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Introduction

THE TANGLED WEB OF BIOLOGICAL SCIENCE

The diverse living things of our world are endlessly fascinating. Living organisms have a profound impact on the physical world of ocean, landscape, and climate, and around us is a multitude of diverse ecosystems that provide us with a livable environment and many valuable resources. There is a vast array of interactions among living things, including those that characterize human society and the relationship between humans and the rest of the living world. The practice of biological science takes many forms, with observation, exploration, and experiment combining in many ways to gather information and test hypotheses. The means by which these practices are actually carried out is profoundly affected by the technologies available, with new tools regularly opening up new realms to experimentation, observation, analysis, and novel conceptual insight. Both biologists and nonbiologists occasionally caricature biology in these terms—a science dedicated to endless observation, collection, and testing, leading to a snowballing accumulation of facts. Life is so complex and science has examined such a small fraction of its diversity that it seems reasonable to think that a great deal more data are needed before unifying theories can emerge that explain life in all its diversity. One goal of this report is to illustrate that we need not, and do not, sit and wait for theory to emerge as the end game of biological research. Theory is already an inextricable thread running throughout the practice of biology, as it is in all science. Biologists choose where to observe, what tool to use, which experiment to do, and how to interpret their results on the basis of a rich theoretical



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1 Introduction THE TANGLED WEB OF BIOLOGICAL SCIENCE The diverse living things of our world are endlessly fascinating. Liv- ing organisms have a profound impact on the physical world of ocean, landscape, and climate, and around us is a multitude of diverse ecosystems that provide us with a livable environment and many valuable resources. There is a vast array of interactions among living things, including those that characterize human society and the relationship between humans and the rest of the living world. The practice of biological science takes many forms, with observation, exploration, and experiment combining in many ways to gather information and test hypotheses. The means by which these practices are actually carried out is profoundly affected by the technologies available, with new tools regularly opening up new realms to experimenta- tion, observation, analysis, and novel conceptual insight. Both biologists and nonbiologists occasionally caricature biology in these terms—a sci- ence dedicated to endless observation, collection, and testing, leading to a snowballing accumulation of facts. Life is so complex and science has examined such a small fraction of its diversity that it seems reasonable to think that a great deal more data are needed before unifying theories can emerge that explain life in all its diversity. One goal of this report is to il- lustrate that we need not, and do not, sit and wait for theory to emerge as the end game of biological research. Theory is already an inextricable thread running throughout the practice of biology, as it is in all science. Biologists choose where to observe, what tool to use, which experiment to do, and how to interpret their results on the basis of a rich theoretical 

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 THE ROLE OF THEORY IN ADVANCING ST-CENTURY BIOLOGY and conceptual framework. Biologists strive to discern patterns, processes, and relationships in order to make sense of the seemingly endless diversity of form and function. Explanatory theories are critical to making sense of what is observed—to order biological phenomena, to explain what is seen and to make predictions, and to guide observation and suggest experimen- tal strategies. Because the living world is so complex, biological theory is also exceptionally rich and varied. Science is facts; just as houses are made of stones, so is science made of facts; but a pile of stones is not a house and a collection of facts is not necessarily science —Henri Poincare, French mathematician and physicist (1854-1912) (Mackay, 1991) What makes the house of biology from the pile of stone facts is the theo- retical component. THE ORIGIN OF THIS REPORT In 1989 the National Research Council released a report entitled Op- portunities in Biology. Over 400 pages long and four years in the making, the report provides a detailed snapshot of the state of biology at that time. Eleven different panels described 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. The technologies span many levels, from the mo- lecular—DNA sequencing technology had recently progressed from manual to automatic—to the ecological, as robotic arms and free-ranging robots were dramatically expanding the ability of deep-sea submersibles to survey and sample the ocean floor. Nearly 20 years later, it appears that in many respects the authors of that report underestimated the power of the new technologies they described. In 1989 a total of 15 million nucleotides of DNA sequence had been determined. The latest generation of sequencing machines can sequence more than 100 million nucleotides per day. Satellites allow biologists to examine changes in landscapes on an ever finer scale and to track wildlife remotely, while the World Wide Web allows them to retrieve and share their data instantly. The productivity of biological research since 1989 has been extraor- dinary. At the same time, the explosion of new biological information has consequences. Individual scientists can now collect data on a scale and at a level of detail that surpass any individual’s capacity to sift through, analyze,

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 INTRODUCTION and interpret all that can be collected. Ever more sophisticated experimental approaches to deciphering how the endless variety of biological systems function opens up a universe of potential experiments so vast that no number of biologists even with unlimited resources could undertake them all. In fact, so much information is accumulating, on so many different biological systems, that it has become impossible for any one biologist to stay abreast of all the advances being made even within one subfield, much less throughout all of biology. There is a growing sense that the ability to collect such a large amount of data, while welcome, also poses new chal- lenges: Are the data already collected adequately organized and accessible, and how can the constant influx of new data be put to best use? How do we decide what experiments to do, which data to collect? There is tremen- dous potential that new technologies and computational approaches will allow biologists to ask and answer questions that were unmanageable in the past and that chemically and physically reasonable explanations for many complicated biological phenomena will continue to emerge. It is worth considering whether we have the tools and resources necessary to identify potentially unifying themes or organizing principles. A sequel to the 1989 report examining in that same spirit today’s “Opportunities in Biology” could easily require 800 pages and 22 subcommittees and would identify hundreds of exciting potential areas for biological discovery. Continuing on the ever-widening research path illuminated in the 1989 report would no doubt lead to great achievements—the record of biological research over the last 20 years has been impressive. At the same time, this is an op- portune moment to take stock of the field of biology and examine whether a different perspective is in order, one that might allow biological science to advance faster and contribute even more effectively to addressing the pressing needs of society. Study Process This project was initiated at the request of, and with the sponsorship of, the National Science Foundation. The committee first met to discuss its charge and goals in October 2006 and then held a workshop to gather additional input in December 2006. Subsequent meetings in the spring of 2007 were held to work on report writing. The committee was charged to identify and examine the concepts and theories that form the foundation for scientific advancement in various ar- eas of biology, including (but not limited to) genes, cells, ecology, and evolu- tion. It was asked to assess which areas are “theory-rich” and which areas need stronger conceptual foundations for substantial advancement and to make recommendations as to the best way to encourage creative, dynamic, and innovative research in biology. Building on these results, the study was

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 THE ROLE OF THEORY IN ADVANCING ST-CENTURY BIOLOGY to identify major questions to be addressed by 21st-century biology. The project was to focus on basic biology, but not on biomedical applications. Questions that could be considered by the committee included: • What does it mean to think of biology as a theoretical science? • Is there a basic set of theories and concepts that are understood by biologists in all subdisciplines? • How do biological theories form the foundation for scientific advancement? • Which areas of biology are “theory-rich” and which areas need stronger conceptual foundations for substantial advancement? • What are the best ways to bring about advances in biology? • What are the grand challenges in 21st-century biology? • How can educators ensure that students understand the founda- tions of biology? At its first committee meeting, in order to identify common theories and concepts in biology, each committee member was asked to present the theories and concepts underlying his or her particular area of research and address how those theories and concepts might apply across biology in gen- eral. If the hope was that the talks would unearth a set of theories in each area of biology, sets that could then be compared to find commonalities and show which areas were particularly “theory-rich” and where theory was notably lacking, the result was quite different. The talks demonstrated that biologists from all subdisciplines base their work on rich theoretical foun- dations, albeit of very diverse types and mixtures. What became evident was the universality of the complex interaction between current theories, new observations and experimental evidence, and evolving technological capabilities. Those areas in which prevailing theory is being challenged through observation, experiment, and analysis are likely to be where the most interesting biology research is being done. This should not have been a surprise for this is a common phenomenon—the recognition that facts are accumulating that contradict the prevailing theoretical framework often characterizes highly active and exciting research and a field in which impor- tant changes are imminent. At its second meeting, the committee invited a diverse group of biologists, focusing especially on researchers in subdisci- plines that were not represented on the committee, to give talks discussing the theories and concepts underlying their research. Again, the talks did not identify discrete sets of theories that characterized particular areas of research, with some areas having richer theory sets than others. The two sets of talks convinced the committee that identifying a list of concepts and theories that underlie different areas of biology, as requested in the first line of the Statement of Task, would not accurately represent the role of theory

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 INTRODUCTION in biology. This is not to say that biology has no foundational theories that are accepted by all biologists; evolution, cell theory, and the role of DNA in inheritance certainly serve that unifying purpose. However, the commit- tee did not find that each subdiscipline of biology has its own more or less well-developed set of foundational theories. The committee’s assessment of which areas of biology were “theory-rich” and which areas needed stron- ger conceptual foundations for substantial advancement concluded that all areas of biology rest on a rich theoretical framework but that the range and types of theories in use were exceptionally diverse. Despite the difficulty that the committee found in responding literally to the Statement of Task, the committee welcomed the opportunity to explore the integral role that theory plays in biology and to point out the ways that theory contributes to creative, dynamic, and innovative research in biology. The committee then decided to use a set of broad questions with relevance across many subdisciplines of biology to illustrate the role that theory now plays and might play even more prominently in the future. The goal was to choose questions that would illustrate the many connections across biologi- cal scales and subdisciplines, not to cover the field comprehensively nor to identify which new areas of research are the most important or promising. Inevitably, this approach precluded covering any area in depth and made it impossible to mention all of the many interesting and innovative areas of current biological research. Where Do Transformative Insights Come From? In the history of biology, one can identify many moments when our understanding of the living world was transformed. Some of these trans- formative moments have resulted from a deep insight that led to a major change in our theoretical framework. Other transformative moments were triggered by a key observation or experimental result, or by the invention of a new tool for making observations or doing experiments. None of these moments came about, though, without complex interaction among the many components that make up the practice of biology. Certainly one of the most transformative moments in biology was Darwin’s exposition of the theory of evolution by natural selection. His insights have since in- spired and elucidated more than a century of rewarding observation and experimentation, richly demonstrating how the process of evolution has resulted in so many diverse life forms, functions, and patterns. But what made possible the transformative moment that was Darwin’s theoretical insight? First, an accumulation of facts (in the form of diverse fossil re- mains) emerged that were difficult to reconcile with the prevailing theory of a fixed and unchanging collection of species. Second, the collection and organization of hundreds of thousands of samples of biological specimens

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 THE ROLE OF THEORY IN ADVANCING ST-CENTURY BIOLOGY in the museums of Europe during the 19th century (made possible by im- provements in navigational tools and motivated by a desire to catalog the diversity of creation), as well as Darwin’s own observations and collection during his famous voyage—in other words, the curiosity-driven collection of data about the living world—provided the raw material that enabled Darwin’s theoretical insight. Another profoundly transformative moment, the elucidation of the structure of DNA, could not have happened before the key technological capability of X-ray diffraction was available. Together with the evidence that DNA was the critical substance that passed from generation to genera- tion and that its four simple components were always found in a consistent ratio, Watson and Crick brought to their efforts a theoretical construct. (They had models of the diffraction patterns that helical molecules should produce.) The physical evidence provided by the X-ray scattering patterns that DNA was a molecular double helix was the final link that tied the theory and all the observations together, suggested molecular mechanisms of replication and inheritance, and gave rise to a transforming era in biology. It is important to note that the tangle of facts, observation, experiment, theory, and technology has no particular beginning and certainly no end. At different times, one of these components may receive more emphasis, but major advances in modern biology have never been completed without all of them. Despite the integral role that theory plays throughout the practice of biology, biologists rarely think of themselves as theoretical scientists. Part of the reason is that the word “theory” can be used to mean many different things, ranging from a mere hunch to a set of mathematical equations codi- fying a “law of nature.” Although the word is generally used by scientists more rigorously than the general public to mean an explanatory framework supported by a large body of observational and experimental evidence, even scientists tend to confine the idea of “theoretical science” to the practice of developing mathematical equations to represent a large body of phenom- ena. While mathematical, computational, and quantitative approaches have important roles in biology, confining the definition of theory to these efforts fails to capture the texture of theory in biology. In Chapter 2 this report adopts a more flexible description of theory as a “family of models” that can be, among other things, physical, visual, verbal, mathematical, statisti- cal, descriptive, or comparative. The models need not even all be entirely consistent with each other (just as it is sometimes useful to model light as a wave, sometimes as a particle), the important characteristic being that the model is a representation of some aspect of nature for the purpose of study. Using this view of biological theory makes it clear how ubiquitous it is in scientific practice. For example, if one’s model of the genome suggests

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 INTRODUCTION that only protein-coding regions are important for development, one may adopt an RNA extraction technique that selects only transcripts with poly- A tails. An alternative model that includes a functional role for noncoding sequences in development would require a different extraction technique. A scientist whose model of cellular robustness rules out the possibility of life below pH 3 or above 90oC will not look for bacteria in the human stomach or in the hot springs of Yellowstone. Explicit recognition that one’s theoretical and conceptual framework is affecting choices throughout one’s research—from the tools used, to the experiments done, to the inter- pretation of the results and more—may help stimulate truly innovative and transformative research. Because theory in biology sometimes corresponds poorly with common stereotypes of theoretical science, biologists and others often fail to recog- nize its importance. Yet theory is clearly an integral part of the process of biological research and is vital to its success. It is time for biology to take a step back and think carefully about balancing the attention being paid to theory in relation to observation, experiment, and technology development. Would an explicit emphasis on the theoretical and conceptual component of biological research be fruitful, and if so, how would that best be done? Facilitating Future Advances in Biology: Achieving a Balance The emergence of a new insight is, by its very nature, unpredictable. In retrospect, however, it is possible in many cases to dissect the relative contribution of theory to the great discoveries of the past. But is it also possible to look at biological research today and determine whether em- phasis on one area or another would be most likely to drive innovation and transformation of the field? The topic of transformative research was recently the focus of a National Science Board report, Enhancing Support for Transformative Research at the National Science Foundation (May 7, 2007). That report states that “[t]ransformative research is defined as research driven by ideas that have the potential to radically change our understanding of an important existing scientific or engineering concept or leading to the creation of a new paradigm or field of science or engineering. Such research is also characterized by its challenge to current understand- ing or its pathway to new frontiers.” This study’s Statement of Task asked the committee to consider whether biology might benefit from an intensive focus on developing theoretical or conceptual foundations: in other words, to consider whether transformative moments would be likely to be driven by a focus on theory. The increasing fragmentation of the practice of biological research into subdisciplines makes it challenging for biologists to recognize theories that cut across biological scales. The body of knowledge about biological sys-

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0 THE ROLE OF THEORY IN ADVANCING ST-CENTURY BIOLOGY tems has grown so vast so rapidly, and the variety of approaches is now so numerous, that it has become impossible for any one scientist to stay fully abreast of the cutting edge of research—where experiment and observation are actively generating new theories and models (and vice versa)—through- out the full range of biological research. Perhaps even more challenging is the effort to understand enough about other scientific disciplines to know whether the research being done on a specific biological question could inform, advance, or build on research being done outside biology. Key Questions The committee chose to illustrate the role theory can play in answering broad questions in the field of biology and addressing grand challenges for society by developing a set of questions that have relevance across many subdisciplines of biology. These questions consider those characteristics that are unique to living systems and are questions that perhaps only the study of living things can answer. The questions vary. Some focus on characteristics that are similar across many biological scales, while others focus on the incredible diver- sity of life. Still others take an explicitly theoretical point of view. The committee makes no claim that this set of questions is comprehensive, but simply aims to give a set of important examples of how explicit attention to theory might contribute to answering these kinds of questions—questions that would be difficult to address through a traditional approach. The goal was to choose questions that would illustrate the many connections across biological scales and subdisciplines, not to cover the field comprehensively, nor to identify which new areas of research are the most important or promising. Inevitably, this approach precluded covering any area in depth and made it impossible to include all of the many interesting and innovative areas of current biological research. The questions are listed below. The summary at the beginning of the report gives a brief overview of each question, and within the body of the report a separate chapter addresses each one. 1. Are there still new life forms to be discovered? 2. What role does life play in the metabolism of planet Earth? 3. How do cells really work? 4. What are the engineering principles of life? 5. What is the information that defines and sustains life? 6. What determines how organisms behave in their worlds? 7. How much can we tell about the past—and predict about the future—by studying life on earth today?

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 INTRODUCTION Technology The focus of this report is on the current and future roles of theory in biology, but it is clear that technological progress will continue to play a critical role in biology research and that it will continue to contribute thereby to advances in theory. Biology has been transformed dramatically in the past decade by technology for the measurement and observation of biological systems and their parts. There are three key features of this technological transformation: (1) the digital information in the genomes of organisms can be fully known; (2) measurements of molecular constituents of cells and their interactions (proteins, gene expression into mRNA, me- tabolites, molecular complexes) can be global; and (3) these measurements can be dynamic so that time-dependent changes can be seen on a whole- system scale. One of the effects this has had on some areas of biology is that networks can begin to be inferred, dynamic models built, and hypotheses formed based on global dynamic data. This emphasizes the potential for building computational models that are much more useful for explana- tion and for prediction than ever before. It is likely that a major part of biological research—including the development and testing of models and theories—in the future may be done in silico. This report hopes to avoid the stereotype that theoretical science is, at heart, a computational and mathematical exercise: Computation is blind and mathematical modeling is pointless without experimental verification and the development of funda- mental concepts and frameworks. Nevertheless, advances in our ability to digitize, store, manipulate, compare, look for patterns in, and interconnect different kinds of biological information represent a technological advance that contributes to all areas of biological practice, from observation, to ex- periment, and to hypothesis testing, as well as the elaboration of theory. Understanding the Elephant In its deliberations on the role of theory in biology, the committee was reminded of the old tale, with roots in African, Indian, and Chinese folk- lore, of the blind men and the elephant. The tale is told in the following poem, written by a contemporary of Darwin’s and published in 1878, just a few years before Darwin’s death.

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 THE ROLE OF THEORY IN ADVANCING ST-CENTURY BIOLOGY Elephant illustration © Jason Hunt (naturalchild.org/jason) It was six men of Indostan, To learning much inclined, Who went to introduction Fig 1 see the Elephant (Though all of them were blind), That each by observation in color Might satisfy his mind. The First approach’d the Elephant, And happening to fall Against his broad and sturdy side, At once began to bawl: “God bless me! but the Elephant Is very like a wall!” The Second, feeling of the tusk, Cried, “Ho! what have we here So very round and smooth and sharp? To me ‘tis mighty clear, This wonder of an Elephant Is very like a spear!”

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 INTRODUCTION The Third approach’d the animal, And happening to take The squirming trunk within his hands, Thus boldly up and spake: “I see,” -quoth he- “the Elephant Is very like a snake!” The Fourth reached out an eager hand, And felt about the knee: “What most this wondrous beast is like Is mighty plain,” -quoth he,- “’Tis clear enough the Elephant Is very like a tree!” The Fifth, who chanced to touch the ear, Said- “E’en the blindest man Can tell what this resembles most; Deny the fact who can, This marvel of an Elephant Is very like a fan!” The Sixth no sooner had begun About the beast to grope, Then, seizing on the swinging tail That fell within his scope, “I see,” -quoth he,- “the Elephant Is very like a rope!” And so these men of Indostan Disputed loud and long, Each in his own opinion Exceeding stiff and strong, Though each was partly in the right, And all were in the wrong! MORAL, So, oft in theologic wars The disputants, I ween, Rail on in utter ignorance Of what each other mean; And prate about an Elephant Not one of them has seen! —John Godfrey Saxe (1816-1887)

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 THE ROLE OF THEORY IN ADVANCING ST-CENTURY BIOLOGY Each biologist interprets biological phenomena using the data and the tools at hand and a theoretical framework, often acquired through years of education and practice. Molecular biologists seek to explain the elephant by exploring the workings of its genome, ecologists by determining the elephant’s role in its environment, neuroscientists by figuring out how the elephant senses and reacts to that environment. Developmental biologists look at how the elephant develops from a single fertilized egg, and evolu- tionary biologists seek the path by which the elephant came to be the way it is. All combine theories, experiments, observations, and inferences to understand something about the elephant. Unlike the blind men, all are well aware that the elephant cannot be explained by its genes, environment, or history alone. Also, use of this metaphor should not be taken to mean that the committee believes that all biologists should be working at the level of the “whole elephant.” Detailed research (the “reductionist” approach) will continue to be critically important and productive. Nevertheless, answers to such questions as “Why is the elephant so large?,” “How will global warming affect the elephant?,” “How many elephants are needed to pre- serve the species from extinction?,” and “What would be the consequences of extinction?” clearly require input from all areas of biology. Combining insights from different scales and explicitly linking them to see how differ- ent approaches complement each other, and to see larger patterns, will al- low a richer conceptual basis for “understanding the elephant” to be built. By explicitly giving theory equal status with the other aspects of biology, biological science can become even more productive in the 21st century.