Compared with physics, chemistry, and other physical sciences, biology has not drawn as consistently, as quickly, or as thoroughly on the capabilities afforded by emerging technologies. With some notable exceptions, traditional imaging, data collection, and analysis techniques have remained the foundation for progress in the biological sciences. However, many of the seminal advances in biology in recent years have been based in large part on the creative application of new technologies. It is likely that this trend will continue, as technological advances continue to open up opportunities for scientific advance. The Directorate for Biological Sciences (BIO) of the National Science Foundation (NSF) is exploring mechanisms for organizing and funding research activities that will foster the development and use of advanced and/or emerging technologies to address fundamental challenges in the biological sciences. In order to gain insights from experts in this area, which could help guide its strategic planning, the BIO Directorate encouraged the directors of the Science and Technology Centers (STCs) it supports to organize a workshop to examine the "Impact of Emerging Technologies on the Biological Sciences." The workshop was held at the NSF in June, 1995. Participants included the directors of the Science and Technology Centers (STCs) supported by the BIO Directorate, along with selected leaders in key research areas in both science and technology, from academe and industry. The two-day session was highly productive, yielding a wealth of ideas, information, and suggestions that will give concrete direction to future BIO efforts in this area. I would like to acknowledge the key role played by Dr. Lans Taylor, Director of the Center for Light Microscope Imaging and Biotechnology, at Carnegie Mellon University; Dr. Taylor worked closely with the BIO Directorate staff in organizing the workshop and developing its themes, and was instrumental in the development of this report. I c ertainly want to thank Dr. Mary Clutter, Assistant Director of NSF for Biology, for her leadership in spearheading this effort and for her interested support during the workshop itself. Thanks also to Dr. James Brown, Director of the Division of Biological Instrumentation and Resources; to Dr. Gerald Selzer, Director of BIO's Special Projects Program, for providing logistical and intellectual support for the workshop; and to Courtland Lewis, consultant, for his assistance in preparing the report of the workshop. Finally, I wish to acknowledge with gratitude the enthusiastic participation of the workshop attendees, who truly "brainstormed" these issues in a mutually cooperative, efficient, and yet intellectually invigorating way. I believe that their efforts reported here have initiated a broader focus on emerging technologies that will provide exciting new directions in biology in the years to come.
Erich Bloch, Chair
These are exciting times for biology. During the next decade, the biological sciences will come of age as basic science merges with new technology. Increasingly, biological research problems drive technology development while, in turn, new technologies stimulate advances in science. This is the report of a workshop held at the National Science Foundation that had two aims: identifying emerging technologies that can have an impact on biological research, and finding ways to develop and harness those technologies more efficiently through changes in the science infrastructure and support mechanisms.
The workshop participants succeeded in identifying a wide range of emerging technologies, including five that they deemed of highest priority. In their report, they urge NSF to place greater emphasis on technology development and to pursue a cross-disciplinary approach to merging biology with new technologies, establishing new programs for that purpose. They recommend a more interdisciplinary science education to reduce the "language barriers" between disciplines and to produce a cadre of researchers able to develop and apply new technologies in biology. They stress that scientific resources must be used conservatively, with more explicit setting of priorities by NSF along with more specialization of facilities and research pursuits by universities. Academic administrators can do much to promote and facilitate interdisciplinary research and technology development by accepting their legitimacy and recognizing it in policies and practices.
The great challenge and opportunity for biological science as we move into the 21st century is to understand biological systems in all their complexity while preserving and exploiting biological systems in a sustainable fashion. The tools for dealing with this complexity will require the adaptation and application of emerging technologies.
Among the many new tools that are or will be needed, some of those having highest priority are:
Expanded university-industry interactions are likely to accelerate the development and application of new technologies to the biological sciences. NSF can facilitate such interactions by funding exchange programs, joint research, and conferences. The Foundation could serve as a clearinghouse for information on underused and potentially valuable technologies currently "on the shelf." Development of more formal standards for intellectual property rights would also be useful.
These and other recommendations are elaborated upon in the first chapter of the report, where their importance and timeliness are made evident.
Biology is at a crossroads. The biological sciences have lagged other sciences such as physics and chemistry in the large-scale application of advanced technology to research problems. Over the past 20 years, however, technology has increasingly demonstrated its potential to catalyze revolutionary breakthroughs in the biological sciences.
From the scanning tunneling microscope to gene cloning technology to the remote sensing satellite, emerging technologies have stimulated new research and even spawned new industries.
Now, new technologies are emerging which give promise of yielding similar rapid advances in the biological sciences, if they can be merged into research and education in a timely and effective way. At the same time, though, another factor has appeared which has sweeping implications for research and education in all the sciences: Declining federal support for academic research, reduced industrial R&D budgets, strong global competition in research as well as technology development, and increasing complexity, cost, and speed of technology development all comprise an historic paradigm shift for scientific research in the United States.
Thus, new technological and scientific opportunities combine with a new environment for research and education to produce a major challenge and opportunity for the biological sciences. The National Science Foundation's (NSF's) Directorate for Biological Sciences (BIO) convened a workshop of leaders in biological research and technology development to explore ways to meet this challenge head-on. They reached a number of conclusions and developed recommendations regarding actions that can be taken to facilitate the successful melding of emerging technologies with research and education in the biological sciences. These conclusions and recommendations are summarized here.
The great challenge and opportunity for biological science as we move into the 21st century is to understand biological systems in all their complexity while preserving and exploiting biological systems in a sustainable fashion. The tools for dealing with this complexity will require the adaptation and application of emerging technologies not only from biology, but also from many other fields of science and engineering. There is a pressing need to take advantage of and develop new analytic tools at all levels - from the molecular to the cellular, the system, the organism, and the community of organisms. The key will be to blend leading-edge biology with the appropriate technologies. In some cases the technology itself will be leading-edge. In other cases, the "right" technologies will be ones that have already been proven in other fields but whose application to biology is novel. In still other areas, the biological sciences could be the first users or might provide the original impetus to new technology development.
The workshop participants identified a wide range of applicable emerging technologies, which are presented in a table in Section III, "The Emerging Technologies." Among the many new tools that are or will be needed, some of those having highest priority are:
We conclude that understanding biological complexity and developing the tools to pursue that aim effectively will demand a cross-disciplinary approach in the context of focused programs of research and development.
Recommendation: NSF should promote and facilitate efforts aimed at developing the tools needed to deal with biological complexity. To that end, the Foundation's overall investment portfolio in biology should place more emphasis on technology development and application. Among the important actions are the need to:
While initiating these changes in funding, it is essential to maintain support for and recognize the central importance of the individual investigator.
A challenge in bringing other disciplines and their technologies into biology is in dealing with the "language barrier" between disciplines. We conclude that one effective approach to reducing this barrier is to modify the education process to be more interdisciplinary. To that end, we suggest the following:
Recommendation: NSF and NIH should expand programs that facilitate interdisciplinary training in biology (i.e., with significant course requirements in the physical and computer sciences, mathematics, and/or engineering) for students and young scientists. Graduate education in biology should include significant course requirements in at least one other discipline outside the major field. Industrial exposure should be an option available to all biology students. To facilitate these enhancements, the Research Training Groups currently funded by the BIO Directorate could be expanded. The aim should be to develop a cadre of researchers with expertise in developing and applying new technologies in the biological sciences.
Recommendation: Science education at the undergraduate level should be broad, with substantialexposure to other science disciplines and engineering fundamentals. Additionally, the education of every biology undergraduate should include a significant research experience.
Since many foreign nations are rapidly developing impressive academic research and science-based industrial capabilities, it is likely that an increasing percentage of foreign students now enrolled in science programs at American universities will return to their home countries after graduation. This trend will leave American university faculties and industries with a shortage of scientists. We conclude that there is a need to attract more U.S. citizens into science; and that the key to doing so is precollege education.
Recommendation: NSF should place special emphasis on K-12 science outreach programs where the imagination of children is captured in their earliest years by the wonders of science. Every science directorate should have some direct responsibilities for K-12 outreach.
Recommendation: Closer cooperation and interaction should be established between the Directorate for Education and Human Resources (EHR) and the science directorates. To ensure appropriate science content, there is a need for more EHR outreach programs that are awarded through the science directorates.
Recommendation: To encourage more science post-doctoral students to take teaching positions in elementary and secondary schools, NSF should develop a mechanism (such as summer research collaborations) that allows them to maintain a connection to a university research department and thereby refresh their knowledge base.
For the next several years at least, NSF is likely to experience no growth or even reductions in its budget. In real terms, this will translate into reductions in government support for university research. We conclude that there are two main implications for the development of emerging technologies.
First, resources must be used conservatively and wisely. To that end, we recommend the following:
Recommendation: All NSF science directorates should closely examine their existing centers, facilities, grants, and other expenditures and to see where resources can be recaptured. A blue-ribbon panel should be established to analyze these expenditures in a uniform way across the directorates and to set appropriate priorities for their support.
Recommendation: There should be more specialization of facilities at a university with, as a corollary, purposeful omission of similar facilities at other universities. Each university should focus on establishing some number of carefully selected specialized facilities.
Recommendation: All new facilities and research centers must have a "sunset clause" in their contract in order to optimize the investment of scarce funds in emerging technologies.
Recommendation: Review of proposals for biological databases should involve more explicit consideration of market forces - i.e., Is it really needed? Can the private sector provide it? Also, the review should consider availability of adequate computer facilities and electronic communication links for access to the database.
Second, high-value resources and facilities will need to be shared. Thus, we recommend as follows:
Recommendation: NSF should place powerful, expensive facilities (e.g., an informatics center, a protein facility, a structural biology facility) at appropriate institutions and require or set up sharing mechanisms for their use by researchers at other institutions, regionally or nationally. Such facilities can be partly "virtual," in that their databases should be accessible electronically and even measurements and analysis can be remote.
In this era of stringent budgets, it is important to seek opportunities for agencies with complementary interests and programs to collaborate on technology development and application in biology. An example might be joint programs between the NSF and the National Institutes of Health, the National Aeronautics and Space Administration, the Environmental Protection Agency, or the Departments of Energy and Agriculture.
Recommendation: NSF should take the lead in encouraging interagency and multiagency collaboration on technology development and application in biology.
Academic attitudes and policies play a very important role in the directions that faculty research efforts take. The current environment at most institutions tends to steer scientists toward "pure" research in specialized areas and away from the development of new tools and technologies as well as industrially oriented research. We conclude that changes are needed in the perception of many administrators regarding what constitutes appropriate academic pursuits by faculty researchers.
Recommendation: Academic administrators and policies should promote and facilitate the crossing of disciplinary boundaries by faculty researchers. Some specific suggestions are:
Collaborations between universities and industry in the application of emerging technologies to biology potentially could be very fruitful. Both sectors, and government, have roles to play.
Recommendation: NSF should expand university-industry sabbatical exchange opportunities such as those offered under the GOALI program. The use of industrial matching funds could be explored.
Recommendation: NSF should make additional funds available to facilitate university-industry interactions - for example, through the Small Business Innovation Research program. Effective mechanisms include joint or collaborative research projects, joint facilities for basic research, and joint seminars and conferences.
We conclude that academic attitudes toward working with industry must change; industry is neither a "deep pocket," nor a competitor, nor an unworthy partner. A relevant observation is that university-industry collaboration appears to be easier if the project is small, focused, and centered around a specific goal.
Intellectual property rights (IPR) frequently present a barrier to university-industry interactions. Negotiations often are long and detailed, and the two parties often fail to understand each other's needs and priorities. Each individual agreement has aspects that make it unique. We conclude that additional understanding and perhaps some further formalization in this area through model agreements would be beneficial.
Recommendation: NSF should convene a workshop on government-university-industry IPR and technology transfer in biotechnology. One issue that should be explored is the development of a set of standards for IPR that would shift the focus of universities and industry away from short-term benefit to long-term opportunity.
Often, potentially useful technologies developed in industry become "orphans" because corporate management does not perceive a sufficient market to justify further development; or they may have applications in biology that are very different from those they were developed for. Similarly, technologies developed by university researchers may languish "on the shelf" because no agency appears that is willing to carry them forward to a more fully realized state of development. We conclude that significant potential may lie in finding appropriate "homes" for such technologies in the biological sciences.
Recommendation: NSF could serve as an information clearinghouse for under-used and orphan technologies residing in industry, universities, and other public and private institutions. The Foundation would prepare a database containing generic descriptions of technology available to entrepreneurs and others, if necessary under agreements of confidentiality. (In this context, perhaps a closer association between NSF and the U.S. Patent Office would yield significant public benefit.)
The process and criteria employed in proposal review are critical in establishing the direction and potential for success of any new research initiative, but especially one involving a mix of disciplines. To achieve a cross-disciplinary approach to research and technology development, we conclude, the proposal review process must accommodate that objective.
Recommendation: NSF should carefully tailor the composition of proposal review panels in this area to suit the cross-disciplinary nature of the work; reviewers should have personal experience with cross-disciplinary research. Social and economic utility should be included as one of the funding criteria in proposal review.
NSF's current proposal review process is conducted piecemeal. Proposals are reviewed separately, not as part of an overall investment portfolio.
Recommendation: Within each directorate, ways must be found to couple the review of potential new programs with the review of existing programs. For example, review panels should be given an overview of the Directorate's expenditures and instructed to consider proposed resource investments critically from a "big-picture," portfolio standpoint.
"Methods" proposals have generally been reviewed unfavorably in the past; in direct comparison to biological research, often they are considered too prosaic. We conclude that methods development will play an increasingly important role in the advancement of the biological sciences.
Recommendation: NSF should solicit medium-to-high-risk proposals on methods development, perhaps including proposals for centers devoted to methods development. These proposals should be reviewed separately from standard research grants.
A number of special issues and topics of concern arose during the workshop that will require further exploration, as workshop participants did not feel qualified to discuss them at length or make recommendations regarding them. They are listed briefly here as possible "food for thought" for the readers of this report or for future study groups.
The exciting new possibilities in biology are just starting to be realized, led by advances in medicine, pharmaceuticals, agriculture, ecology, and forensics. This is only the beginning. Just as chemistry and electronics helped to define the 20th century, the biological sciences could easily help to shape life in the 21st century. But the ability to make rapid progress across a wide front of fields in biology will depend to a great extent on the integration of emerging technologies with biological research. It will require a new systems view of the biological sciences, a more coherent understanding of the relationships among the sciences and between the sciences and technology.
The recommendations and actions proposed in this report, if taken, will significantly enhance progress in the biological sciences and thus the quality of life in the coming century.
Traditionally, we think of scientific discovery as driving technology development; but frequently the opposite is true. In fact, there is a close symbiosis between the two. Especially today, with the seeming proliferation of multidisciplinary research groups and centers, it is common for groups of investigators to pursue basic science and tools development at the same time. Researchers in all disciplines are accustomed to the fact that they must capitalize on the latest technological advances in order to remain at the forefront of their field. Thus, technology today plays a key role in the advancement of biological science, a role that contrasts sharply with its traditionally low status in the scientific enterprise.
The revolution occurring in the biological sciences is based on the fact that, today, biological information can be deciphered and manipulated at exponentially increasing rates. Biological information falls into three general categories that represent increasing levels of complexity: (1) the one-dimensional information of DNA - the digital information archive - with its four-letter language; (2) the three-dimensional information of proteins, the molecular machines of life, with their twenty-letter language; and (3) the most challenging of all, the four-dimensional information of living systems - the interplay of complex systems including molecules, cells, tissues, organs, organisms, populations, and communities - with its as-yet only partially defined language. This last category integrates the first two and encodes the most fascinating of traits of microbes, plants, and animals, including individual humans and populations of living systems.
Major advances in science, including the biological sciences, have been stimulated by the application of new technologies to specific challenges such as these; indeed, the common denominator in the majority of significant advances in biology in recent decades has been the optimal application of technology to a particular challenge. In some cases, major developments initially targeted to one field have been applied with great success to another area. This interdisciplinary cross-fertilization has become a hallmark of American science. Examples of fields that have been created or greatly stimulated by the advent of new (or newly applied) technologies would include:
And of course, nearly every field of science and technology has been spurred - in some cases revolutionized - by advances in solid-state electronics and the accompanying advent of powerful, low-cost computers that permit fast computation, modeling and simulation, and rapid access to enormous databases.
It is possible to cite, somewhat speculatively, examples of potential fields in the biological sciences whose development might be driven by emerging technologies. These would include: comparative genomics (by advanced rapid sequencing technologies); terrestrial ecosystem ecology (by scale modeling tools, microsensors, and remote sensing); structural biology (by improved x-ray sources and nuclear magnetic resonance devices); bioinformatics (by improved computer hardware and software); biotechnology (by advanced processing technologies); bioremediation (by advances in site characterization and monitoring capabilities); and cell, developmental, and neurobiology (by improved reagents and imaging modalities).
In considering how to facilitate the development of new technologies, an important question is: How do new technologies emerge?
Some breakthroughs have been stimulated by a focused effort to develop technologies in order to solve significant research problems that were technology-limited - a process that might be termed "market-pull." For example, the size and complexity of the genetic material that controls the form and function of living systems required dramatic developments in technology to map, sequence, and manipulate DNA with high throughput. Large-scale DNA mapping and sequencing methods have evolved to meet the challenge to produce high-throughput tools. In addition, microfabrication technologies that combined silicon wafer material with solid-phase chemical array methods have made it possible to screen matrices of specific DNA sequences rapidly and with small sample sizes. More advanced, automated tools are now on the horizon, based on the development of new microfabrication and analysis methods using hybrid technologies from biology, chemistry, materials science, physics, engineering, and computer science. High-performance computing and communication will also be required to process, analyze, display, search, and archive the huge data sets.
In other cases, new technologies emerge as a result of serendipitous breakthroughs in either basic science or the application of newly discovered scientific principles. A good example is the development of magnetic resonance imaging (MRI) to study physiological processes in living plants and animals, including humans. Physicists, in the 1930s, characterized the magnetic properties of the nuclei of the elements with the goal of understanding the structure of the nucleus. Chemists, starting in the 1950s, developed the tool of nuclear magnetic resonance for chemical analysis. Subsequently, biologists with an interdisciplinary background in physics and chemistry recognized the potential of harnessing magnetic fields to create images of the nuclei in a sample. Today, MRI is a major tool for studying fundamental physiological processes in living systems and has become an important medical diagnostic tool. Future developments will include the incorporation of high-performance computing and communication technologies to acquire, process, analyze, display, search, and archive complex images through "virtual laboratories."
Typically, new technology development occurs through either industrial innovation (sometimes serendipitous but more often in the form of a focused development effort) or discovery by academic researchers (usually serendipitously). Federal funding for academic research has been key to many of the academic advances.
Once a technology exists and is in use, there are a variety of mechanisms by which it may be applied to new and different fields. A primary vehicle is the recognition of its utility across disciplines by researchers who become aware of the technology and make the creative connection to their own needs - a process sometimes called "technology-push." Improvements in capability certainly tend to broaden the applicability of a new technology, particularly if they are in form of modifications specific to the needs of a particular field. Reductions in cost, typically through wider use and the accompanying economies of scale, lead to even wider use.
Some of the traditional mechanisms that have worked well in producing this "aha!" of recognition are professional awareness through publications, conferences, and other venues of professional communication; those who maintain an interest in developments in other disciplines are the most likely to encounter and recognize new technological opportunities.
We might well ask how these processes of technology development and implementation might be different in the future. It is likely that there will be a greater number of strategic, planned efforts - especially in academe. We are also likely to see more interdisciplinary collaboration. Serendipity will always play a role, but the interdisciplinarity of future research will create a new environment for creative people to pursue scientific discovery.
It is evident to the workshop participants that we are undergoing a major paradigm shift in the way that science and technology development are pursued. There are two equally important components of this paradigm shift:
The post-War World II era of open-handed, expanding public support for science and technology appears to be over. Science now competes, often on a less-than-level playing field, with a constantly shifting panoply of high-profile social imperatives. As a recent report of the American Association for the Advancement of Science noted:*
Scientists and engineers are struggling to interpret the new paradigm created by the most significant across-the-board funding cuts to the R&D enterprise in the post-World War II era.
Thus, a primary question that the workshop participants attempted to address is, What are the evolving paradigm changes that will impact the development of new technologies applicable to biology? We anticipate that the following will be integral elements of the new environment for R&D:
A corollary question relates to how these changes will be felt at the level of the academic researcher or research unit. The primary change, already being felt, is reduced funding for academic research. Federal programs will be consolidated and their budgets reduced; many will be cut entirely. Government funding of university research is likely to become much more focused and strategically targeted, with direct applicability to national interests being a more important consideration. Market forces will increasingly be taken into account in making funding decisions. Since the pool of researchers seeking funding will not immediately shrink in response, for the foreseeable future there will be increased competition for available funds. Industrial funding for in-house R&D, especially longer-term work, will continue to decline.
There will be more pressure to set priorities and milestones, among some federal funding agencies but especially in industry-funded academic research. Stronger foreign competition in research and education will keep many of the best and brightest foreign students at home - or at least in other countries besides the United States - reducing the tuition income that now helps to support the U.S. academic research endeavor. Despite the atmosphere of greater austerity, increasingly, the performance of cutting-edge research will require more sophisticated and expensive equipment. Partly as a result of higher costs, there will be a continuing trend toward more university-industry and industrial collaboration. Industrial support for academic research will increasingly take the form of in-kind grants of equipment and pooled funding for collaborative, pre-competitive or generic R&D. Relatively less industrial funding will be available for single-investigator basic research.
Based on these premises, it is a relatively simple matter to project what the major changes will be in the way that biological research and education are pursued in academic institutions, industry, and government over the next 5-25 years. We would anticipate that the educational experience will become more interdisciplinary, with wider exposure to other disciplines and often at least two thesis advisers per graduate student. Teamwork will be emphasized. Students will experience more industrial interaction at various points in their education; indeed, graduate training will be more geared to the industrial job market. Research will also reflect greater industrial interaction and a higher percentage will be of an applied or quantitative nature. Faculty researchers will gain a better understanding of the business culture and drivers. Academic research in the biological sciences will see more group activities and more sharing of facilities.
These changes will be sweeping and profound in their impact. In many ways, the new paradigm will not be as hospitable to science and scientists as the past has been. The environment will be more austere and demanding, both personally and socially. Inevitably, there will be (and already is) a strong resistance to accepting the fact that a shift to a new phase has occurred. This resistance is seen not only on the part of individuals but also of institutions. The temptation is not to accept the reality of change until it is forced upon one. But many long-held attitudes and practices will have to change. For example, it is clear that there is a need for a better mutual understanding of needs, drivers, and terms of interaction between industry and academe (e.g., regarding royalty rates and intellectual property in general).
We can predict the broad outlines of this new paradigm for science, but we do not yet know the exact conditions or what the rules are. What can be said with confidence is that the environment for science will not be the same in the next 25 years as it has been over the past 40. These transformations portend major changes in the way researchers must approach their work and perceive their role in society. As biologists move to bring new technologies more fully and routinely into their research, they have an opportunity to lead the scientific community in adapting to this new paradigm.
Much of the workshop was spent in identifying the key emerging technologies (including technologies already being applied in other fields) that show promise for stimulating progress in the biological sciences. Workshop participants were asked to come prepared to make presentations on several candidate technologies relevant to their own area of expertise, in order to initiate subsequent group discussion. (Appendix A summarizes those presentations.)
Table 1 summarizes the results of that discussion. The table lists more than 30 emerging technologies, along with the scientific and technical goal(s) whose achievement the technology is expected to facilitate, and any related, more specific technology that will be needed to realize the application of the new technology in biology. A small number of these technologies were identified as having the highest priority for support and further development. These highest-priority technologies are elaborated upon in the text following the table.
It is worth noting that many of the emerging technologies identified in the table have a direct relevance to the strategic research areas identified by NSF that are technology-limited and that bear on the biological sciences. Those broad areas are: global change, environmental research, and biotechnology. For example, research on global change and the environment is supported by remote sensing, biosensors, and computational modeling and simulations. Biotechnology is supported by many of the technologies that appear in the table, including: mapping, sequencing, and analysis of DNA; production of biological molecules; development of modulation reagents based on the manipulation of DNA, proteins, and complex systems; analysis of complex biological systems and networks; and creation and analysis of genetically modified plants and animals.
Out of the many emerging technologies identified in Table 1, the workshop participants identified the following as having the highest priority for the biological sciences.
"Highest priority" is, of course, a highly subjective designation. There are many technologies and tools which have substantial promise and are deserving of support. Indeed, the most important scientific breakthroughs may come from any of the technologies on the list (or perhaps some not even envisioned here); it is in the nature of scientific discovery that such events cannot be confidently anticipated.
However, workshop participants agreed that the technologies cited above offer the broadest applicability across disciplines in biology for understanding biological complexity. Analysis of complexity - from the molecular to the cellular, the system, the organism, and the community of organisms - will require these tools for analysis and manipulation of biological systems. Thus, their potential is the greatest because it is the most versatile.
It is worthwhile to discuss these five technologies in greater detail, in terms of (1) their nature, (2) likely applications, (3) potential impacts, and (4) development bottlenecks (current or expected).
Bioinformatics. Bioinformatics involves all aspects of advanced computer science and engineering. It includes the high-speed acquisition of biological data, followed by the high throughput processing, analysis, archiving, data search and retrieval, networking, and display of complex biological data sets. This may be the single most pervasive emerging technology in terms of applications for biological research.
Large databases that can be accessed and analyzed with sophisticated tools will become central to biological research and education. The information content in the genomics of organisms, in the molecular dynamics of proteins, and in population dynamics, to name but a few areas, is enormous. Biologists are increasingly finding that the management of complex data sets is becoming a bottleneck for scientific advances. Therefore, bioinformatics will rapidly become a key technology in all fields of biology.
The present bottlenecks in bioinformatics include the education of biologists in the use of advanced computing tools, the recruitment of computer scientists into this evolving field, the limited availability of developed databases of biological information, and the need for more efficient and intelligent search engines for complex databases. Common data structures and user interfaces will be necessary to leverage investments in software development.
Computational Biology. Computational biology involves the use of computational tools to discover new information in complex data sets and to decipher the languages of biology (e.g., the one-dimensional information of DNA, the three-dimensional information of proteins, and the four-dimensional information of living systems).
The applications of computational biology are broad. They include: the analysis of structure of macromolecules based on high-resolution data; the prediction of structure from sequences of proteins and nucleic acids; the prediction of population dynamics; the molecular design of engineered organisms; molecular phylogeny; and predictions of future evolution. The use of fractals, chaos theory, and artificial intelligence/knowledge-based systems to explore the complexity of biology will become important.
The bottlenecks to further development include the availability of high-performance computers for computing power; the poor state of data bases; the education of biologists in the use of advanced computing tools; the recruitment of computer scientists into this field; and the low level of development of all the components of bioinformatics.
Functional Imaging of the Chemical and Molecular Dynamics of Life. The technologies that have evolved to allow functional imaging of living systems include: the instrumentation for acquiring images based on one of the spectroscopic methods such as fluorescence and nuclear magnetic resonance (NMR); the software for processing, analyzing, displaying, archiving and searching image data-bases; and the reagents developed as contrast enhancers and/or biosensors of specific chemical activities. The integration of these technologies has created a new technology for measuring and manipulating the chemical and molecular dynamics of living systems. Light optical methods allow the exploration of the molecular and chemical dynamics of single molecules, sub-cellular domains, whole cells, populations of cells, tissues, organs and even whole organisms. NMR imaging technologies permit some sub-cellular investigations up through whole organisms including man. Therefore, tools are rapidly becoming available to study the dynamics from molecules to man.
The likely applications include basic research in biology where the living cell or whole organism is treated as a "living microcuvette" to measure and manipulate the temporal-spatial dynamics of the chemical and molecular processes that produce specific functions. The wealth of biochemical and molecular knowledge that has been gained in vitro can now be extended to living systems. Therefore, mechanisms of functions can be defined by literally mapping the specific biochemical and molecular events in time and space. Basic mechanisms of cell functions such as cell locomotion, cell division, and endocytosis can be defined. Basic mechanisms responsible for carrying out development of organisms can be defined. Living systems can be investigated from the single cell stage through adulthood. The same technologies can also be applied to applied problems such as advanced methods for toxicology screening, drug discovery and diagnostic tests.
The impact of this technology is expected to be enormous. The ability to map specific chemical and molecular events in living systems will permit investigation of the four-dimensional information responsible for life. In addition, the development of the technology for basic research is expected to radically change the methods used in toxicology, drug discovery, and clinical diagnostics.
Development bottlenecks include the application of high performance computing to acquire, process, analyze, display, archive, and retrieve complex image data sets. The goal will be to perform all of these functions in real-time, so there must be an efficient and ultra-fast communication from the imaging hardware to the computational hardware and the performance of the software. New classes of detectors are required that have the performance specifications, but that are reasonably priced for biomedical researchers. In addition, new classes of reagents are required for improving the contrast of specific molecules and/or processes; as well as sensing specific chemical and molecular events. A major challenge/bottleneck is to construct the necessary reagents using genetic engineering. The goal is to produce molecules, cell lines, and organisms that express the optimal reagent(s) for measuring specific chemical and molecular processes.
Transformation Technology. The most revolutionary recent development in the biological sciences is the methodology for manipulating DNA molecules and introducing nucleic acids in genetically competent form into cells. Introduced DNA may be integrated into the nuclear or other DNA of a cell such that genes encoded in the DNA are expressed, and the DNA is replicated and transmitted to progeny cells. In this process of genetic transformation, a new gene is introduced into the organism, potentially increasing the value of its progeny. A methodology that is distinct from genetic transformation and that has great potential for biotechnology applications is "transient expression." In transient expression, DNA or RNA molecules are introduced into the cell but not under conditions or in a form that will integrate into the cell DNA. Transient expression vectors usually are based on virus genomes, so that the introduced DNA or RNA molecule can mediate its own replication, thereby vastly increasing the number of copies of the introduced nucleic acid. At this time, the fraction of animal experiments with demonstrated expression of a novel protein is about two orders of magnitude greater for transient expression systems than for genetic transformation.
Likely applications include new crop products and new products from domestic animals, including foods, fibers, chemical feedstocks, bioplastics, and "edible pharmaceuticals" in the form of proteins tailored to the needs of the individual patient (e.g., for inducing immunotolerance). Among the potential impacts are new biotechnology products produced from solar energy. There are four main bottlenecks to development: (1) a very limited understanding of the processes by which DNA is transferred from cell-to-cell and is integrated into the genome of the target cell; (2) lack of a scientific understanding of regeneration of plants from single cells and animals from embryos or fused cells; (3) incomplete information on the control mechanisms of transcription, translation, and post-translational modification of proteins; and (4) the need for more information on metabolic processes and animal and plant physiology to fully exploit these technologies.
Nanotechnologies. Nanotechnologies represent a remarkable technology that will have broad implications in many sciences, including biology. This technology employs microelectronic fabrication techniques to integrate mechanical and biosensors, computer power, and electromechanical outputs into an integrated microchip. The ability to sense, compute, and move within microscopic dimensions opens up opportunities in basic biomedical research as well as applied research.
The technology will provide both in vitro and in vivo applications. In vitro applications will occur at the macro-level, for example, moving cells into position in cell/tissue cultures to form synapses in order to build specific neuronal circuits or to construct other specialized tissues. The technology will also allow for flexible and complex cell sorting strategies. Applications at the micro-level will include moving molecules together in a highly controlled fashion and perhaps shuttling specific molecules in and out of cells. Another type of application is in laboratory instrumentation for performing high-speed electrophoretic and chromatographic separation of molecules on silicon chips. Nanotechnology also will have a host of in vivo applications, including in situ measuring of blood parameters within blood vessels and organs, measurement and localized release of chemicals to regulate diseased or defective homeostatic systems (e.g., monitoring of blood glucose, oxygen, brain temperature), and repair of damaged nervous tissue (for example, by electrical sensing and then the controlled and localized release of neurotransmitters). The technology may also enable a new form of microsurgical repair, with large numbers of "nanomachines" working in concert (under computer control) to repair, for example, clogged arteries or to remove tumors and other tissues.
The development of a highly sophisticated, biologically oriented nanotechnology will have a profound impact on biological research, medical practice, and perhaps the pharmaceutical industry. Clearly, the ability to perform incision-free surgery, replace diseased or defective tissues, and regulate endogenously systems that now require exogenous treatment (e.g., diabetes) could revolutionize medical practice. In addition, the ability to control the spatial and temporal aspects of how molecules interact may lead to tremendous efficiencies in the production of new drugs.
Probably, however, the electronic fabrication technology will far outpace the biology. Many uses of nanotechnology will require a better understanding of the basic biology that is being manipulated and, in particular, new techniques will have to be devised to interface the silicon chip with the nervous system. For example, while it may be possible to monitor acceleration and position with a biochip that replaces a defective semicircular canal, it may be impossible to effectively interface the output of the biochip with the nervous system. It will most likely be the melding of silicon and tissue that provides the greatest challenge to in vivo nanotechnologies.
Adapting successfully to the changing paradigm for biological research and technology will require changes in the organizations that sponsor and pursue this work, as well as in the supporting infrastructure. This will require flexibility and a willingness to change - where appropriate - the structure, policies, practices, and attitudes prevailing in government agencies, in industry, and in academe. As a major sponsor of research in the biological sciences, the role of NSF is particularly critical.
A number of the suggestions given below are novel and, we believe, original to this rather productive workshop group; they are specific to the question of how to facilitate the melding of new technologies with biology. However, some of the issues discussed in this section are not new and have arisen before in other contexts. We believe that the situation has changed; now those issues are timely and must be readdressed.
Government Agencies. As the primary source of funding, and thus as the institutions that establish the broad directions of biological research and technology development, government agencies in general have enormous influence on the type and amount of research that is carried out. Through program definition and management, the wording ofproposal solicitations, and funding criteria they can bring rapid change - or forestall it. We suggest that the following will hasten the development of emerging technologies and their application to the appropriate biological sciences:
Industry. Much of the actual technology development is carried out in industry. Under strong competitive pressure and tight budgets, industrial managers are often hard-pressed to see the need for specific technology development efforts, particularly if they are relatively expensive and/or long-range. Sharing the cost burdens and maintaining links to those who can provide both the rationale and part of the market for new technology - namely, academic researchers - are important ways to maintain both momentum and perspective in technology development. Some specific suggestions:
Academia. Universities, although bastions of liberal education and intellectual inquiry, are perhaps more conservative organizationally than either government or industry. Yet it is at universities that most future progress in the biological sciences will be made. But first, barriers to that progress must come down. To that end, universities should:
Supportive programs, policies, and attitudes are necessary but not sufficient for technology development and application. Also essential is a strong supporting "infrastructure" - i.e., the laboratory facilities, computing and database resources, communication lines, etc., that enable cutting-edge research and development to occur. All of the following need attention from government, universities, and industry if this work is to go forward rapidly and successfully:
In the view of workshop participants, the future should see more specialization of facilities at a university. That is, while a university may identify one or a few primary areas of expertise and cluster high-cost facilities around those, it is likely that no university will have more than a few specialized, high-cost facilities. This will be a pragmatic response to the shrinking pool of resources for biological (and other scientific) research. Funding agencies should spread their investments in this manner, in order to maximize access to facilities across the research community.
A corollary to this projection is the idea that specialized core facilities and instruments will be shared regionally or nationally. To some extent, researchers will travel to the facilities; and to some extent the use of specialized facilities will become electronic, or "virtual."
A few specific issues are worth noting here. First, the increasing use of instruments that require one or more technicians to oversee the operation or perform the operation itself means that the overhead burden for research will grow. Second, the distance of a researcher from his/her analysis requires increased attention to the interpretation of data and their significance. In that light, training of graduate students may require a greater emphasis on careful interpretation of machine-generated data as well as on multivariate statistics.
As the primary federal funding agency for basic research in the biological sciences, the role of the National Science Foundation is critical if rapid progress is to be achieved. The workshop participants suggested a number of changes in patterns of funding, in organizational structure, in project selection priorities, and in education programs.
Changes in Funding/Support Patterns. In summary, the suggestions in this area are as follows:
Changes in Programs and/or Organizational Structures. The suggestions in this area are as follows:
Regardless of organizational and program changes, take care to safeguard NSF's mission as maintainer of the engine of basic research.
Project Evaluation and Priority-setting. In an atmosphere of fiscal austerity, evaluation criteria and prioritization become more critical. Some suggestions are:
Education. One barrier to the further development and application of emerging technologies in the biological sciences is the relatively narrow, theoretical, specialized education that students tend to receive - even at the undergraduate level. In addressing this issue, the NSF can at best be a catalyst. The universities themselves need to address the problem and implement solutions. The workshop participants propose the following groundrules:
Given the fact that technology traditionally has not held a prominent position in biological research (compared to fields such as chemistry and physics, for example), there is a need to explain what the opportunities and potential benefits are - in other words, to communicate the change in course that biology must undergo in order to deal with biological complexity.
To a large extent this is a role for NSF in its communication with the research community. But government, academia, and industry all have a responsibility for communicating, to Congress and the general public, the importance of stimulating the development of emerging technologies applicable to biology.
All these sectors also have a new responsibility for educating the general public in a more formal sense, and especially for improving science and mathematics education so as to improve the pool of potential researchers in the biological sciences. K-12 education is an important key. Research centers such as the Science and Technology Centers have proven to be excellent vehicles for exposing young students - and their teachers - to the excitement of scientific discovery and the pursuit of knowledge. Programs in which scientists visit K-12 classrooms to give talks and make presentations are also effective. K-12 involvement should become a permanent component of academic life.
Technology development has long been a globally competitive enterprise. More recently, however, even basic research is becoming increasingly global as foreign universities build up their research capabilities and infrastructure. What are the implications of this trend, both positive and negative, for the future of U.S. research universities? We believe they are both positive and negative, and in some case neutral.
On the negative side, intellectual property rights are likely to be unevenly honored worldwide. Just as vendors in some nations are allowed to market "pirated" software with impunity, corporations in some countries will be allowed to use unlicensed technology without fear of reprisals. Another decided negative will be a curtailment of the currently strong flow of top-notch foreign students to U.S. universities and industry, which now provides a substantial percentage of tuition monies as well as graduate students for teaching and research assistantship. More such students will stay at home for their schooling; or if they do come, they will be more inclined to leave afterward, taking their knowledge and potential with them.
On the positive side, U.S. researchers in academe and industry alike will gain better access to foreign faculties and researchers, and to the knowledge they offer. There will also be increasingly strong foreign contributions to science; this will be particularly important in large, high-cost scientific endeavors such as the Human Genome Project.
We may class as neutral the expectation that, in the future, more insights and changes in science will come from outside the United States. The import will be that U.S. researchers may not be the first to recognize and adapt to changing conditions that might affect their viability and success.