1
Introduction

Early humans relied heavily on the ability to successfully scan their environment to hunt for food or to detect threats. While all five senses played a role in survival, vision was paramount. The human brain is designed to quickly process visual images and search for patterns, which early humans used to detect subtle changes that could indicate either hunting game or physical threats. As a result, visual images are a very “natural” and important means of obtaining information. This can be seen in everyday examples such as the preference for visual symbols over written words in traffic signs or advertising efforts to associate a specific visual image with a particular brand. In both of these examples, the choice of a symbol over words is intentional and results from the fact that the brain can grasp images faster than it can process written text.

Science has also exploited the power of imaging. A great deal of information can be obtained about a patient’s condition through metabolic readings and lab tests. However, the development of medical imaging techniques such as magnetic resonance imaging (MRI) or X-ray computed tomography (CT) as standard tools for medical diagnosis has provided physicians with a new level of insight into the workings of the human body and the identification of disease at its earliest stages.

In addition, most space probes contain an imaging camera as part of their instrument package, including those operating in environments where visual images are exceedingly difficult to obtain (e.g., on the surface of Saturn’s moon Titan, which is located more than 1 billion miles from the sun and is perpetually shrouded by thick clouds). These planetary images do more than provide interesting photos for public enjoyment; they also allow scientists the opportunity to make a quick determination of features of interest for further exploration, to gain



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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging 1 Introduction Early humans relied heavily on the ability to successfully scan their environment to hunt for food or to detect threats. While all five senses played a role in survival, vision was paramount. The human brain is designed to quickly process visual images and search for patterns, which early humans used to detect subtle changes that could indicate either hunting game or physical threats. As a result, visual images are a very “natural” and important means of obtaining information. This can be seen in everyday examples such as the preference for visual symbols over written words in traffic signs or advertising efforts to associate a specific visual image with a particular brand. In both of these examples, the choice of a symbol over words is intentional and results from the fact that the brain can grasp images faster than it can process written text. Science has also exploited the power of imaging. A great deal of information can be obtained about a patient’s condition through metabolic readings and lab tests. However, the development of medical imaging techniques such as magnetic resonance imaging (MRI) or X-ray computed tomography (CT) as standard tools for medical diagnosis has provided physicians with a new level of insight into the workings of the human body and the identification of disease at its earliest stages. In addition, most space probes contain an imaging camera as part of their instrument package, including those operating in environments where visual images are exceedingly difficult to obtain (e.g., on the surface of Saturn’s moon Titan, which is located more than 1 billion miles from the sun and is perpetually shrouded by thick clouds). These planetary images do more than provide interesting photos for public enjoyment; they also allow scientists the opportunity to make a quick determination of features of interest for further exploration, to gain

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging insights into geological and weather modifications, and to help correlate data returned by parallel instruments on board the spacecraft. WHAT IS CHEMICAL IMAGING? While chemical imaging means many things to many people, concisely it is the spatial (and temporal) identification and characterization of the molecular chemical composition, structure, and dynamics of any given sample. Today’s technologies and demands on imaging are growing well beyond traditional “photographic” imaging as exemplified by medical X-ray applications. To address issues such as the next generation of microelectronics technologies, disease detection and treatment, chemical manufacturing, and advanced materials development, the ability to perform spatially resolved measurements of chemical structure, function, and dynamics is vital. For example, the location and identification of atoms and molecules in the heterostructures within a state-of-the-art microprocessor are crucial to developing faster and more reliable computing architectures. Imaging the dynamic chemical processes involved in the catalytic production of chemicals is essential to improving chemical manufacturing. Imaging and tracking molecular biochemical processes is central to the development of new ways to detect and treat diseases. Modern spectroscopic techniques rely on the interaction of light or other radiation with a sample of interest. The resulting spectra from these techniques provide vast amounts of information about molecular interactions and structures that occur in chemical processes. Even the best spectra, however, are limited in their ability to reveal the exact characteristics of a chemical reaction definitively. Most common spectroscopic methods require significant samples; for example, nuclear magnetic resonance (NMR) spectroscopy usually requires on the order of a milligram or more. While NMR is not as sensitive as many of the other techniques, in general spectra acquired using standard spectroscopic methods are the result of the accumulation of data from millions (or billions) of individual molecules. In other words, most common spectroscopic techniques provide only an approximation of what occurs between individual units in a single chemical reaction. Chemical imaging takes advantage of a number of spectroscopic techniques (which will be discussed in depth in Chapter 3). These techniques provide the needed information about the molecular composition, structure, and dynamics of a given sample in space and time. Unlike traditional spectroscopy, however, it is now possible in certain implementations of chemical imaging to obtain images on the molecular scale, where interactions between the smallest units of structure are revealed. These advances greatly enhance the fundamental understanding of chemical interactions. As shown in Figures 1.1A and 1.1B, imaging techniques cover a wide range of time scales and penetration depths for samples of varying lateral dimension.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging Development of scanning tunnel microscopy (STM) by Gerd Binnig and Heinrich Rohrer in 1981 pointed the way to breakthroughs in understanding basic chemical processes. Since then, STM and atomic force microscopy (AFM), as well as optical force microscopy proximal probes,1 have been used to manipulate individual atoms and molecules on surfaces. Since then, advances in instrumentation, particularly better probes, and the enormous advances in computational power promise to revolutionize chemical imaging capabilities. The potential to perform chemical imaging in real time across spatial dimensions from the nanometer to the meter scale would lead to fundamental breakthroughs in our understanding of basic chemical processes and, with this, anticipated advances in capabilities both within the chemical sciences and in a number other fields of interest. CHEMICAL IMAGING AND FUNDAMENTAL CHALLENGES As noted above, advances in imaging not only will benefit the chemical sciences, but also fundamental understanding in many other areas. For example, biological processes, materials, medicine, and national security provide excellent examples important application areas for advances in chemical imaging. Biological Processes Tremendous advances have been made in the understanding of such fundamental biological processes as cell function and protein folding. The ability to obtain in situ data on the complexity and dynamics of biological processes, however, continues to pose challenges. Because most of these processes are essentially chemical interactions, advances in chemical imaging with applications to living systems hold the potential for fundamental breakthroughs in the understanding of biological systems. Materials Imaging is a common technique for assessing materials. For example, airliner structural materials are often X-ray-imaged to check for hairline cracks or other signs of imminent failure. In scientific applications, advances in nanotechnology have produced a parallel need for improved methods of imaging nanomaterials on the molecular scale. Advances in chemical imaging will have a direct impact on the ability to design, test, and alter novel materials. In addition, these advances will also contribute to the ability to control reactions at the molecular level by using various imaging modalities to project spatial and temporal information into chemical systems as well as extract information from them. This is a fundamental goal of total chemical-based synthetic processes. Exercising a greater degree of control will have a profound impact on the development of improved materials.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging Medicine Although the development of new drugs for the treatment of disease has progressed significantly beyond simple empirical “hit-or-miss” methods, comprehensive understanding of the actual interactions that take place during the delivery of medicines to a patient remains elusive. As an example, the basic principles of the physiological mechanisms by which anesthesia functions in the body (i.e., interactions between the pharmaceutical molecule and the active site within the body) are not well understood. Advances in chemical imaging, particularly in the resolution of molecule-to-molecule interactions, would help further the understanding of these processes and could contribute to innovations such as personalized medicine. National Security As the threat of terrorism has grown over the past decade, work toward detecting these threats has also increased. A key aspect of this work is the development of new and better sensors aimed at detecting nuclear, chemical, and biological threats. Significant hurdles complicate the ability of sensors to operate effectively in the “real world.” For example, spectrometric detection is sometimes impeded by signals arising from a “noisy” background; common environmental obstacles such as smoke, moisture, or even perfume may interfere with

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging FIGURE 1.1 Imaging techniques compared by their time scales, penetration depths, and ranges of lateral dimensions. All scales are logarithmic, and all box boundaries are estimates of typical present practices and are much fuzzier than the crisp lines shown. (A) Each time span, except for electron microscopy (EM) techniques, indicates the range from the shortest time difference that can comfortably be resolved by a particular technique to the maximum duration of continuous observation. For EM techniques, the time scale indicates the estimated time required for freezing or fixing the tissue. Lateral dimensions range from the finest spacing over which separate objects can be discriminated up to the maximum size of a single field of view. (B) Depth dimensions range from the minimum thickness for an adequate signal to the maximum depth of imaging without a severe loss of sensitivity or lateral resolution. Again, lateral dimensions range from the finest spacing over which separate objects can be discriminated up to the maximum size of a single field of view. NOTE: AFM = atomic force microscopy; CARS = coherent anti-Stokes Raman scattering; FL = fluorescence microscopy at visible wavelengths; IR = infrared; MEG = magnetoencephalography; MRI = magnetic resonance imaging; NSOM = near-field optical microscopy;; PET = positron emission tomography; SERS, surface-enhanced Raman spectroscopy; STM = scanning tunneling microscopy, TIR-FM = total internal reflection fluorescence microscopy. SOURCE: Modified version of figure supplied by Roger Tsien.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging the ability to pick up a signal arising from a threat agent such as an explosive or a biological weapon. In addition, the detection of extremely dilute substances in an enormous volume of background is another difficulty that must be overcome. While work on improved spectrometric methods continues, imaging techniques are and will continue to be powerful sensing tools to help guard against threats. Potential advantages of improved imaging techniques include the ability to assess threats in real time (allowing ample time for effective countermeasures) and the improved capability to detect threats at a distance before populations and valued assets become affected. CHEMICAL IMAGING—WHY NOW? A number of factors have combined over the past several years to make chemical imaging a field ripe for explosive growth. Advances in optics and nanotechnology—nanotips as probes and optical quantum dots2 as labels3—have made continued improvements in imaging common. The phenomenal growth in desktop computing power—combined with the now commonplace ability to network computers—greatly diminishes the challenges once posed by storage requirements for real-time imaging. New research applications are being pursued by combining different imaging techniques to enhance imaging capabilities. Continued advances in chemistry require more powerful techniques to visualize and manipulate matter and to efficiently manage the vast quantities of data resulting from imaging. At present, imaging techniques such as STM are limited to probing the surfaces of metals. In the short term, advances in chemical imaging that enable researchers to “see deeper” (i.e., real-time imaging below surfaces) and the ability to image “soft” materials would provide much more information than is currently available. In the long term, new capabilities in imaging will almost inevitably lead to new questions for researchers to ask, and the subsequent answers will result in the development of new capabilities as the fundamental understanding of chemical processes increases. FOCUS OF THIS REPORT With this wide range of applications and drivers, the approach of this report is to look for high-impact areas in which novel chemical imaging techniques can be developed either from new fundamental mechanisms of imaging or from the synergistic combination of existing techniques that will provide new information. To provide the broadest basis for these developments, an inclusive approach to chemical imaging technique development and potential has been adopted. As with all branches of science, breakthroughs will undoubtedly occur outside the scope of this report. The aim is to identify promising areas in which imaging techniques can evolve to have the greatest impact on critical problems in science and technology.

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging To address the current state of the art in chemical imaging and determine promising areas for advances in the field, the National Academies has undertaken the present study. The goals of the study, as described in the statement of task,4 include: a review of the current state of the art in chemical imaging, including likely short-term advances; identification of gaps in our knowledge of the basic science that enables chemical imaging; identification of a grand challenge for chemical imaging; research required to meet this challenge; institutional changes that could help catalyze advances in this field. To carry out its tasks, the Committee on Revealing Chemistry through Advanced Chemical Imaging held a series of meetings at which various imaging experts were invited to present testimonials and participate in discussions about their relevant research areas. The invited panelists included scientists and engineers from academic, government, and industrial research labs. This report is based on the information gathered at these meetings as well as the expertise of the committee members. The committee has written its report such that these objectives are described and addressed to multiple audiences. For the nonscientist, the report seeks to describe the importance of chemical imaging not only in the chemical sciences but also for practical applications beyond the chemical research laboratory. For the student considering study in chemistry, the report aims to show that both near- and long-term advances in chemical imaging hold the potential to fundamentally alter our understanding of how a chemical reaction occurs and, perhaps more important, of what new capabilities this knowledge can enable. For chemists and chemical engineers, the report should serve as the collective judgment of experts in the field that can be used to identify new capabilities that are needed in chemical imaging and areas of research that offer the best promise of new imaging capabilities. Chapter 2 presents a series of scientific applications of chemical imaging capabilities. Through case studies, the use of chemical imaging is detailed, including the limits on chemical imaging techniques currently in use and a discussion of the developments in chemical imaging required to fully address these scientific applications. These are discussed in the context of both short-term and long-term goals. In Chapter 3, current imaging techniques are presented in a higher level of technical detail. Furthermore, a discussion is provided of (1) the possibilities of current techniques; (2) desirable imaging tools that currently do not exist; and (3) the practical steps necessary to acquire new imaging techniques. Chapter 4 presents the committee’s key findings and recommendations, which are offered as guidance for setting priorities and mapping plans toward funda-

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Visualizing Chemistry: The Progress and Promise of Advanced Chemical Imaging mental breakthroughs in areas of imaging research as well as other areas that impact development of chemical imaging. CONCLUSION As work progresses to improve chemical imaging capabilities, the fundamental challenges will be to observe, understand, and control the spatial and temporal evolution of single molecules, molecular assemblies, and chemical pathways in complex, heterogeneous environments.5 Achieving these goals will require answers to the following questions: How can single-molecule events be imaged in functional detail, rather than imaging the average of a collection of molecules? Is it possible to use chemical imaging to differentiate between intrinsic molecular behavior and cases in which molecular behavior is influenced by the environment (e.g., healthy versus diseased tissue structure or function)? Is it possible to control the position and/or reactivity of chemical reactions and behavior? What can be understood about mapping dynamics or dynamic interactions in chemical reactions? What role do natural processes such as self-assembly, dynamics, and environment play in controlling chemistry? Can chemical imaging provide insights into biological and chemical processes that inform each other? By linking technological advances in chemical imaging with a science-based approach to using these new capabilities, it is likely that fundamental breakthroughs in our understanding of basic chemical processes in biology, the environment, and man-made creations will be achieved. NOTES    1. The term “probe” or “proximal probe” used in this document refers to any of the wide variety of tips used in tunneling, force, and near-field optical microscopies. That is, a metallic, semiconducting, or optical-fiber probe is positioned in close proximity to a sample for the purposes of recording images.    2. Kim, S., Y.T. Lim, E.G. Soltesz, A.M. De Grand, J. Lee, A. Nakayama, J.A. Parker, T. Mihaljevic, R.G. Laurence, D.M. Dor, L.H. Cohn, M.G. Bawendi, and J.V. Frangioni. 2004. Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat. Biotechnol. 22: 93-97.    3. In this report, the term “label” or “marker” will be used to refer to molecules or nanoparticles that covalently or otherwise chemically interact with a sample.    4. The full statement of task for this study is given in Appendix A.    5. Walter Stevens, Division of Chemical Sciences, Geosciences, and Biosciences, U.S. Department of Energy, presentation to the committee.