The development of technologies for molecular imaging should be driven principally by biological questions to be addressed rather than by simply modifying existing imaging technologies

Arguing against the Proposition is John Hazle, Ph.D. Dr. Hazle received the Ph.D. from The University of Texas Graduate School of Biomedical Sciences. He joined the M. D. Anderson faculty in 1989 as Assistant Professor in the Department of Radiation Physics. He is now Professor and the first Chair of the Department of Imaging Physics. John is certified in diagnostic radiological, therapeutic and magnetic resonance physics. His research interests are minimally-invasive image-guided therapies and small animal imaging. He is Director of the NCI-funded Small Animal Cancer Imaging Research Facility and a driving force in the creation of a new Center for Advanced Biomedical Imaging Research at M. D. Anderson. The statement, “The development of technologies for Molecular Imaging should be driven principally by biological questions to be addressed rather than by simply modifying existing imaging technologies,” proposes a fundamental shift in the paradigm responsible for the development of medical imaging since the discovery of x rays. Over the 20th century, medical imaging development was driven by technological innovation and engineering improvements in physical equipment. A new imaging modality driven by development of the biological knowledge base represents a fundamental change. Understanding such an important change is of utmost importance to medical physicists working in imaging research. The measure of success, and the economic growth of medical imaging, reside firmly in the ability to implement new procedures with higher diagnostic specificity and sensitivity. Such imaging methods, though expensive in themselves, can in many cases provide cost-competitive resolution of patient healthcare problems. We will consider three arguments; (1) the opinion of leaders in molecular imaging, (2) the scientific focus of self-proclaimed molecular imaging investigators and (3) the major NIH investment in genomic and proteomics research. These arguments lead me to conclude that the statement by Dr. Piwnica-Worms is correct. Medical physicists must either learn to include the biology of molecular imaging in their research programs or prepare to become irrelevant to the future of radiology. A search of the molecular imaging literature leads to a small circle of key individuals and institutions. They are the leaders of the Society of Molecular Imaging which has the stated purpose, “An international scientific educational organization whose purpose is to advance our understanding of biology and medicine through noninvasive in vivo investigation of cellular molecular events involved in normal and pathologic processes.”2,3 It is clear from this statement and from the web pages of the leaders of molecular imaging that they as a group believe that biology rather than an underlying technology is driving their field. A review of the most recent program of the Society of Molecular Imaging4 shows a primary focus on biological questions, design of optical or radioactive molecular imaging probes and/or potential clinical applications. Less than 10% of the program (only one of twelve major symposia) is devoted to technological development, while the remaining 90% is devoted to biology and chemistry. The ACR Primer on Molecular Imaging,5 a commercial special issue on Molecular Imaging,6 and the more popular radiology news journals7 all share this focus on biology. The bulk of specialists in molecular imaging are conducting studies of biology using imaging as the tool of choice. The final consideration is the substantial refocus of federal funding on genomics, proteomics and the relation of these concepts to medicine and health care. Examples of the growing significance of these areas to world science are the special issue focus of journals such as Science8 and Nature9 on the fundamental importance of these discoveries. All three arguments support the contention that biological knowledge, rather than technological evolution of existing devices, dominates the development of molecular imaging. This is a recognizable shift from the development of imaging in the 20th century. It holds great promise for increasing the importance of medical imaging in healthcare decision making around the world. I agree with many of the points made by my colleague, but he has missed the main point of the discussion, which is “should technology development be driven by biological questions or the evolution of existing imaging technologies?” There are two examples that clarify the magnitude of this omission. First consider the only session on technology at the 2004 Society of Molecular Imaging Congress which had the following objective: “To address molecular and small animal imaging challenges, revolutionary developments have occurred in hardware and software. This session is designed to highlight the newest cutting edge developments in instrumentation and new strategies that will enable us to “see” more with greater sensitivity and specificity.” Existing imaging technologies are being reconfigured and adapted to the size and biology of mouse and rat models. Rodent biology is driving technology development. A second example is the introduction of human CT/PET units for clinical molecular imaging. These instruments are optimized to integrate anatomical information from CT with molecular functional information from PET. The medical need for co-registration of anatomical and functional information has driven the development of the technology. I readily accept that molecular imaging cannot prosper without continued improvement of imaging technology. The direction of these developments, however, will be dictated by biological questions that can only be answered through molecular imaging. At the end of the first Michigan State workshop on Molecular Imaging in 2001, Dr. Elias Zerhouni moderated a discussion to define molecular imaging in the context of creating a new scientific society (Society for Molecular Imaging). The discussion was lively, and eventually a vision for the new society was adopted consistent with the definition of molecular imaging accepted by The American College of Radiology's Commission on Molecular Imaging. The ACR definition is: “Molecular imaging may be defined as the spatially localized and/or temporally resolved sensing of molecular and cellular processes in vivo.” I will argue that for most in vivo applications the best approach to developing molecular imaging hardware is to optimize existing technologies. It is relatively clear that new molecular probes have a significant probability of yielding leap-step advances. The lofty goal of molecular imaging cannot be achieved without significant advances in instrumentation as well. The two imaging modalities that will likely have the most impact in patients over the next decade are positron emission tomography (PET) and magnetic resonance (MR). For PET, sensitivity has been an issue since the technology's inception. Detector composition, electronic component capability and instrument geometries have all been improved in order to enhance sensitivity. Advances in crystal design and composition still hold promise for improving overall sensitivity. New experimental systems and flat-panel detectors may provide significant improvements in sensitivity. Further, advances in electronics are permitting new counting strategies, and advances in computing power are allowing for new reconstruction algorithms with enhanced sensitivity.10 Biology will drive the development of new probes that will create opportunities for rapid advancement. Refining existing technologies to detect positron-induced annihilation radiation is the approach most likely to yield significant results for instrumentation. The case is much the same for MR. Advances in magnet design are allowing higher field strengths for both animal and human imaging. There are now several whole-body instruments operating at , and there is an system at Ohio State and a system at the University of Illinois at Chicago. These magnets provide improved sensitivity, with detectability of low-contrast detail improving by a factor of 10–15 in going from . Coupled with advances in coil and electronics performance, a 20–30 fold increase in sensitivity may be achievable. The real opportunity for leap-step improvement in detectability is the development of field-strength-specific contrast agents.11 Although the potential sensitivity of new probes may be 10–100 fold, the mechanism of detection is likely to be a permutation of an existing approach (pulse sequence of acquisition strategy). That is, continued development of more mature instrumentation is likely to yield the most significant advances in the modality. Optical imaging is an exception in this debate. Here probes and detector systems are tightly coupled. The potential is present to find a new probe system based on biology that requires a new detector technology. This potential could drive instrumentation development. Nevertheless, there is still a lot of potential in continuing to optimize existing technologies for improved sensitivity and depth resolution. In conclusion, I believe the development of the instrumentation used for molecular imaging is best driven by continued optimization of existing instrumentation for known tracers and contrast mechanisms. I whole-heartedly agree that medical physicists must learn more biology, including physiology and metabolism, to pursue research in molecular imaging. However, we need to remember that our core value comes from the deep technical knowledge we have of the instrumentation (i.e., tools) used to detect these processes, and the optimization of the performance of these devices. To fully exploit this knowledge we must understand the biological questions to a degree greater than most of us were prepared for in our educational careers. Second, the focus on genomics and proteomics is not surprising because these are new fields with broad potential applications. The molecular imaging community needs to develop ways to exploit advances in these areas with new probes and tracers. Unless these systems require fundamentally new imaging techniques, we will need to incrementally build better instrumentation technologies for molecular imaging.