineering emphasis than are Americans. In the United States, we prize "basic science," often calling it "pure science," as if to imply that practical applications are a form of impurity. Japan instead emphasizes "basic technology."

Nanotechnology is a basic technology, and the Japanese recognize it as such. Recent changes at the Tokyo Institute of Technology—Japan's equivalent of MIT—reflect their views of promising directions for future research. For many decades, Tokyo Tech has had two major divisions: a Faculty of Science and a Faculty of Engineering. To these is now being added a Faculty of Bioscience and Biotechnology, to consist of four departments: a Department of Bioscience, a Department of Bioengineering, a Department of Biomolecular Engineering, and what is termed a "Department of Biostructure." The creation of a new faculty in a major Japanese university is a rare event. What U.S. university has a department explicitly devoted to molecular engineering? Japan has both the departments at Tokyo Tech and Kyoto University's recently established Department of Molecular Engineering.

Japan's Institute for Physical and Chemical Research (RIKEN) has broad-based interdisciplinary strength. Hiroyuki Sasabe, head of the Frontier Materials Research Program at RIKEN, notes that the institute has expertise in organic synthesis, protein engineering, and STM technology. Sasabe says that his laboratory may need a molecular manipulator of the sort described in the next chapter to accomplish its goals in molecular engineering.

Research consortia in Japan are also moving toward nanotechnology. The Exploratory Research for Advanced Technology Organization (ERATO) sponsors many three-to-five year projects in parallel, each with a specific goal. Consider the work in progress:

Yoshida Nanomechanism Project

Hotani Molecular Dynamic Assembly Project

Kunitake Molecular Architecture Project

Nagayama Protein Array Project

Aono Atomcraft Project

These focus on different aspects of gaining control over matter at the atomic level. The Nagayama Protein Array Project aims to use proteins as engineering materials to move toward making new molecular devices. The Aono Atomcraft Project does not involve nuclear power—as its translation might imply—but is instead an interdisciplinary effort to use an STM to arrange matter on the atomic scale.

At some point, work on nanotechnology must move beyond spin-offs from other fields and undertake the design and construction of molecular machinery. This shift from opportunistic science to organized engineering requires a change in attitude. In this, Japan leads the United States.

What Is a Good Educated Guess of How Long It Will Take to Develop Molecular Nanotechnology?

Molecular nanotechnology will emerge step by step. Major milestones, such as the engineering of proteins and the positioning of individual atoms, have already been passed. To get a sense of the likely pace of developments, we need to look at how various trends fit together.

Computer-based molecular-modeling tools are spawning computer-aided design tools. These will grow more capable. The underlying technology base—computer hardware—has for decades been improving in price and performance on a steeply rising curve, which is generally expected to continue for many years. These advances are quite independent of progress in molecular engineering, but they make molecular engineering easier, speeding advances. Computer models of molecular machines are beginning to appear, and these will whet the appetites of researchers.

Progress in engineering molecular machines, whether using proximal probes or self-assembly, will eventually achieve striking successes; the objectives of research in Japan will begin to draw serious attention; understanding of the long-term promise of molecular engineering will become more widespread. Some combination of these developments will eventually lead to a serious, public appraisal of what these technologies can achieve—and then the world of opinion, funding, and research fashion will change. Before, advances will be steady but haphazard; afterward, advances will be driven with the energy that flows into major commercial, military, and medical research programs, because nanotechnology will be recognized as furthering major commercial, military, and medical goals. The timing of subsequent events depends largely on when this threshold of serious attention is reached.

In making time estimates, people are prone to assume that a large change must take a long time. Most do, but not all. Pocket calculators had a dramatic effect on the slide-rule industry: they replaced it. The speed of this change caught the slide rule moguls by surprise, but the pace of progress in electronics didn't slow down merely to suit their expectations.

One can argue that nanotechnology will be developed fast: many countries and companies will be competing to get there first. They will be driven onward both by the immense expected benefits—in many areas, including medicine and the environment—as well as by potential military applications. That is a powerful combination of motives, and competition is a powerful accelerator.

A counterargument, though, suggests that development will be slow: anyone who has done anything of significance in the real world of technology—doing a scientific experiment, writing a computer program, bringing a new product to market—knows that these goals take longer than expected. Indeed, Hofstadter's Law states that projects take longer than expected, even when Hofstadter's Law is taken into account. This principle is a good guide for the short term, and for a single project.

The situation differs, though, when many different approaches are being explored by many different groups over a period of years. Most projects may take longer than expected, but with many teams trying many approaches, one approach may prove faster than expected. The winner of a race is always faster than the average runner. John Walker notes, "The remarkable thing about molecular engineering is that it looks like there are many different ways to get there and, at the moment, rapid progress is being made along every path—all at the same time."

Also, technology development is like a race run over an unmapped course. When the first runners reach the top of a hill, they may see a shortcut. A trailing runner may decide to crash off into the bushes, and stumble across a bicycle and a paved road. The progress of technology is seldom predictable because progress often reveals new directions.


How close we are to goal depends on whether technological advances are a constant pace of accelerating. In this diagram, the dashed line represents the current level of technology, and the large dot in the upper right represents a goal such as nanotechnology. With a straight-line advance, it's easier to estimate how far away a goal is. With an accelerating advance, a goal can be reached with little warning.

So how can we estimate a date for the arrival of nanotechnology? It's safest to take a cautious approach: When anticipating benefits, assume it's far off; when preparing for potential problems, assume it's right around the corner. The old folk saying applies: Hope for the best, prepare for the worst. Any dates assigned to "far off" and "right around the corner" can be no better than educated guesses—molecular behavior can be calculated, but not technology timetables of this sort. With those caveats, we would estimate that general-purpose molecular assemblers will likely be developed in the early decades of the twenty-first century, perhaps in the first.

John Walker, whose technological foresight has led Autodesk from start-up to a dominant role in its industry, points out that not long ago, "Many visionaries intimately familiar with the developments of silicon technology still forecast it would take between twenty and fifty years before molecular engineering became a reality. This is well beyond the planning horizon of most companies. But recently, everything has begun to change." Based on the new developments, Walker places his bet: "Current progress suggests the revolution may happen within this decade, perhaps starting within five years.

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