At the moment, however, the breakthroughs have been modest as researchers struggle to come to grips with the challenge of creating three-dimensional structures and functional tools on a nanoscale. It's because of this gap between reality and promise that the most influential research has been on technologies that make it possible to create simple nanostructures and to study those structures once they've been laid down on surfaces. This has made Harvard chemist George M. Whitesides among the most highly cited, high-impact researchers in nanotechnology, not to mention the #1-ranked chemist in the ISI web-based evaluation tool Essential Science Indicators, with more than 10,000 citations to his credit since 1991. Whitesides is the author of over 70 papers with more than 100 citations each, while his classic—"Formation of monolayer films by the spontaneous assembly of organic thiols from solution onto gold," (C.D. Bain, et al., J. Amer. Chem. Soc., 111[1]:321-35, 1989)—has been cited well over 1,400 times. (A table of Whitesides’s most-cited papers published since 1992 appears on page 2.)

Whitesides, now 62, received his bachelor’s degree in chemistry from Harvard University in 1960 and then went to the California Institute of Technology, where he worked with John D. Roberts and received his Ph.D. in 1964. Whitesides joined the faculty of the Massachusetts Institute of Technology in 1963. In 1982, he moved back to Harvard, where he is now the Mallinckrodt Professor of Chemistry. In 1998, Whitesides was awarded the National Medal of Science.

To start simply, what are monolayer films, the subject of your seminal 1989 paper, and why has that paper been so influential?

One of the reasons why this broad area of research is interesting is that if you think about the world, there are certain major classes of things: in particular, there are gasses, liquids, and solids. There should be a fourth item on that list: surfaces. Surfaces are everything we see; they are where many properties of materials are determined, and they are what gives shape to everything. Surfaces are a particularly important arrangement of matter that should be ranked up there with those other three.

The emphasis in surface science in the 1970s and early 80s was on studying the surface chemistry of metals, and, sometimes, metal oxides. This research produced an enormous amount of information about how surfaces work, but only under high vacuum, which, although interesting, is a relatively limited part of the world. And most of the surfaces one sees—whether a desktop or skin or wood or fabric—are made of organic materials rather than metals. So the key issue was to develop a system in which one could study the chemistry of organic surfaces. The trouble with organic surfaces, however, is that they are usually highly disordered, and it’s hard to study disordered things. Self-assembled monolayers, or SAMs, showed that organic surfaces could be ordered—a fact established by Ralph Nuzzo and Dave Allara in their early work. Since SAMs are relatively ordered, they provided the basics for a method of building surfaces that had the order and regularity necessary for good physical chemistry. So SAMs opened the study of organic surfaces for real exploitation.

This work also has another very important characteristic: SAMs make it possible to design surfaces at the molecular scale. Essentially any molecule that has a thiol group—a sulfur atom bonded to hydrogen, for instance—will stick to gold and silver and copper to form these ordered layers. And simply by doing organic synthesis, by sticking that molecule to a metal surface, you can introduce a broad range of organic functional groups onto the surface. So by changing the organic group that you attach to the underlying substrate, you can make surfaces with polar groups and ionic groups and hydrophobic groups and groups that are resistant to the absorption of proteins and groups that attach proteins and groups that attach nucleic acids, etc. It's a very, very flexible technology.

And what role does the self-assembly play?

Here is the crucial notion in all this: Simply take two components—a solution of molecules and a surface—and put them together, and the molecules will order themselves onto the surface. That is, they assemble themselves into a kind of structure. It's like a pinspotter in a bowling alley, except the things being assembled—the pins—are the size of molecules, and there is actually no physical pinspotter. The bowling pins assemble themselves, so to speak. This is a very, very powerful idea. Because as you go to very small structures, you can't use robots at that scale. So it's not clear how to build things at those small scales. Of course, chemists are forever in the business of attaching individual atoms to other atoms. Chemists are the ultimate nanotechnologists. If you're faced with the problem of trying to cover a small area of a surface with molecules, a very powerful way to do it is using this idea of self-assembly of molecules.

And this is why it's proven so useful and influential?

Yes. And you end up with something that can be studied because of its regularity. It’s the basis for the molecular-level engineering of surfaces using a combination of organic synthesis, which people already knew how to do. And the fabrication techniques are very simple, in that you either dip the substrate into materials or print materials using the soft lithographic technique.

Your lab pioneered soft lithography. Could you tell us what it is and how it's used now?

Soft lithography is a set of techniques that rely on printing and molding to make microstructures and nanostructures. We developed it in order to circumvent some of the problems that come with photolithography, which has been the basic technology used for making all microelectronic systems. Photolithography is probably as important an invention as the wheel and bronze and movable type in terms of its influence on society, but it's a technology that is specialized for use in microelectronics. For other kinds of microsystems, it’s not necessarily the right technology to use. It’s limited in the materials it can use and in the geometries it can produce, and it's expensive and can only pattern a small area at any given time.

It also turns out that one of the limitations of photolithography is that the size of the features you can make is limited by diffraction of light. In soft lithography, there are quite different limitations, but the physics-based constraints in these techniques are quite small. You can make structures, for example, with molding techniques that are a few nanometers across. (Just for reference, 10 nanometers is the size of 20 gold atoms.) We developed these sorts of high-precision molding techniques, along with Grant Willson of the University of Texas at Austin and Steve Chou at Princeton.

So how exactly does soft lithography work?

It's either like molding—the same kind of thing you do on a larger scale to make automobile body parts—or like printing, in the sense of stamping a letter "confidential." But you're doing these things to make features anywhere from tens of microns to tens of nanometers in size. And it doesn't use light.

Are there other kinds of microsystems that soft lithography might be better suited for, compared to photolithography?

One that has become important very rapidly is microanalytical systems for biology: chips for high-throughput screening and microfluidic systems for microanalysis. These kinds of applications are important in testing and development of drugs, in genomics, and in a wide variety of problems in research biology. In these areas, the issues are that the necessary features are not particularly small, generally speaking, but you want the parts to be inexpensive, biocompatible, optically transparent, and easy to work with, and you'd like to be able to change the designs quickly. That's a very different set of design considerations than what is optimal for photolithography.

Where do you see nanotechnology going in the next five or ten years?

Nanotechnology is in an interesting state. It's a word, not a field. The science of nanotechnology is basically that of looking at phenomena that become apparent when one goes to very small scales. Out of that, I believe, important technologies will emerge. I believe it will be important in studying quantum phenomena. As you make things small enough you begin to see quantum behavior at room temperature. It's interesting science, and I'm sure it will become interesting technology.

Another intriguing idea is to use these technologies to build sub-cellular probes for investigating processes that go on in a cell. And there's going to be a range of possibilities; whether they become reality or not, we'll have to see. People also talk about nanoelectronics. Everything in electronics is about the cost-performance ratio. If it's very expensive to make nanostructured electronic systems, then nanoelectronics may not happen. But recently there have been the first stages of a transistor-like device that uses just a single molecule as an active element. We have to see right now what all this will come to: maybe nanoelectronics, maybe new classes of materials—new sources of devices. It's a little bit early to say but the science is fantastic.

Do you personally have a Holy Grail that you'd like to achieve?

Yes. To be able to make complex systems, either structurally or functionally, by self-assembly. What we have at the moment is a fairly simple set of structures. We would like to develop a synthesis technology that would enable the making of nanometer-scale, three-dimensional structures on surfaces with arbitrarily chosen properties. It's materials by design.

Do you think it’s possible?

Well, 20 years ago one never would have guessed at things that are now possible with surfaces. A major component of this progress has been the scanning probe microscope and high-resolution scanning electron microscopy, which made it possible to visualize, explore, and manipulate surfaces in atomic detail. We don't yet have the same kinds of techniques for working in three dimensions. We know how to make molecules very well, and we know how to make things a micron in size very well, but if you talk about putting together structures that are 10 nanometers in size, that's an area that is still not very well understood.

There's a basic and very interesting issue in this question of fabricating complex structures: that is, should the strategy be "bottom-up" or "top-down"? Chemists work from the bottom up, so to speak, and can make molecules that have dimensions of a tenth of a nanometer to a few nanometers. They're working to make larger and larger structures. And people who do conventional microfabrication, using photolithography and soft lithography, are working top-down to make structures smaller and smaller. Both groups are now advancing into this nanoscale regime.

What will certainly happen in the next few years is that researchers will bring a broad range of technologies to bear on engineering and synthesizing and exploring matter in that regime. Until now, it has been an area of physical science and biological science that has hardly been explored because it's so hard to make the requisite tools and the structures you're interested in, and then equally hard to study them when you have them. All that is going to change in the next couple of years. Many, many new technologies are emerging. My guess is that it will be a field where we’ll all have lots of fun.

In ESI-Special Topics, George M. Whitesides has the top rated paper in Nanotechnology and the #2 rated paper in Molecular Self-Assembly. View both special topic:

• Molecular Self-Assembly
• Nanotechnology