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chemistry at the nanoscale frontier By Chad Mirkin, Professor of Chemistry and Director of the Institute for Nanotechnology, Northwestern University Dr. Mirkin (Ph.D., Penn State, 1989) researches methods for controlling the architecture of molecules and materials on the 1- to 100-nm length scale and for utilizing such structures in the development of analytical tools. Dr. Mirkin joined the faculty at Northwestern in 1991; in 1997 he became Charles E. and Emma H. Morrison Professor of Chemistry. He has won numerous awards, including the ACS Nobel Signature Award, the Raymond and Beverly Sackler Prize in the Physical Sciences, and the Discover 2000 Innovation of the Year Award. In 1992, Dr. Mirkin received the Young Investigator Award from the Arnold and Mabel Beckman Foundation. In 1997, he was corecipient of a prestigious BF Goodrich Collegiate Inventors Award for one of the three most outstanding collegiate inventions in all of medicine, science, and engineering. Dr. Mirkin has helped found two companies, Nanosphere, Inc., and NanoInk, Inc. form of new functional materials and devices. A t sizes below about 100 nanometers, materials have very different properties than they do at larger scales. That is one of the exciting aspects of the rapidly growing field of nanotechnology, which seeks to put these novel properties to use in the For example, consider the technology called dip-pen nanolithography, which we invented in 1999 (Figures 19 and 20). This technology can be seen as a distant descendant of some of the inking technologies Arnold Beckman invented early in his career. Nanoscale cantilevers are constructed using lithography on silicon chips. At the end of each microscopic can- tilever is a sharp tip that functions as a nanoscopic pen to transfer a soluble substance to a substrate. Different microscopic ink wells can be used to ink different pens, and the can- tilevers in large arrays can be controlled individually. It's a fantastic research tool that is beginning to become a powerful commercial nanofabrication and production tool. It can work on almost any substrate, and we can put multiple functionalities on a single nanochip. We can use it as the world's smallest printing device to build and study struc- tures composed of almost any material on the nanoscopic scale (Figure 20). For instance, we have been using dip-pen nanolithography to print on the scale of biolog- ical systems, so that one can begin to build multivalent architectures that can interface with, for example, the surfaces of cells. This is going to allow researchers to probe some of the most fundamental cellular processes, including adhesion, movement, signaling, growth, differentiation, and death. In the physical sciences, the technology can be used to build or repair the masks used for microelectronic circuits. It can even be used to repair individual circuits. For instance, one early application of the technology has been to 36 INSTRUMENTATION FOR A BETTER TOMORROW

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detect and repair defects in plas- ma screen televisions. The idea is not to compete with existing semiconductor technologies but rather to provide a complementa- ry tool that provides capabilities not available with conventional semiconductor fabrication tools. These capabilities include ultra- high resolution, registration, and the ability to interface hard and FIGURE 19 A cartoon diagram of dip-pen nanolithography. The atomic-force microscope (AFM) is coated with the molecules in solution and then dragged across the solid sub- soft matter. strate. Molecular transport causes an orderly monolayer to be deposited on the surface, enabling the creation of complex nanoscale patterns and structures. A start-up company called NanoInk, Inc., is pursuing a num- ber of commercial applications of the technology. In 1999 there was only one lab in the world using this technology. Today, because of their efforts and ours, there are more than 60 users of dip-pen nanolithography in 18 countries. The sensitivity and selectivity of nanotechnologies offer many other opportunities. One is in the area of personalized medicine, which Leroy Hood discussed in his presentation. Diagnostic tools based on nanomaterials can measure very low concentrations of biologi- cal molecules that serve as markers of health or disease. Our goal is to use these tools to decentralize diagnostics; we would like to move diagnostic technologies to the doctor's office, the post office, the battlefield, and maybe even the home. Today we think of diag- nostic technologies as very advanced, but in many respects we're still in the Stone Age. We can't go to the doctor and immediately get screened for different types of diseases. Rather, the doctor takes a sample of blood or urine and sends it to an outside lab, and it takes two days to two weeks to get the results. The holy grail of these efforts is to develop a detection technology that is as sensitive as the polymerase chain reaction (PCR) for nucleic acids without requiring the enzymatic ampli- fication of target molecules. Moreover, we want these systems to be general for all analytes, including proteins, small molecules, and metal ions. I believe that nanomaterials may be one of the only routes to fast, reliable, robust systems that do not involve the hassles of PCR and that provide the targeted generality. My group has been working on various detection systems based on nanoparticles. In one system, called the bar code assay, parti- cles that have specific DNA strands and antibodies on their surface can detect proteins at INSTRUMENTATION FOR A BETTER TOMORROW 37

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3-attomolar concentrations--six orders of magnitude more sensitive than conventional ELISA and Western blot assays. This extraordi- nary sensitivity is allowing medical researchers to identify and validate new biomarkers for neurodegener- ative diseases such as Alzheimer's disease, HIV, and many forms of cancer. Another start-up company, Nanosphere, is seeking to create a FIGURE 20 A fitting example of the capabilities of dip-pen nanolithography. universal platform that uses these approaches in diagnostic systems. The goal is a mobile diagnostic platform with target generality, high stability, high selectivity, and high sensitivity that can be maintained and operated by relatively low-skilled personnel. We seek to identify and validate new markers for many debilitating diseases that cannot be studied with conventional tools, which do not possess the requisite sensitivity. This tech- nology will change the way the medical community thinks about diagnostic systems-- what they can consider as a marker, the types of markers that can be validated, the samples that can be used, and where they can use the marker. 38 INSTRUMENTATION FOR A BETTER TOMORROW