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Nanoscale Science and Engineering By Michael L. Roukes, founding director, Kavli Nanoscience Institute and professor of physics, applied physics, and bioengineering, California Institute of Technology Dr. Roukes (Ph.D., Cornell, 1985) joined the Quantum Structures Research Group of Bell Laboratories after his dissertation and in 1992 joined the physics faculty of Caltech, where he established laboratories for the fabrication and study of nanoscale structures. His research group focuses on the scientific foundations for nanotechnology, specifically, nanoelectro- mechanical systems (NEMS). Among his activities, Dr. Roukes is cofounder, vice president, and chief technology officer of Nanotechnica Corporation and cofounder and codirector of the Caltech Initiative in Computational Molecular Biology. A fellow of the American Physical Society, he was a Lillian M. Gilbreth lecturer of the National Academy of Engineering in 2002. t has become much easier for Caltech professors to spin off commercial enterprises I since Arnold Beckman's time as a faculty member. But cross-disciplinary research still remains somewhat of a challenge. As a physicist, I'm slowly learning how to transition my own work from fundamental studies into applications relevant for the medical and life sciences. In this process, interdisciplinary collaborations are key. The underlying focus of most of my current efforts is the creation of new tools from nanotechnology for biomedical and life sciences research. Today, we should probably characterize most ongoing work as "nanoscience," rather than nanotechnology. What's mostly been done so far is science that still needs to be transitioned into technology. My view is that this transitioning is going to be driven by the corporate sector rather than by university researchers. Why? Well, a major endeavor here is the development of nanosys- tems, complex and integrated devices analogous to computer chips. These will enable large-scale genomics and proteomics discovery to be carried out universally. The future era that this technology will enable is going to stand in contrast to today's paradigm, which involves centralized research at large technology-intensive centers. Today's organization of resources is, of course, necessary for economy of scale. But tomorrow's chips will put this technology in the hands of every able researcher, and that is certain to lead to an explosion in our knowledge base. Unlike computer chips, these nanosystem chips must consist of far more than simply semiconductor elements of today's computer chips. Rather, they fuse a variety of different technologies from completely different fields--for example, microfluidics, biochemistry, photonics, and electrochemistry. These extra dimensions of complexity require entirely new avenues for integration and mass production. Collectively, industry has hardly start- ed in this area. Even within the university research community, realizing this new technol- INSTRUMENTATION FOR A BETTER TOMORROW 39

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ogy requires new, highly collaborative forms of doing science. The good news on this front is that the early phases of this are already well under way (Figure 21). Ultimately, a single nanosystem biochip will contain many thousands of biological sensors. To characterize future devices, only a few such chips are necessary. But to make real and innovative progress that has relevance to biological and medical discovery, such chips need to be produced en masse. In short, they must become commodities, since their useful life under the conditions of operation will be short. For example, their small plumbing, pores, and sensors typically become fouled with biological materials after just a few experiments or the effectiveness of their preprogrammed surface chemistry fades. We will literally need boxes of these chips to fuel the coming era of discovery and clinical application. The demand for such quantities, even from the basic biological and medical research communities, will from the outset outstrip the capability of university fabrication centers to produce them. What does "nano" bring to the table here? A key element of these chips is that they must be able to detect biological molecules at very low concentrations--even down to the level of single molecules, which is, after all, the "quantum" of biochemical information exchanged within cells and organelles. Today, the conventional way of detecting specific molecules in proteomics is predominantly mass spectrometry, but the state of the art in mass spectrometry is a system that fills a good fraction of a room and typically requires something like 100 million molecules to achieve detection. That is very different from the single-molecule paradigm that nanotechnology is poised to enable. Recently, we developed a nanomechanical device capable of registering the adsorption of individual macromolecules, one by one, on its surface. The next step is to take this capa- bility from the realm of the fundamental physics lab into a setting where it can be applied to biological problems, that is, the realm of proteomics. This new approach might ulti- mately complement, or even replace, mass spectrometry as we know it today. It is certain- ly not a short-term goal, but it is a worthy one, which we think is probably achievable within the next 5 years or so. This dream is fueling our research today. Another major challenge that my collaborators and I are focusing on is shrinking analyti- cal instruments--specifically, bioarray detectors--to the size of an individual cell. Since cells are anywhere from a fraction of a micron to hundreds of microns across, the individ- ual sensors absolutely must be at the nanoscale. The motivation here is not simply to achieve some form of nanoscale feat: It is to match the scale of detection--within both the spatial and temporal domains--to that on which cellular processes occur. One can liken 40 INSTRUMENTATION FOR A BETTER TOMORROW

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a b FIGURE 21 Nanoelectromechanical devices are starting to approach the ultimate quantum mechanical limits for detecting the exciting motion at the nanoscale: (a) A 20-MHz nanomechanical resonator capacitively coupled to a single-electron transistor (Keith Schwab, Laboratory for Physical Sciences). The resonator's motion induces a charge on the gate electrode of the single-electron transistor; the resulting changes in the conductance can be directly monitored. (b) An ultrasensitive magnetic force detector that has been used to detect a c d single electron spin (Dan Rugar, IBM). When a given electron spin is the right distance from the magnetic cantilever tip and therefore exposed to the right steady magnetic field, a resonance occurs, causing the electron spin to flip direction and generating a small change in force that can be monitored by interferometric observation of the cantilever oscillations. (c) A torsional resonator used to study Casimir forces and look for possible corrections to Newtonian gravitation at short-length scales (Ricardo Decca, Indiana UniversityPurdue University, Indianapolis). (d) A parametric radio-frequency e f mechanical amplifier that provides a thousandfold boost of signal displacements at 17 MHz (Michael Roukes, Caltech). (e) A 116-MHz nanomechanical resonator coupled to a single-electron transistor (Andrew Cleland, University of California, Santa Barbara). (f) A tunable carbon nanotube resonator operating at 3 to 300 MHz that exploits the strain dependence of electron transport through a suspended carbon nanotube (Paul McEuen, Cornell University). the cell to a computer chip; its "logic gates" are individual biochemical processes that, con- catenated, form biological regulatory networks. Signaling, or information exchange between individual logic gates (or subnetworks), is mediated by "bits" of information that may involve only the aforementioned fundamental "quanta" represented by single mole- cules. Information flow happens at the millisecond, or even microsecond, scale--the scale of the underlying biochemical reactions. How can we tap into this vast and prolific information stream, ongoing within even the smallest and most primitive of cells? Certainly today's gene chips and protein chips are too large and far too slow to follow biochemical processes in real time. Also, they require large quantities of DNA or proteins to produce a signal. For DNA, if we're willing to wait and add extra steps to the observation process, we can employ the polymerase chain reaction (PCR) to amplify the individual bits (nucleic acid molecules) of information exchanged. But for proteins, no such amplification trick exists, so we clearly need techniques to sense at the single-molecule level. Given this technology chasm, today's proteomics and systems biology typically are carried out by homogenizing (that is, averaging) information from millions or billions of cells to have enough signal to detect in conventional assays. The dream of nanobiotechnology is, instead, to monitor the processes of individual cells in real time and to do this simultaneously on the cells of entire systems: organelles, immune sys- tems, organisms. INSTRUMENTATION FOR A BETTER TOMORROW 41

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As Lee Hood mentioned, a group of us have formed the NanoSystems Biology Alliance to take concrete steps today toward realizing this dream. Many significant individual ele- ments of the technology exist, but they have yet to be integrated and deployed in a single device. This Alliance is a collaboration among seven West Coast-based scientists. We are adapting devices from nanophysics and nanochemistry, such as nanowires, nanocan- tilevers, optical tweezers, and atomic force microscopes, to observe and measure the behav- ior of single cells. Microfluidics is an underlying technology that ties all of this together. It enables cells to be placed within wells on chips outfitted with nanosensors that bind to par- "New directions ticular proteins or nucleic acids--for example, those that the cell secretes during part of the cell cycle or in response to stimuli. Proteins produced by the cell bind to these nanosen- in science are sors and change their mechanical or electrical properties, which can then be measured in the electrical domain by electronic transducers integrated within the chip. The overarch- ing principle here is that it is now feasible to make devices so small and so sensitive that we launched by new can resolve individual binding events--that is, resolve the individual biochemical bits of information exchanged by the cell. And because it is feasible to do this quickly, we can fol- tools much more low the stochastic chemistry of life processes in real time. often than One early supporter of our own work in this domain has been the Department of Defense (specifically DARPA), which has been interested in the development of first, simplest by new concepts." realizations such as chips to detect biopathogens. I see many potential applications of this technology--the payoff is certain to be immense. One possibility is high-throughput drug screening, in which the responses of particular cells are measured to detect drugs effective --Freeman Dyson against various diseases. The responses of individual cells also could be measured when they are exposed to toxins or pathogens. But the really exciting coming era, for me, will be when these chips become commonplace in everyone's homes and lives--just like today's computer chips. They will be the enablers of the inevitable, coming era of personalized medicine. The changes they will bring to medicine and health care will be profound. Let me conclude by quoting Freeman Dyson on the importance of new technologies."New directions in science are launched by new tools much more often than by new concepts," Dyson wrote. "The effect of a concept-driven revolution is to explain old things in new ways. The effect of a tool-driven revolution is to discover new things that have to be explained." Nanoscience is now revealing new domains within our natural world, and these new domains will produce advances that are only the faintest of glimmers today . 42 INSTRUMENTATION FOR A BETTER TOMORROW