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Grand Challenges

As discussed in Chapter 1, this intersectional work between the biological and physical sciences can be characterized as efforts to tackle new issues, typically biological in nature, by adapting ways of addressing problems whose genesis are in another field, typically one of the physical sciences. These adapted ways might be how to conceptualize the problem, or how to evaluate or otherwise draw information out of data, or how to collect the necessary data. In this chapter, the committee sets out five areas of potentially transformative research it believes are particularly susceptible to significant advancement by taking this approach.

Each of these areas, presented in the form of a grand challenge, describes research questions where the scientific challenges are compelling to those in the constituent disciplines, where researchers are poised to make a breakthrough—the goals are attainable in the foreseeable future—and where the payoff of success would be substantial. These are questions whose answers not only will transform our knowledge of the physical world, but also will substantially impact our society.

The committee does not claim that these five grand challenges are the only areas for investment, as there are many areas that could benefit from collaborative attention from the physical and life sciences. But the committee has identified these as among the most urgent, the most important, and the most achievable.



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2 Grand Challenges As discussed in Chapter 1, this intersectional work between the biological and physical sciences can be characterized as efforts to tackle new issues, typically biological in nature, by adapting ways of addressing problems whose genesis are in another field, typically one of the physical sciences. These adapted ways might be how to conceptualize the problem, or how to evaluate or otherwise draw informa- tion out of data, or how to collect the necessary data. In this chapter, the committee sets out five areas of potentially transformative research it believes are particularly susceptible to significant advancement by taking this approach. Each of these areas, presented in the form of a grand challenge, describes research questions where the scientific challenges are compelling to those in the constituent disciplines, where researchers are poised to make a breakthrough—the goals are attainable in the foreseeable future—and where the payoff of success would be substantial. These are questions whose answers not only will trans- form our knowledge of the physical world, but also will substantially impact our society. The committee does not claim that these five grand challenges are the only areas for investment, as there are many areas that could benefit from collaborative attention from the physical and life sciences. But the committee has identified these as among the most urgent, the most important, and the most achievable. 

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gRAnd chAllenges  GRAND CHALLENGE 1. SYNTHESIzING LIFELIkE SYSTEMS Living systems provide proof-of-concept for what can be achieved physically. Can the combined skills and knowledge sets of biological and physical scientists provide greater insight into identifying those structures, capabilities, and processes that form the basis for living systems and then, with that insight, construct systems with some of the characteristics of life that are capable, for example, of synthesizing materials or carrying out functions as yet unseen in natural biology? For centuries, humans have analyzed the properties of living organisms and built structures to mimic their functions. While most efforts have been at somewhat rudimentary levels, advances in the physical and life sciences now provide us with the technical and scientific sophistication to pursue almost limitless possibilities in this arena. Concepts such as emergent properties, familiar to condensed matter theorists, are helping to describe how biologically complex systems arise from prebiotic chemistry and geochemistry. Other ideas from the physical sciences, such as dynamical systems theory, energy landscapes, and multistability, are helping to explain fundamental issues such as how organisms behave in response to their environments and how information is used to sustain life.1 Using the knowledge gained in these and other studies, we face the ambitious possibility of generating synthetic units with basic attributes of living matter such as compartmentalization, metabolism, homeostasis, replication, and the capacity for Darwinian evolution. Such self-replicating, evolving organisms have the potential to create more efficient functions for a broad range of applications. At the same time, pursuing this chal- lenge will provide us the opportunity to explore and expand our understanding of the principles of self-replication and evolution. Any such efforts will require the duplication of essential components of living systems. For example, Darwinian evolution requires a molecular basis for heritable variation, suggesting that any such system must contain a polymer like RNA or DNA with the ability to store and encode information in a simple way. This genetic material must be able to replicate, which requires either a simple autocatalytic sys- tem or chemistry that enables spontaneous replication. The scientific community has made some progress toward these goals by, for example, chemically synthesiz- ing natural genomes and then replacing the original genomes in living cells with these synthesized genomes and, in a more bottom-up approach, developing and studying “protocells” as a demonstration of how simple nucleic acids self-replicate within a lipid envelope. In addition, the products of replication must be held in proximity for some 1 Many of these topics are touched on in more detail in Chapter 4. Also, see National Research Council, The Role of Theory in Advancing st Century Biology, Washington, D.C.: The National Academies Press, 2008, for related discussions.

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ReseARch inteRsection PhysicAl life sciences  At the of the And time, so that advantageous mutations can exhibit their phenotypes and result in enhanced fitness, leading to differential reproduction and changes in population abundance. Such an achievement will probably require some form of compartmen- talization of the components. Cell membranes are possible candidates, since they are composed of a wide variety of amphiphilic molecules. Artificial membranes have been constructed of a wide range of nonbiological materials. However, the specific control of the shape and the osmotic properties when the number of components in the surface and interior of the membrane increases, is unknown. The questions become more interesting as the chemical components diverge more from standard biological components. The section in Chapter 5 entitled “Interac- tions within Cells” discusses some of the strategies under way to explore how to synthesize such structures. There is no reason, in principle, why self-reproducing, evolving systems can- not be generated in a wide range of chemical formats. Unfortunately, very little research has systematically approached the chemistry of self-replication based on nonbiological materials. Moreover, a deep understanding of how to efficiently encode and transfer information in highly fluctuating nonequilibrium environ- ments is required. However, attempting to create autonomous synthetic devices capable of self-replication and evolution undoubtedly will generate new principles and tools for synthesizing, assembling, and programming dynamic entities cur- rently unimagined. GRAND CHALLENGE 2. uNDERSTANDING THE BRAIN The human brain may be nature’s most complex system. Unraveling the mys- teries of how it works is one of the greatest of challenges facing the scientific world, and the tools and ideas developed in the physical sciences will play a pivotal role in this undertaking. One promising approach to understanding the brain is the reverse engineering of neural circuits. This reverse engineering has been accomplished for simple model nervous systems typically consisting of a few dozen cells. For example, neurons in the stomatogastric ganglion of the crab control the musculature of the crab’s stomach. Understanding the mechanism of this simple system was accomplished in five steps: (1) cataloguing the different cell and synapse types; (2) measuring their properties; (3) mapping the wiring diagram (the detailed connectivity between neurons); (4) measuring the electrical dynamics of many neurons simultaneously; and (5) creating a model that predicts and simulates behavior. Understanding the much more complex mammalian brain will require a similar program of reverse engineering albeit on a much larger and more com- plex scale. Some first progress has recently been made in the form of large-scale, physiologically realistic models of a cortical hypercolumn, of the hippocampal

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gRAnd chAllenges 5 dentate gyrus, and of the entire human brain. Unfortunately, current experimental tools are woefully inadequate for this task, although there are possibilities on the horizon. The physical sciences are particularly adept at developing tools to meet some of the most significant needs—namely, new methods of high-resolution, high-throughput microscopy and imaging to monitor the functions of the brain components, ideally in the intact brain. One key challenge is to trace the thinnest neuronal wires (100 nm and less) throughout the entire brain (tens of millimeters and more in length). This would allow the reconstruction of neuronal shape and the mapping of wiring diagrams (Steps 1-3, above). One such technique, diffusion tensor imaging, is discussed in Chapter 5, in Figure 5-5. Finally, data and under- standing are necessary to create a predictive model that will represent a new level of understanding neural function. GRAND CHALLENGE 3. PREDICTING INDIvIDuAL ORGANISMS’ CHARACTERISTICS FROM THEIR DNA SEquENCE Individuals belonging to the same species exhibit remarkable diversity in form and function. For example, humans not only look much different from one another, they also differ significantly in their susceptibility to disease. Geographi- cally isolated populations of butterflies develop striking differences in coloration. How much of this variation results from differences in genome sequence, and how much is due to gene-environment interactions? Likewise, how does DNA sequence change in response to interactions with other living things and with the environ- ment? Life and physical scientists will need to work together to develop the theory and modeling to understand these phenomena. Ultimately, the blueprint for form and function lies in an organism’s DNA sequence. A major challenge is to understand the relationship between the DNA sequence (genotype) and the individual’s characteristics (phenotype). Small differences in genotype can interact to produce large changes in phenotype. To understand how genetics underlies phenotype, we need quantitative models of genetic interactions. DNA sequences change over time in response to selective pressures. Selection acts at the level of the individual but is defined by the individual’s fitness relative to the rest of the population, which, in turn, is affected by the results of selection. Thus, the outcome of selection manifests itself at the level of the population. The population exists in a particular environmental niche, and changes in the environ- ment can affect the population; likewise, the population can have dramatic affects on the surrounding environment. All of these components feed back to affect the survival and therefore selection of the individual (and thus its genes). Interactions between the environment and genes, interactions between organisms of the same and different species, interactions between different species and their environment,

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ReseARch inteRsection PhysicAl life sciences  At the of the And and how all of these interactions iteratively feed back to alter the environment and thus selection must be understood. Here again, interactions between life scientists and physical scientists will be needed to develop models that help to understand these phenomena. Thanks to high-throughput DNA sequencing, we now possess the complete code of hundreds of organisms, including humans. A major challenge going forward is to decipher the principles underlying the organization of the information in the DNA. Interactions between DNA elements introduce a combinatorial wealth of possibili- ties for stringing sequences together to impart complex patterns of gene expression. Deciphering the logic of gene regulation will require theorists, at times drawing on theoretical constructs originally developed in the physical sciences, to work hand in hand with molecular biologists. The gains from those efforts will allow us to more fully exploit the information we have garnered from the human genome sequence and learn how it relates to health and disease, aging, and the quality of life. GRAND CHALLENGE 4. INTERACTIONS OF THE EARTH, ITS CLIMATE, AND THE BIOSPHERE Many of the most challenging and potentially most important questions in science involve interactions among actors or processes governed by strikingly dif- ferent mechanisms. Often these processes operate on much different scales of time and space, unfolding over spatial scales ranging from the microscopic to the global and on temporal scales from fractions of a second to many millions of years. In the past, these questions were often discussed but rarely tackled in a comprehensive way. The difficulties in undertaking quantitative studies of these matters typi- cally loomed so large that the interactions were simply considered to be outside the boundaries of the inquiry at hand. Questions about, for example, the role of microorganisms in shaping Earth’s near-surface environment or the role of forests in modulating the tempo of glacial-interglacial transitions were, until recently, too complex, too multidisciplinary, and too multiscale for profound treatment with available scientific tools. Now, however, they are ripe for joint investigation by life and physical scientists. Such joint efforts are needed, in part because many of the processes involve intricate, continual interactions between physical and biological parts of the system. Consider, for example, the global nitrogen cycle. At the spatial scale of microns, the transformation of organic nitrogen to NH4+, NO3, N2, NO, and N2O appears to be controlled by, among other things, the microscale soil moisture and the respiration rate of the organisms in the microsite. But these transformations interact to adjust soil fertility over thousands of years. The compounds released have the potential to influence global climate and vast stretches of aquatic habitat. As with most of

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gRAnd chAllenges  the interactions between the living and the nonliving parts of a system, even a complete knowledge of all the separate parts still falls short of allowing us to under- stand how they interact over different timescales. The challenges of understanding the interactions among living and nonliving parts of the Earth system are often exacerbated by the consequences of human actions. In the example of the global nitrogen cycle, human actions have more than doubled the amount of biologically available nitrogen moving through the Earth system, making it difficult to observe or understand the system free of anthropogenic influences. Many of the foundations for rapid progress in addressing these questions are either in place or nearly in place. Increasingly powerful computer models can link, for example, the global climate with site-to-site variations in the biological parts of the global carbon cycle, which, in turn, feed back to the global climate. Space- based sensors provide access to a growing set of observations at regional to global scales, facilitating the coordinated analysis of, for example, shifts in the locations of the major biomes, changes in the distribution of pests and pathogens, changes in regional water balance, and feedbacks to climate change. See, for example, Figure 5-6 in Chapter 5, on satellite imaging technologies. Other approaches to observing the physical parts of the system—for example, from familiar com- puterized axial tomography (CAT) scans to the less-well-known spectroscopies such as extended X-ray absorption fine structure (EXAFS), X-ray absorption near edge structure (XANES), and secondary ion mass spectroscopy (SIMS)—provide access to sites that are smaller, bigger, more protected, or more complex than have been accessible so far. The range of tools either available or becoming available in molecular biology is increasing the power and sweep of experimental studies by many orders of magnitude. In short, the scientific community has the questions, the tools, and the concepts to effectively tackle the questions surrounding interac- tions between living and nonliving parts of the Earth system. Broad question areas related to this grand challenge that are ripe for future breakthroughs include the following: • How have life and Earth coevolved over time? For instance, what climate changes can be attributed to the evolution of key biochemical processes, and what events in evolutionary biology were triggered by geochemical events? • How are changes in Earth’s climate affecting terrestrial and marine biology? How will changes to these ecosystems feed back into the climate system? • How does the physical diversity of Earth’s habitats help to control the bio- logical diversity of its organisms, and how does biological diversity alter the functioning of ecosystems? • How does the ability of organisms and ecosystems to cope with change depend on the complexity of the physical environment?

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ReseARch inteRsection PhysicAl life sciences  At the of the And • Through what mechanisms are interactions among the living and nonliving parts of the Earth system coordinated, and when does that coordination fundamentally shift or disappear? • In an era of increasingly pervasive human influence on physical and biologi- cal components of the Earth system, what are the most effective strategies for maintaining the integrity of natural systems and the services they provide? GRAND CHALLENGE 5. uNDERSTANDING BIOLOGICAL DIvERSITY Life on Earth is astoundingly diverse, a result of evolution. While such diversity has been recognized for centuries, its role in the health of a species or ecosystem has only recently begun to be studied. An understanding of diversity is becoming increasingly important as human activity has a larger and larger impact on the natural world. The modeling capabilities and tools of the physical sciences will play a critical role in such studies. Diversity appears in the natural world at many levels. A single multicellular organism can consist of more than 1015 cells, divided into many different organs. In some organs, no two cells are identical. Within a single species, individual organ- isms vary extensively at the DNA sequence level, and this translates into substantial diversity in appearance and behavior. Dogs are in breeds that range from Great Danes to Chihuahuas. However, we have only rough estimates of the extent of existing diversity. While the diversity of well-studied groups like birds and mam- mals is generally well known, data on the diversity of insects, microorganisms, and marine invertebrates are thin. Recent estimates conclude that only 5-10 percent of such species have been classified.2 Diversity within populations and organisms is known for very few taxa. Within a species, diversity in the sequence of genes protects against extinction by infectious agents or predators and may allow species to function efficiently across a wider range of environmental conditions. The role of diversity in the functioning of ecosystems is only beginning to be understood. A number of studies indicate that plant communities tend to be more productive, more resistant to bio- logical invasives, or less sensitive to disturbance when they are more diverse. Some evidence supports the hypothesis that increasing diversity increases the probability that a community contains at least one well-adapted species (a sampling effect). Other evidence points to a complementarity in which diversity allows species to forage more efficiently for resources. For example, a more diverse community could contain species active at different times of the year, species that extract water and 2 Available at http://www.globalchange.umich.edu/globalchange2/current/lectures/biodiversity/ biodiversity.html#readings. Accessed April 21, 2009.

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gRAnd chAllenges  nutrients from different depths in the soil, or microbes that specialize on different substrates. It is likely that diversity influences ecosystem function through a wide range of mechanisms. Some are structural (rooting depth), some behavioral (feeding time), and some biochemical (optimum temperature for an enzyme). Human activities have tended to reduce the diversity of organisms and eco- systems, in some cases dramatically. The widespread use of limited numbers of cultivars has rendered many of our agricultural crops potentially very sensitive to disease outbreaks or climate fluctuations. The same concern exists for commercial livestock. Now, in an era of rapid global changes driven by human actions, the role of diversity and the processes that maintain diversity take on dramatic new impor- tance. Many kinds of human impacts on the natural world, especially landscape fragmentation, climate change, pollution of air, soil, and water, and stimulation of biological invasives, threaten to decrease biological diversity. At the same time, the novel habitats these impacts create may need the maximum possible biodiversity if they are to cope effectively in the novel conditions. The Intergovernmental Panel on Climate Change (IPCC) estimates that a global average warming of as little as 2°C could commit 30 percent of the world’s species to extinction. We do not know the mechanism, the timetable, or the consequences, nor do we know the features that make some communities extremely resilient, while others collapse with only modest forcing. Our ability to sequence DNA rapidly and inexpensively is increasing expo- nentially. This promises to provide the capability to extensively characterize the diversity of species and to allow predicting its functional consequences. We have begun to be able to determine the DNA sequences of complete simple ecosystems, and this will inevitably progress to more complete and interesting communities and organisms. These tools, combined with advanced techniques for analyzing the physical and modeling tools of ecology, offer the potential for huge breakthroughs in coming decades. A clearer picture of the role of diversity in ecosystem function- ing will make it feasible to specify the diversity level required to secure sustainable provision of key services. A clearer understanding of existing diversity and the factors that lead to extinction should enable a suite of strategies for protecting diversity in key areas. For this challenge, there are opportunities for the biological and physical sci- ences to interact at a range of levels. Physics will be able to extend the tools needed to quantify diversity quickly and cheaply, which is crucial for understanding the consequences of altering diversity for ecosystem functioning.