5
Infrastructure and Resources

The effect of concept-driven revolution is to explain old things in new ways. The effect of tool-driven revolution is to discover new things that have to be explained.

—Freeman Dyson, Imagined Worlds, p. 50


There is a healthy tension between concept-driven and tool-driven learning. Biology relies on the available tools to develop new concepts; physics and chemistry bring concepts for rigorous thought and measurement. Advancement in biomolecular materials and processes will require both perspectives working together so that concepts and tools are integrated in common pursuits for understanding.

Work at the intersection of disciplines challenges traditional ways of conducting research and training researchers. Institutions will have to confront these challenges as they implement structures and mechanisms for supporting research that spans disciplinary and departmental boundaries, brings the academic and industrial sectors together with national laboratories, and spans both basic and applied questions. Some of these challenges include the following: Within academic institutions, how are collaborations with industrial partners managed? How are faculty given credit for their work, and how are their contributions considered within their discipline when it comes to tenure and promotion decisions? How are faculty positions allotted to different departments and who gets credit for teaching at the intersection of disciplines? The answers to these questions are important to advancing work in biomolecular materials and processes. But because they are not specific to this field, providing a thoughtful vetting of these issues is beyond the



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5 Infrastructure and Resources The effect of concept-driven revolution is to explain old things in new ways. The effect of tool- driven revolution is to discover new things that have to be explained. —Freeman Dyson, Imagined Worlds, p. 50 There is a healthy tension between concept-driven and tool-driven learn- ing. Biology relies on the available tools to develop new concepts; physics and chemistry bring concepts for rigorous thought and measurement. Advancement in biomolecular materials and processes will require both perspectives work- ing together so that concepts and tools are integrated in common pursuits for understanding. Work at the intersection of disciplines challenges traditional ways of con- ducting research and training researchers. Institutions will have to confront these challenges as they implement structures and mechanisms for supporting research that spans disciplinary and departmental boundaries, brings the academic and industrial sectors together with national laboratories, and spans both basic and applied questions. Some of these challenges include the following: Within academic institutions, how are collaborations with industrial partners managed? How are faculty given credit for their work, and how are their contributions considered within their discipline when it comes to tenure and promotion decisions? How are faculty positions allotted to different departments and who gets credit for teaching at the intersection of disciplines? The answers to these questions are important to advancing work in biomolecular materials and processes. But because they are not specific to this field, providing a thoughtful vetting of these issues is beyond the 

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infrastructure resources  and scope of this committee. The Committee on Science, Engineering, and Public Policy (COSEPUP) of the National Academies recently addressed what is needed to facili- tate interdisciplinary research in general1 and other committees of the National Academies continue to conduct studies on research at particular intersections.2 There is also a tension in the education of students, which must be deep enough in traditional physics, biology, or chemistry to give identity and a strong foundation for later learning. However, that education must also be wide enough to allow an understanding of the questions and available techniques of other disciplines and to facilitate meaningful collaboration. The appropriate balance between breadth and depth is a challenge, because the time and attention given to one topic in a syllabus or curriculum necessarily restricts the time given to another topic. Using new tools, scientists can teach themselves to think physically or chemi- cally while learning from biological systems. Thus facilities that serve these different modes of thinking and learning are needed. In addition, industry, academia, and national laboratories bring unique strengths to the conduct and advancement of research. These strengths should be coordinated and exploited for the advancement of biomolecular materials research. All of these elements contribute to the progres- sion from basic discovery to the development of a practical device. EDUCATION AND TRAININg To realize the opportunities in biomolecular materials research, the next gen- eration of scientists and engineers should be taught to work at the intersection of disciplines and to build productive collaborations that span disciplinary bound- aries. Institutions should take advantage of institutional strengths and needs in considering undergraduate and graduate curricula and should involve all relevant parties in these discussions. For example, departments of physics, chemistry, biol- ogy, engineering, and mathematics should work cooperatively to consider and reform their programs of study. One department should not reform its own curriculum without involving colleagues from other related departments or con- sidering the increasing interdisciplinarity of science and the interests of students. Only by involving all of the players in curriculum (and course) development can a balance be achieved between focused study and general education in the relevant scientific disciplines. Education should be (1) deep enough in traditional physics or biology or chemistry to give identity and a strong foundation for later learning and 1 COSEPUP, Facilitating Interdisciplinary Research, Washington, D.C.: The National Academies Press, 2004. 2 For example, National Research Council (NRC), Mathematics and st Century Biology, Washing- ton, D.C.: The National Academies Press, 2005; J.C. Wooley and H.S. Lin, eds., Catalyzing Inquiry at the Interface of Computing and Biology, Washington, D.C.: The National Academies Press, 2005.

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insPired biology  by (2) broad enough to allow an understanding of scientific questions and techniques and meaningful collaboration. The correct approach is probably not to simply burden students with a large number of additional classes from existing offerings, tacking materials science courses onto a current biology major, for example. Rather, it will probably require retooling existing courses or creating new ones. For example, an institution might decide to provide a broad baseline for all students but offer in-depth preparation in one or more specific areas in which the institution has particular resources. The discussions of what to include and how to fit them into current undergraduate and graduate training will help institutions consider some of the fundamental ques- tions at the intersection of these disciplines and what best builds on institutional strengths. How to achieve the appropriate breadth and depth will be different for each setting. A variety of approaches are being explored around the country to achieve balance and cross-disciplinary perspectives in existing structures. In one model, examples from different disciplines are described in the context of traditional courses—for instance, using examples from the biological sciences in a traditional physics course. The NRC report Bio00 called for integrating introductory science courses by using examples from one discipline in another.3 An extension of this is to offer a foundation experience that brings together students—and perspectives— from different disciplines explicitly, for example a capstone course of case studies that aims to reverse engineer biological systems using the principles of physics and chemistry. Another response has been the creation of entirely new disciplines, such as systems biology or biological engineering, that bring together aspects of physics, chemistry, and biology, with an emphasis on quantitation. The essential interdisciplinary nature of the research demands careful con- sideration of the education of the next generation of scientists. Exactly how to accomplish such interdisciplinary education is best left to the universities. However, the need for interdisciplinary education must be emphasized, particularly at the graduate level, where the primary training of the next generation of scientists takes place. Some additional mechanisms can be used to encourage and enhance this, drawing on successful programs that have worked in the past. For example, block training grants for graduate students are a very effective means of encouraging the collaboration among students that is the hallmark of successful interdisciplinary research. For example, the National Institutes of Health (NIH) training grants for students and the National Science Foundation (NSF) Integrative Graduate Educa- tion and Research Traineeship (IGERT) program4 are both successful methods for 3 NRC, Bio00: Transforming Undergraduate Education for Future Research Biologists, Washington, D.C.: The National Academies Press, 2003. 4Available online at http://www.nsf.gov/crssprgm/igert/intro.jsp. Last accessed March 27, 2008.

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infrastructure resources  and training students in interdisciplinary research. An evaluation of the IGERT pro- gram showed that these students were better prepared to work in multidisciplinary teams and communicate with people outside their own fields while maintaining the level of in-depth preparation in their chosen field.5 One possible method of enhancing cross-agency interactions is to consider jointly funded training grants. These are mechanisms that are already in place at the different agencies, so the modifications to jointly fund them should be minimal. In addition to integrating a variety of academic disciplines in education, insti- tutions should strongly consider the need to incorporate the perspectives of differ- ent sectors. The field of biomolecular materials and processes has a particular need to integrate basic and applied approaches and the viewpoints from industry and national laboratories, as well as academic research. For example, it may be appro- priate to include industrial advisors in discussions about the most appropriate training mechanisms and educational experiences. Beyond education for the next generation of researchers, there is a need to provide opportunities for today’s scientists to be able to work—and even simply talk—together. The different cultures and languages of the various disciplines can hamper collaboration. While some of these differences have deep historical roots, it would be relatively easy to provide additional opportunities for scientists from different disciplines to meet together for extended conversations and to learn to speak the same language. One promising idea is a sort of scientific “study abroad” to educate physical scientists and engineers in the tools and concepts of biology and biologists in the tools and concepts of the physical sciences. Following models such as intensive research courses and week-long conferences, the committee rec- ommends the development of summer courses in which scientists can work across disciplines and learn ways of communicating across disciplinary boundaries. Part of the challenge of different language is the degree of mathematical rigor. Biology has traditionally employed mathematical approaches different from many of those used in the physical sciences. It is likely that the appropriate level of mathematical sophistication necessary for work in biomolecular materials and processes is somewhere between that customarily used in biology and that used in the physical sciences. This need for a common mathematical perspective provides an opportunity for researchers and, especially, educators to develop courses and textbooks that can give biologists opportunities to learn the appropriate math- ematical techniques and for physical scientists to appreciate the difficulties of modeling complex biological phenomena. 5 National Science Foundation (NSF), Evaluation of the Initial Impacts of the National Science Foundation’s Integrative Graduate Education and Research Traineeship Program, Arlington, Va.: NSF, 2006. Available online at http://www.nsf.gov/pubs/2006/nsf0617/nsf0617.pdf. Last accessed March 27, 2008.

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insPired biology 0 by To engage students in the culture of different disciplines, they should also be provided with a diverse collection of experiences, such as through graduate research rotations. Because much research in biomolecular materials and processes is applied in nature, it is especially important that both industrial and fundamental scientific perspectives are included, both in the classroom and in research settings. As this type of translational experience becomes more common in this field, it will be necessary to determine which approaches are most successful. Most inter- disciplinary programs at various institutions are very new. It is difficult to evaluate successes or failures of these educational programs at the time of publication of this report. Federal and philanthropic grants for different kinds of interdisciplinary learning, and their evaluation, are crucial and are strongly encouraged. It will also be important to ensure that interdisciplinarity does not come at the expense of depth in specific skills and knowledge. Institutions could then use these evaluations to develop a successful approach to interdisciplinary education at the local level. MECHANISMS FOR BRIDgINg BIOLOgICAL AND MATERIALS SCIENCES Research in the field of biomolecular materials and processes is inherently inter- disciplinary. Funding for this type of research can often fall through the cracks of what is supported by different funding agencies. This is particularly true for many of the more speculative research areas identified in this report, which represent much higher risk but which also represent those areas likely to yield the most significant and far-ranging advances. Moreover, because the most important component is related directly to biotechnology and medical technology, research in this field tran- scends traditional materials research and strongly overlaps with the medical research field. As a result, there should in principle be funding available for this area from the traditional sources of support for the physical sciences, including the NSF, the Department of Energy (DOE), and the Department of Defense (DOD), as well as from the sources of support for the life sciences, primarily the NIH. While there should be many sources of support for research in biomolecular materials, there is, in fact, an inherent problem in obtaining funding for such an interdisciplinary research field. In part, this is a result of the dichotomy in the underlying philosophies of the funding agencies that should fund this type of research. Work in the life sciences is typically supported by the NIH, where grantees are expected to propose relatively low-risk steps forward, with substantial proof of principle already obtained before a proposal is submitted. By contrast, work in the physical sciences is typically supported by NSF, DOE and, to some extent, DOD, where grantees are expected to take larger risks and to propose work with a much riskier vision. However, these agencies shy away from support of anything that may have direct medical applications, as this is viewed to be the realm of the NIH. Some of work identified in this report falls naturally into one or the other of these

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infrastructure resources  and basic funding models. However, there is also a great deal of crossover work, which transcends the individual agencies and the separate funding philosophies. Indeed, it is this work that might have the greatest potential for having a truly significant impact on both science and society. This leads to significant opportunities being missed because the funding for them falls between the agencies. For example, there are many opportunities for research in materials and physical sciences to have significant impact on disease, biomedicine, or drug discovery, but these opportunities are not funded by NSF or DOE because of their overlap with the mission of the NIH. Similarly, some of the very physical and quantitative problems in biomolecular materials and processes, which intrinsically rely on the knowledge of the biological processes developed within the medical community, are not funded by NIH because the impact may not be sufficiently clearly related to the medical problems that are its purview. There is clearly room for some funding of the research discussed here within the present boundaries of the funding agencies, and the committee strongly sup- ports those funding mechanisms that currently exist. The committee also strongly supports any additional funding that is made available within the current funding constraints of the agencies; this is the surest way to seed new developments in the field. Although federal research support has been especially constrained in recent years, the time seems ripe for new investment. For example, the America Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science (COMPETES) Act (Public Law No. 110-69), passed in 2007, authorizes a doubling of the NSF budget over 7 years and a general desire to increase support for research agencies supporting the physical sciences.6 If appropriations follow authorization, new resources might be made available for research in biomolecular materials and processes. However, even with the current and potential sources of funding, the commit- tee feels that the inherent interdisciplinary character of the work also requires a change in funding policies to cater to this class of research. For example, the com- position of review panels and study sections may need to be altered to be sure that interdisciplinary proposals receive a fair review by true peers instead of a review structure tilted to a single discipline. The committee also feels that there should be a change in the attitudes of scientists who do get funded by any of these agencies to appreciate the nature of high-risk interdisciplinary research. Thus researchers in the physical sciences should recognize that materials research can play an incred- ibly important role in the life sciences even if it is not strictly funded by the NIH. Similarly, researchers typically supported by the NIH must recognize the impact that materials research can have on the medical field and must be more prepared 6A fact sheet on the America COMPETES Act is available at http://www.whitehouse.gov/news/ releases/2007/08/20070809-6.html. Last accessed March 27, 2008.

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insPired biology  by to accommodate the more speculative nature of proposals in this area. The ongoing discussions at many agencies on how to foster additional investment in such risky research might be of help in this regard. NIH, for example, has established the NIH Director’s Pioneer Award and the NIH Director’s New Innovator Award to encour- age creative, outside-the-box thinking and focuses on the promise of the individual rather than of a single detailed research proposal.7 In addition, four of the NIH institutes have recently requested applications for Exceptional, Unconventional Research Enable Knowledge Acceleration (EUREKA),8 a new program to foster exceptionally innovative research expected to have a high impact; programs such as these might help to foster not only transformative research within a discipline but also additional opportunities for groundbreaking work at the intersection of existing scientific disciplines. To encourage this change in attitude, the committee recommends that work- shops be held within both the life sciences and the physical sciences communities as well as jointly. The goal of these workshops should be to encourage the inter- disciplinary research required for high-impact work and to educate the commu- nities about both the opportunities and the research requirements. An important goal of these workshops would be to broaden the base of each class of research by exposing each community to the potential of interdisciplinary research. Thus, for example, in the physical sciences it is important to have a broader acceptance of the close interplay between the physical sciences and the medical sciences and to recognize the potential applications and outlet of the research in the biomedical fields. Similarly, in the life sciences, it is important to recognize the great potential that an understanding of biological processes can have on materials science and how exploiting this knowledge can also lead to great improvements in many areas of biotechnology. In addition, these workshops can help program managers gauge interest in the scientific community and help demonstrate the great potential of the field, especially as it impacts their own specific areas. SHARED RESOURCES AND ESSENTIAL FACILITIES Biomolecular materials and processes have been fortunate to be among the research areas included in a variety of interdisciplinary programs and centers. Perhaps most prominent are the NSF-funded Materials Research Science and Engi- neering Centers (MRSECs) that support interdisciplinary and multidisciplinary research and education addressing fundamental problems in science and engineer- ing. Biomolecular and biomimetic materials are studied in several MRSECs.9 7 http://nihroadmap.nih.gov/highrisk/. 8 http://grants1.nih.gov/grants/guide/rfa-files/RFA-GM-08-002.html. 9 See http://www.mrsec.org/research/biomolecular_biomimetic_materials/ for a list of research groups currently working in these areas.

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infrastructure resources  and MRSECs provide one model for structuring and supporting research in bio- molecular materials. The National Academies’ Board on Physics and Astronomy recently completed an assessment of the MRSEC program and recommended future directions and roles for the program.10 It might prove valuable to carry out similar comprehensive reviews of other research centers conducting related research to learn which programs have been successful and why. As described in Chapter 4, many of the advances in understanding the behav- ior and properties of biomaterials have come from the increasingly sophisticated experimental tools developed in recent years. Continued progress in solving the challenges of biomolecular materials research, highlighted in Chapters 2 and 3, will also depend on new tools and techniques. Indeed, state-of-the-art research will likely be restricted to those scientists who have ready access to sophisticated equipment. Increasing sophistication inevitably increases the costs of acquisition and maintenance. Not all of these new developments require national-level shared facilities, such as a synchrotron or neutron source. Some of the most powerful new technologies (for example, a cryo-EM microscope and ancillary support) are fea- sible acquisitions for research universities or individual investigators (for example, single-molecule microscopic instrumentation). However, at each of these instru- mentation scales, costs can rapidly become the main constraint on research. As costs increase, federal funding agencies are less able to provide the bulk of the funding for purchase of experimental equipment. Moreover, funding agencies have rarely provided sufficient infrastructure support to operate and maintain equipment. This limited support holds particularly for highly skilled technical staff, a condition that is likely to impair ongoing use and development of the needed equipment. The constraints on current federal funding might be loosened, at least in part, by new funding models. In particular, the wealthier American universities are beginning to put more of their own resources into shared on-campus research facilities. This is a funding model that is more common in some European coun- tries, particularly Germany. For the United States, it is a new paradigm. While direct university support is of great value to the total national research establishment, relying on such local efforts might increase disparities in research quality between universities with larger endowments or clinical revenues and less well-off or state institutions. The next level of single-university, shared facilities that impact biomolecular materials research are the cryo-electron microscopy, micro- and nanofabrication, and molecular expression and modification facilities. Core facilities for these ser- 10 NRC, The National Science Foundation’s Materials Research Science and Engineering Center Pro- gram: Looking Back, Moving Forward, Washington, D.C.: The National Academies Press, 2007.

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insPired biology  by vices exist in many locations, although modernization and enhancement with new tools is difficult. Both NSF and NIH have major shared-instrument funding programs for acquiring such cores, but demand for the funding of these is far outpacing the amount of money available, as more and more universities try to upgrade their research infrastructure with such equipment. Furthermore, main- tenance of them as service operations after expiry of the seed grant is sometimes uncertain. Individual faculty start-up funds are often used to supplement such shared facilities, whereas a program for continued support of effective facilities would provide more continuity. Unfortunately, however, the pace of advance in instrumentation is such that equipment must be upgraded or replaced every 5 to 10 years. Individual faculty commonly obtain high-end commercial equipment or build special-purpose instruments when they begin appointments or move between institutions. Securing funds for mid-level or senior investigators to obtain new instruments or enhance or upgrade machines is notoriously difficult. Funding overhead models also discourage applying for high proportions of equipment on renewal applications. Instrumentation funding for smaller purchases would allow productive investigators to leverage their investment in instrumentation and main- tain state-of-the-art methodologies. The cyclic nature of research funding availability forces agencies to adjust pri- orities to maintain both targeted programmatic and investigator-initiated research at appropriate levels. The committee encourages the funding agency representatives to realize the importance of methods and technology development for continued progress in advanced materials research and to gain the requisite biological and biophysical knowledge to utilize the striking features of biological systems for producing the new materials envisioned in this report. Major infusions of funding have resulted in the commissioning of facilities such as the Spallation Neutron Source (SNS) at Oak Ridge National Laboratory and the BioCAT beam line at Argonne National Laboratory. Until the SNS comes on line, there is agreement that high-quality neutron radiation is sparse. For low-angle X-ray scattering, small-angle X-ray scattering, and imaging, experiments requiring the brightest and most collimated beams have few options. These facilities have an ongoing need to improve cameras, detectors, computational facilities, and mainte- nance by staff. Another very successful method of introducing students to the field is through intense summer workshops. Examples of these in other fields include the workshop on cell biology and physiology held each summer at Wood’s Hole and the summer school in condensed matter physics held in Boulder. These programs are highly successful and the committee strongly recommends maintaining them.

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infrastructure resources  and PARTNERSHIP AMONg INDUSTRY, ACADEMIA, AND THE NATIONAL LABORATORIES Translation of biomolecular material discoveries into useful applications has motivated an increasing number of industrial partnerships. While these partner- ships are often nurtured by different sources (government, industry, academia), they all aim to improve the efficiency of knowledge transfer from discovery to development and to increase returns on investment. Such returns can be defined in many ways, some more quantitative than others, but all entail increased involvement, communication, and contact between academic and industrial investigators and management. The expected products of these interactions include shared authorships on research papers, new intellectual property generation, as well as undergraduate and graduate training for new jobs in industry. While all of these outcomes are important, two—the generation of intellectual property and the translation of this property into licenses and product development within industry—are especially so. A very productive partnership between national laboratories, academia, and industry has been provided by the sharing of large, capital-intensive resources that are housed and maintained at the national laboratories. Good examples of this are neutron beam lines, synchrotrons, and supercomputer centers. The contin- ued development and sustenance of such facilities centered around large instru- ments will remain key to research and development in biomolecular materials and processes. Another model for developing such partnerships that has recently been intro- duced is exemplified by the Molecular Foundry at Lawrence Berkeley National Laboratory (LBNL). Such shared user facilities are not built around one large instrument but rather include various experimental and computational platforms that are necessary to carry out research in a particular thematic area. For example, the synthesis, characterization, and computational user facilities required to create biomolecular nanostructures are grouped together. This model has not been in existence for a long enough time for the committee to have an informed opinion about its impact on the discovery process. Such an evaluation should be carried out in the near future. How then to measure the return on investments for these partnerships? Cer- tain measures, such as the number of peer-reviewed manuscripts or patents, are quantifiable. But these are not the only outcomes. It is difficult to measure the success of new research, of discoveries that have industrial value but that may not be realized for some time after the investment, or of the intellectual property and the commercial products that may derive from such long-term efforts. How does one measure the contribution of partnerships to the training of people who move between industry and academia? This is difficult to measure but is a very important

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insPired biology  by factor in the success of an industrial partnership. These partnerships continue to generate fundamental research across different sectors and remain a vital oppor- tunity for biomolecular material research and development. COMMERCIALIzATION OF BIOMOLECULAR MATERIALS The application of useful biomolecular materials has long had a powerful impact on commercial product development. For example, in the food industry, bulking agents such as algae polymer (for example, carageenan) from marine sources are used in everyday foods such as ice cream. Bovine or porcine collagen is used as a structural material in medical devices. In these examples, the low cost of production compared to that of alternative, less functional synthetics, plus the abundance of the materials in nature, adds further to the advantages of bio- molecular materials. Biomolecular Properties, Processes, and Products For the commercialization of biomolecular materials, it is useful to define bio- molecular material properties used in the development of products and to relate the properties to particular industries (both current and future) that derive useful products from these characteristics (Table 5.1). New tools have been developed around these applications to create useful prod- ucts. They include the ability to process biomolecular materials such as through microfluid transport, assembly tools for two-dimensional and three-dimensional fabrication, and high-throughput mutagenesis or synthesis. Some of these tools have already been commercialized and play a major role in the translation of bio- molecular material science and technology into product development. Examples are show in Table 5.2. TABLE 5.1 Unique Properties of Biomolecular Materials Drive a Number of Important Applications and Products Property Product Molecular recognition and binding Sensors, medical diagnostics, drugs, and therapeutics Mechanical and structural strength Bulking agents in foods, medical devices, and biomaterials High information content Sensors, diagnostics, implants, storage devices High energy content Biobatteries, biofuels

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infrastructure resources  and TABLE 5.2 New Tools That Aid in the Development of New Products Process Tool Transport of biomolecular materials Microfluidics Assembly of biomolecular materials Lithography, stamping, polymerization, writing and capture tools Biomaterial selection Combinatorial methods, directed evolution Manufacturability and Production Some of the tools developed around the science and technology of biomolecular materials help to translate fundamental research into commercial development of the materials. One example is the ability to efficiently transport liquids (micro- liters to nanoliters) in high throughput for separating cells or biomolecular spe- cies. These devices permit the use of biomolecular species in sensor or diagnostic applications and are good examples of tools that have contributed significantly to commercialization efforts. To make products based on biomolecular materials, large-scale manufacturing is required. In many cases—such as growing antibodies, producing recombinant proteins or other species, and bioprocesses for cell “expansion” (production in bulk)—large-scale production uses methods from biological sources while main- taining consistency of production during scale-up. For example, antibodies often change their activity based on production and process methods, large-scale protein production is hampered by inability to control protein folding and aggregation, and a bioorganic chemical industry is developing in order to make proteins, but cell phenotypes can be altered or lost during increased passage. An instance of the last mishap occurred during the effort to grow blood cells. While the biochemical triggers to derive useful blood cell lineages (red blood cells, platelets) have been identified, it is still necessary to engineer useful cell expansion methods that could efficiently yield a unit of therapeutic blood cells. The ability to grow a unit of blood efficiently and economically would qualitatively improve the practice of blood transfusion. Specific Biomolecular Material Product Areas Following on fundamental discoveries, biomolecular materials are candidates for new products such as sensors, diagnostics, prosthetics, fuels, and computers. In this section, current and future product areas are described that employ bio- molecular materials.

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insPired biology  by Sensors and Diagnostics The most mature application based on biomolecular materials is products that rely on the recognition and binding properties of biomolecular materials in sensor and diagnostic applications. These applications have created a large indus- try based on the practice of detection in the environment and in a clinical sample for predicting medical outcomes. Sensor and diagnostic products include devices that use antibodies, peptides, receptors and their antagonists, ribozymes, nucleic acids and biological cells to specifically and sensitively detect and report events as a result of molecular recognition and binding events. For well-established products that employ components such as antibodies, the development of useful diagnos- tics using biomolecular materials is a low-cost, high-volume technology that can be fabricated into easy to use kits, such as enzyme-linked immunosorbent assay (ELISA) for a number of diagnostic applications. Medical diagnostics is a global industry practice with substantial contributions to human and animal health. This multibillion dollar global industry has moved into health screening, prognostics, and companion therapeutics, which consistently drive new products and revenues. These applications are an important example of the value of biomolecular science and technology and how it feeds commercializa- tion efforts with significant societal impact. The required biomolecular property specifications for sensor or diagnostic products will ultimately be set by market-required performance and regulatory and reimbursement practice. The current trend toward combining a diagnostic test with a therapeutic regimen to afford better individualized and more economically efficient medicine practice should facilitate the exploration of biomolecular mate- rial science and product development. New sensor applications that employ biomolecular materials have also recently been motivated by the increased awareness and need in public health application driven by new or perceived threats in biodefense. In many cases, components or reagents (for example, antibodies) are being used in new biodefense applications. The performance specifications for biodefense can be more demanding, where the speed of response and its predictive value in the context of public health risk assessments are paramount. These assets also have implications for national secu- rity, public policy, and homeland defense. Commercial practices such as DNA sequencing or genotyping are emerging rapidly. New service-based companies are expanding interest and growth in DNA microarray analysis. The tools to more accurately amplify and define nucleic acid sequence content of a sample have become much more robust, and there is sub- stantial industrial activity in areas using PCR and genotyping. There have been substantial investments in high-throughput, cell-based diagnostics and in driving the information content from cells using microscopic and biochemical cell tests.

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infrastructure resources  and This has been motivated by the interest on the part of pharmaceutical companies in identifying targets and leads from combinatorial chemical libraries of potential drugs. High-throughput G-coupled protein cell assays to look for receptor binding are also common practice, based on the biomolecular assembled properties of the G protein system important in many cellular interactions. Other cell-based tests have utilized green fluorescent protein or luminescence to drive cell-specific information of inter- est. One test employs the use of B cells engineered with aquoerin (jellyfish protein) to create a commercial cell-based test for food contamination with E. coli. Medical Devices Biomolecular materials in the medical device industry have already achieved considerable penetration into the market. This includes the use of biomolecular polymers in a number of medical devices, including bandages, drug delivery vehicles, stents, orthopedics, and dentistry. These products capture structural properties of these materials (for example, collagen, ceramics, bioglass, dental polymers, and hydrogels), release properties (for example, hydrogels and coatings) and delivery of specific agents (for example, liposomes and imaging agents). They rely on careful identification of properties such as molecular interactions (collagen with growth factors or coagulation proteins), porosity and permeability, and surface modifica- tion for specific targeting of drugs and therapeutics. Therapeutics Biomolecules and their assemblies have also provided useful therapeutics for application in medicine. The use of assembled phospholipids in liposomes and other lipid emulsions as drug delivery vehicles has been widely practiced in the delivery of toxic agents (for example, antifungals) and antibiotics for extended release and targeting to specific sites in the body. Biomolecules as contrast imag- ing agents for PET or fMRI applications have also been very useful for in vivo medical diagnostics, and their use continues to grow rapidly. Other biomolecular properties exploited in useful therapeutic applications include adhesives such as thrombin (surgical glues) and absorbable biocompatible polymers (sutures made of polylactides and polyglycolides). These are mature examples of the utility of biomolecular material products and generate revenues of millions of dollars in commercial markets. Challenges and Opportunities in Commercialization Biomolecular science and technology enjoy wide application and generate correspondingly broad commercial interest. This interest is due to the unique

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insPired biology 0 by properties of the biomolecular materials described in this report, such as bio- molecular recognition and communication, structural and dynamic strength, and high information and energy content. To maximize the commercial potential of these properties, the specific products that demonstrate these properties must be carefully assessed. Advancing a technology to product development often requires an understanding of the mechanisms of action and interactions in complex sys- tems as well as the product’s manufacturability. If they can meet a specific market demand, these systems will be commercialized. Specific challenges for future commercialization efforts include translation to large-scale production and manufacturing (described earlier), increasing the long-term stability of products with biomolecular materials, and integrating the materials into devices and products (see Chapter 3). While long-term stability is not a problem for some materials, some biomolecules and their assemblies cannot be preserved easily or for long periods. The stability of other biomolecular materials (such as antibodies) can be lost through production methods. Further research and development in these three challenge areas are needed to fully realize the potential of biomolecular materials in commercial markets. Public/private partnerships are one route to nurture commercialization efforts. The use of these enterprise zones to seed such efforts is warranted and should be encouraged. Careful attention to specific issues such as intellectual property and ways to increase its sharing and transfer should also be encouraged and used to evaluate the commercialization outcomes of these investments.