The Role of Theory in Advancing 21st-Century Biology: Catalyzing Transformative Research (2008)

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Summary From microorganisms to whales, from single cells to complex organ- isms, from plants to animals to fungi, from body plans to behavior, the di- versity of life is amazing. Living organisms have a profound impact on our physical world of ocean, landscape, and climate; around us is a multitude of diverse ecosystems that provide a livable environment and many valuable resources. The study of life—biology—is a multifaceted endeavor that uses observation, exploration, and experiments to gather information and test hypotheses about topics ranging from climate change to stem cells. The field of biology is so diverse that it can sometimes be hard for one individual to keep its breadth in mind while contemplating a particular question. This study was initiated at the request of, and with the sponsorship of, the National Science Foundation. It was conceived as a new approach to a question that has been asked before: What is the future of biology? In 1989 the National Research Council released a report on this topic entitled Opportunities in Biology. Over 400 pages long and four years in the mak- ing, the report provided a detailed snapshot of the state of biology at that time. Eleven different panels detailed the opportunities awaiting the rapidly diversifying field of biology. Reading the report today, the excitement of that time is palpable. Section after section describes new technologies and promises new discoveries. Each section focuses on a different subdiscipline of biology. This report takes a different approach by looking for commonalities across subdisciplines. The committee was charged with examining the role of concepts and theories in biology, including how that role might differ across various subdisciplines. One facet of that examination was to con-  

 THE ROLE OF THEORY IN ADVANCING 21ST-CENTURY BIOLOGY sider the role of the concepts and theories in driving scientific advances and to make recommendations about the best way to encourage creative, dynamic, and innovative research in biology. The charge was to focus on basic biology, not on biomedical applications. At the first committee meeting, to begin identifying the theoretical foundations of biology, each committee member discussed the theories and concepts underlying his or her particular area of research and addressed how those theories and concepts might connect across the field of biology. The talks demonstrated that biologists from all subdisciplines base their work on rich theoretical foundations, albeit of very diverse kinds. They highlighted the varied extent to which theories are an explicit focus of at- tention and discussion. For example, cell theory underpins much research, but the theory itself is rarely the topic of explicit attention in the research literature. The committee concluded that a more explicit focus on theory and a concerted attempt to look for cross-cutting issues would likely help stimulate future advances in biology. To illustrate this point, the commit- tee chose seven questions to examine in detail. The list of questions is not comprehensive but rather illustrative. The questions, as shown below, were chosen to show that a focus on theory could play a role in helping to ad- dress many different types of interesting and important questions at many different levels. 1. Are there still new life forms to be discovered? New organisms continue to be discovered, some in environments that were once thought incompatible with life. How many new life forms remain to be discovered? What additional strategies for movement, sensation, and chemical synthesis will be found? How diverse are the variations on the pat- terns of development of organisms’ body plans? How do complicated com- munities of different organisms affect each other’s evolution and what can be learned from the diversity of social organizations that have evolved in different species? How is diversity encouraged and limited by environment? For billions of years, life was exclusively microbial—to what degree can a better understanding of that early evolution change our understanding of the present microbial world, which is turning out to be vastly more diverse than ever imagined, and the processes that underlie all life forms? The diversity of life presents a huge challenge to biologists but also a virtually limitless opportunity. Both the unity and the diversity of life are explained by the theory of evolution: All life forms share many characteris- tics because all are descended from a common ancestor and life has become diverse through billions of years of descent with modification. However, the extent and implications of all that diversity are not yet fully understood. An 

SUMMARY  enormous amount of productive research has demonstrated many mecha- nisms by which evolution leads to diversity. However, much remains to be described and explained. There is need for further theoretical insight into how diversity is generated and maintained, not to mention understanding the implications of losses of diversity. These are exciting challenges. 2. What role does life play in the metabolism of planet Earth? Diverse as life is, the metabolic pathways that support it are, perhaps surprisingly, quite well conserved and are based on just a few basic strate- gies. These metabolic pathways, which are the means by which organisms acquire the energy and material components they need to survive and re- produce, have a profound global impact as living organisms form part of global geochemical cycles. The Earth today has been shaped in many ways by metabolic processes, which are key molecular processes at the cellular level as well. Understanding the evolution of these pathways, how they in- tegrate, and how living systems are coupled to environmental conditions is a profoundly important question to several areas of biology and on many scales of time and space. 3. How do cells really work? The living cell is a marvel, containing thousands of interlocked chemical reactions that harvest energy from the environment, synthesize thousands of different chemicals, manage waste, and recycle components. Ultimately, the cell makes a copy of itself. No human factory can rival the cell’s com- pact and coordinated productivity. Only a fraction of its pathways can be reproduced in the test tube. The laws of physics and chemistry apply, of course, to all living organisms. However, most life processes are maintained far from chemical and thermodynamic equilibrium. Thus, understanding how chemical reactions take place in the crowded and highly organized mo- lecular environment of the cell, or how physical variables like temperature and concentration gradients affect and are affected by living processes (for example, during development, or in the cell cycle or circadian cycle, when the instructions encoded by DNA are manifested in physical processes), is a major challenge of biological research. The interfaces between some cur- rent research areas of physics, chemistry, and biology that elucidate these questions are expected to be very fruitful. 4. What are the engineering principles of life? DNA is made up of nucleotides, proteins of amino acids. Organisms contain many types of cells, ecosystems many different species. The hierar- 

 THE ROLE OF THEORY IN ADVANCING 21ST-CENTURY BIOLOGY chical organization of building blocks at different scales is a common theme in biology, whose evolution is not fully understood. Complicated systems at every scale are made up of simpler modules that vary in definable ways and combine in ways that result in structures capable of much more than the in- dividual parts. This characteristic of complicated structures, functions, and behaviors arising from the combination of simple parts represents an almost universal theme in biology. Furthermore, across all scales of biology, from subcellular circuits to ecosystems, many biological systems demonstrate “robustness”: in other words, they continue to function despite defective parts or changes in the environment. Like the workings of the living cell, this robustness is a biological phenomenon­­ that has evolved through varia- tion and selection and that human engineers would be proud to duplicate. Understanding the principles by which modules combine to create systems with particular properties (another useful, cross-cutting concept) will un- doubtedly result in theoretical insights that would apply across biological scales from the molecular to the ecosystem—and perhaps provide valuable lessons for human efforts in design and engineering. 5. What is the information that defines and sustains life? The power of the computer rests in its ability to represent an immense range of phenomena in digital form that can then be manipulated. Many of the characteristics of life can similarly be represented as flows of informa- tion, as it is striking that all living organisms and communities of organisms are able to sense, process, remember, and respond to many different kinds of external and internal stimuli that can be conceptualized as information. Evolution, for example, can be viewed as a process whereby selection of variant genomes is affected by the information provided by the environ- ment. In this view, the information defining the relevant environmental variables is partly encoded in the genome of the adapted organisms by the process of selection, and evolution is thus a process of selective memory in molecular form stored in the genomes of living organisms. The complexity of biological systems can be described using the ideas of information sci- ence, but there are deeper conceptual problems in making full use of those concepts of information that were developed for engineering and physics, where they are used in pattern recognition, communications, and thermo- dynamics. In biological systems, information is intimately dependent on context, making it difficult to apply the concept of information in ways that do not oversimplify complicated biological phenomena. Thus, further development of both concepts and tools will be required to realize the po- tential of this powerful conceptual point of view. 

SUMMARY  6. What determines how organisms behave in their worlds? Organisms as diverse as bacteria and humans possess the ability to respond to their environments and to shape their behaviors in response to specific environmental variables. Understanding how organisms live requires determining the rules that govern how organisms behave in their world, how they sense their environments, and how they use this informa- tion to change their behavior. It is important to remember that organisms do not simply wait passively for information from their environments. Their physiology is internally generated, by genetically determined rules, and input from the environment is used to alter the behavior of the organ- ism. In addition, much behavior is generated to actively explore the envi- ronment in search of specific sensory signals. For example, bacteria have receptor proteins that allow them to sense concentrations of chemicals in their environment and use these gradients to govern their movements. The integration of sensory information into a form that can be processed by the organism, the nature of the processing machinery, the influence of the internal states of the organism, the influence of the experience on the future states of the organism, memory mechanisms, and many other issues have direct relevance to many different biological regimes, scales, and kinds of organisms. There is a remarkable potential for finding commonalities amid the diversity addressed by this question. 7. How much can we tell about the past—and predict about the future—by studying life on Earth today? The ability of living systems to pass on the directions for reproducing themselves and for surviving in the environments where those offspring will find themselves is fundamental to the living state, and it is more than a loose metaphor to say that organisms’ genomes represent an imprint of past environmental conditions, history, and the selection pressures on the ancestors of organisms. The sequences of the genome are not the only re- cords of past conditions; the ways in which those sequences are put to use are also affected by other past conditions that are carried forward by living systems—from stable physiological states, to imprinted DNA that modifies gene expression, to memories stored in the brain and nervous system, and behaviors remembered and taught to descendants. New mechanisms and new applications of this common ability of living things to record informa- tion about the past in some physical, molecular form continue to emerge. Thus, the commonality and diversity in the ways in which organisms rep- resent and use this kind of information are very promising and very chal- lenging frontiers for future research. The record of the past is imprinted in both the fossil record and the DNA of today’s living world. Whatever life 

 THE ROLE OF THEORY IN ADVANCING 21ST-CENTURY BIOLOGY on Earth looks like 1 million years from now, it will evolve from what is currently alive. If scientists truly understood how current organisms and environments interact to produce future generations, could the course of evolution be predicted? FINDINGS AND RECOMMENDATIONS Of course, it is impossible to cover all of biology in so short a report. If the average freshman biology textbook needs hundreds of pages to cover the basics, a mere seven questions cannot possibly introduce even a fraction of the exciting and innovative biology research that is currently underway. The questions are meant to be illustrative, not all-inclusive, and should be read not as a guide to the most important or promising areas for future emphasis but as several examples of the way that concepts and theories can connect the different areas of biology. After exploring this set of seven questions, the committee came to consensus on several findings and recom- mendations that flow from the idea of looking at cross-cutting issues in biology with an eye to the role of theory. Finding 1 Biological science can contribute to solving societal problems and to economic competitiveness. Basic and applied research targeted toward a particular mission is one way to accomplish this important goal. However, increased investment in the development of biology’s fundamental theoreti- cal and conceptual basis is another way to reap practical benefits from basic biological research. Theory is an integral part of all biological research, but its role is rarely explicitly recognized. The living world presents a vast reservoir of biological solutions to many practical challenges, and biological systems can inspire innovation in many fields. The many ways that basic biological research contributes to medicine are very familiar, but basic biology can also contribute to advances in fields as diverse as food, fishery, and forest production; pest management; resource management; conservation; transportation; information process- ing; materials science; and engineering. Biological research breakthroughs, therefore, have the potential to contribute to the solution of many pressing problems, including global warming, pollution, loss of biodiversity, fossil fuel dependence, and emerging infectious diseases. As the many examples in this report attest, biology is characterized by unity and diversity. There is unity because many biological processes have been preserved through evolution. There is also diversity because natural selection has led to many innovative solutions to the practical problems that living organisms have encountered over billions of years. Therefore, discov- 

SUMMARY  eries about a particular organism, sensory pathway, or regulatory network can have immediate applications throughout biology, and the transforma- tive insight that provides the most direct path to a practical solution may arise in a seemingly unrelated research area. Giving explicit recognition to the role of theory in the practice of biology and increasing support for the theoretical component of biology research are ways to help make such con- nections and thus leverage the value of basic biological research. The extent of life’s diversity has not yet been plumbed, and many biological processes are understood only imperfectly. New tools and com- putational capabilities are improving biologists’ ability to study complex phenomena. Tying together the results of research in the many diverse areas of biology requires a robust theoretical and conceptual framework, upon which a broad and diverse research portfolio of basic biological investiga- tions can be based. The impact of biology on society could be enhanced if discovery and experimentation are complemented by efforts to continu- ously enrich biology’s fundamental theoretical and conceptual basis. Recommendation 1 Theory, as an important but underappreciated component of biology, should be given a measure of attention commensurate with that given other components of biological research (such as observation and ex- periment). Theoretical approaches to biological problems should be ex- plicitly recognized as an important and integral component of funding agencies’ research portfolios. Increased attention to the theoretical and conceptual components of basic biology research has the potential to leverage the results of basic biology research and should be considered as a balance to programs that focus on mission-oriented research. Finding 2 Biologists in all subdisciplines use theory but rarely recognize the inte- gral and multifaceted role that theory plays in their research and therefore devote little explicit attention to examining their theoretical and conceptual assumptions. Major advances in biological knowledge come about through the interplay of theoretical insights, observations, and key experimental results and by improvements in technology that make new observations, experiments, and insights possible. The fragmentation of biology into many subdisciplines means both that the mix of these components can differ dra- matically from one area to another and that the development of theoretical insights that cut across subdisciplines can be difficult. It is the committee’s opinion that all subdisciplines of biology would benefit from an explicit 

 THE ROLE OF THEORY IN ADVANCING 21ST-CENTURY BIOLOGY examination of the theoretical and conceptual framework that characterizes their discipline. Recommendation 2 Biology research funding portfolios should embrace an integrated va- riety of approaches, including theory along with experiment, observa- tion, and tool development. Biologists in all subdisciplines should be encouraged to examine the theoretical and conceptual framework that underlies their work and identify areas where theoretical advances would most likely lead to breakthroughs in our understanding of life. Workshops sponsored by funding agencies or scientific societies would be one way to facilitate such discussions. The theoretical and concep- tual needs identified by such subdisciplinary workshops should then be integrated into the funding programs for those subdisciplines. It would also be worthwhile to sponsor interdisciplinary workshops to identify theoretical and conceptual approaches that would benefit sev- eral subdisciplines. Finding 3 New ways of looking at the natural world often face difficulty in ac- ceptance. Challenges to long-held theories and concepts are likely to be held to a higher standard of evidence than more conventional proposals. Proposals that break new ground can face difficulty in attracting funding, for example those that cross traditional subdisciplinary boundaries, take a purely theoretical approach, or have the potential to destabilize a field by challenging conventional wisdom. Such proposals are likely to be perceived as “high-risk” in that they are likely to fail. However, their potential for high impact warrants special attention. Successfully determining which of them deserve funding will require input from an unusually diverse group of reviewers. Recommendation 3 Some portion of the basic research budget should be devoted to sup- porting proposals that are high risk and do not fall obviously into present funding frameworks. One possibility is to initiate a program specifically for such “high-risk/high-impact” proposals—whether they are purely theoretical, cross-disciplinary, or unconventional. Another is to encourage program officers to include some proportion of such proposals in their portfolios. A third is to provide unrestricted support to individuals or teams of scientists who have been identified as particu- 

SUMMARY  larly innovative. Evaluation of these proposals should be carefully de- signed to ensure that reviewers with the requisite technical, disciplinary, and theoretical expertise are involved and that they are aware of the goal of supporting potentially consensus-changing research. Proposals that challenge conventional theory require not only that the originality and soundness of the theoretical approach be evaluated but also that the biological data being used are appropriate and the question being asked is significant. Finding 4 Technological advances in arrays, high-throughput sequencing, remote sensing, miniaturization, wireless communication, high-resolution imaging, and other areas, combined with increasingly powerful computing resources and data analysis techniques, are dramatically expanding biologists’ ob- servational, experimental, and quantitative capabilities. Questions can be asked, and answered, that were well beyond our grasp only a few years ago. It is the committee’s contention that an increased focus on the theoreti- cal and conceptual basis of biology will lead to the identification of even more complex and interesting questions and will help biologists conceive of crucial experiments that cannot yet be conducted. Biologists’ theoretical framework profoundly affects which tools and techniques they use in their work. All too frequently, experimental and observational horizons are un- consciously limited by the technology that is currently available. Advances in technology and computing can provide biologists with many new op- portunities for experimentation and observation. For many of the multiscale questions raised in this report, there is a strong need for teams of biologists, engineers, physicists, statisticians, and others to work together to solve cross-disciplinary problems. The interac- tion and collaboration of biologists with physicists, engineers, computer scientists, mathematicians, and software designers can lead to a dynamic cycle of developing new tools specifically to answer new questions rather than limiting questions to those that can be addressed with current technol- ogy. The growing role and shortening life cycle of technology mean that biologists will have to become ever more adept in the use of new equipment and analysis techniques. Understanding the capabilities, and especially the limitations, of new instruments so that experiments are designed properly and results interpreted appropriately will be important in more and more areas of biology. Because the potential benefits of more precise and rapid measurements of biological phenomena are so high, it will be important for biologists to be aware of both instrumentation capabilities in the physical and engineering sciences and theoretical advances in physics, chemistry, and mathematics 

10 THE ROLE OF THEORY IN ADVANCING 21ST-CENTURY BIOLOGY that could be integrated into biological research. Conversely, if researchers outside biology are aware of the kinds of questions biologists are now ask- ing, they can use their techniques, instruments, and approaches to advance biological research. Close collaboration between biologists and researchers in other fields has great promise for leveraging the value of discoveries and theoretical insights arising from basic biological research. Recommendation 4 In order to gain the greatest possible benefit both from discoveries in the biological sciences and from new technological capabilities, biolo- gists should look for opportunities to work with engineers, physical scientists, and others. Funding agencies should consider sponsoring interdisciplinary workshops focused on major questions or challenges (such as understanding the consequences of climate change, addressing needs for clean water, sustainable agriculture, or pollution remediation) to allow biologists, scientists from other disciplines, and engineers to learn from each other and identify collaborative opportunities. Such workshops should be designed to consider not just what is possible with current technology but also what experiments or observations could be done if technology were not an obstacle. Opportunities for biologists to learn about new instrumentation and to interact with technology developers to create new tools should be strongly sup- ported. One possible approach would be the creation of an integrative institute focused on bioinstrumentation, where biologists could work in interdisciplinary teams to conceive of and develop new instrumenta- tion. The National Center for Ecological Analysis and Synthesis and the National Evolutionary Synthesis Center could serve as models for the development of such an institute. Finding 5 To get the most out of large and diverse data sets, these will need to be accessible and biologists will have to learn how to use them. While technol- ogy is making it increasingly cost-effective to collect huge volumes of data, the process of extracting meaningful conclusions from those data remains difficult, time-consuming, and expensive. Theoretical approaches show great promise for identifying patterns and testing hypotheses in large data sets. It is increasingly likely that data collected for one purpose will have relevance for other researchers. Therefore, the value of the data collected will be multiplied if the data are accessible, organized, and annotated in a standardized way. While it is somewhat new to many areas of biology, other fields—like astronomy and seismology—that create massive data sets rely 

SUMMARY 11 on theory to guide pattern detection and to direct in silico experimentation and modeling. Getting the most out of the extensive biological data that can now be collected will increasingly require that biologists broadly develop those skills and collaborate with mathematicians, computer scientists, stat- isticians, and others. This process of building community databases is well underway in many areas of biology, genomics being a prominent example, but the specialized databases developed by one research community may be unknown or inaccessible to researchers in other fields. Significant resources are needed to maintain, curate, and interconnect biological databases. Recommendation 5 Attention should be devoted to ensuring that biological data sets are stored and curated to be accessible to the widest possible population of researchers. In many cases, this will require standardization. Pro- viding opportunities for biologists to learn from other disciplines that routinely carry out theoretical research on diverse data sets should also be explicitly encouraged.