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How the New Biology Can Address Societal Challenges

In the 1800s, those who studied the living world were called “naturalists” and they were highly interdisciplinary, combining observations from biology, geology, and physics to describe the natural world. In this 200th anniversary year of Darwin’s birth, after decades of highly productive specialization, the study of life is again becoming more interdisciplinary, by necessity combining previously disparate fields to create a “New Biology.” The essence of the New Biology is re-integration of the subdisciplines of biology, along with greater integration with the physical and computational sciences, mathematics, and engineering in order to devise new approaches that tackle traditional and systems level questions in new, interdisciplinary, and especially, quantitative ways (Figure 2.1).

As illustrated in Figure 2.1, the New Biology relies on integrating knowledge from many disciplines to derive deeper understanding of biological systems. That deeper understanding both allows the development of biology-based solutions for societal problems and also feeds back to enrich the individual scientific disciplines that contributed to the new insights. It is critically important to recognize that the New Biology does not replace the research that is going on now; that research is the foundation on which the New Biology rests and on which it will continue to rely. If we compare our understanding of the living world to the assembly of a massive jigsaw puzzle, each of the subdisciplines of biology has been assembling sections of the puzzle. The individual sections are far from complete and continued work to fill those gaps is critical. Indeed, biological systems are so complex that it is likely that major new discoveries are still to be expected, and new discoveries very frequently come from individual scientists who make the intellectual leap from the particular system they study to an insight that illuminates many biological processes. The additional contri-



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2 How the New Biology Can Address Societal Challenges In the 1800s, those who studied the living world were called “naturalists” and they were highly interdisciplinary, combining observations from biology, geology, and physics to describe the natural world. In this 200th anniversary year of Darwin’s birth, after decades of highly productive specialization, the study of life is again becoming more interdisciplinary, by necessity combining previously disparate fields to create a “New Biology.” The essence of the New Biology is re-integration of the subdisciplines of biology, along with greater integration with the physical and computational sciences, mathematics, and engineering in order to devise new approaches that tackle traditional and sys - tems level questions in new, interdisciplinary, and especially, quantitative ways (Figure 2.1). As illustrated in Figure 2.1, the New Biology relies on integrating knowl- edge from many disciplines to derive deeper understanding of biological sys - tems. That deeper understanding both allows the development of biology-based solutions for societal problems and also feeds back to enrich the individual sci - entific disciplines that contributed to the new insights. It is critically important to recognize that the New Biology does not replace the research that is going on now; that research is the foundation on which the New Biology rests and on which it will continue to rely. If we compare our understanding of the living world to the assembly of a massive jigsaw puzzle, each of the subdisciplines of biology has been assembling sections of the puzzle. The individual sections are far from complete and continued work to fill those gaps is critical. Indeed, biological systems are so complex that it is likely that major new discoveries are still to be expected, and new discoveries very frequently come from individual scientists who make the intellectual leap from the particular system they study to an insight that illuminates many biological processes. The additional contri - 

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 A NEW BIOLOGY FOR THE ST CENTURY ENVIRONMENT FOOD HEALTH ENERGY Biology-Based Solutions to Societal Problems Deeper Understanding NEW BIOLOGY of Biological Systems: • Organizing Principles • Predict/Analyze/Modulate Scientific Integration Physical & Mathematics Biology Chemical Sciences Computer Science Science EngineeringEducation FIGURE 2.1 What is the New Biology? SOURCE: Committee on a New Biology for the 21st Century. bution of the New Biology is toFigure 1 connections between the partially focus on the assembled puzzle sections and dramatically speed up overall assembly. R01620 vector editable WHO IS THE NEW BIOLOGIST? The committee believes that virtually every biologist who reads this report’s description of the New Biologist will recognize him or herself. All biologists think across levels of biological complexity—molecular biologists consider the impact of genetic regulatory pathways on the health of organisms, ecologists consider the impact of environmental change on the gene pool of an ecosys - tem, and neuroscientists link cell-to-cell communication with behavior. Rare is the biologist who does not use computational tools to analyze data, or rely on large-scale shared facilities for some experiments. And an increasing fraction of biologists collaborate closely with physical scientists, computational scientists or engineers. The workshop held at the beginning of this committee’s work highlighted a number of laboratories where the New Biology is already well advanced (Box 2.1). The committee does not intend to suggest that there is a stark division between ‘old’ biologists and ‘new’ biologists, but rather that there is a continuum from more reductionist, focused research within particular

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES BOX 2.1 A Wiring Diagram for Cells Cellular systems can be represented in “wiring diagrams” analogous to those of electronic circuits. But the components in the diagram are proteins, nucleic acids, and other biologically active molecules while the wires are interactions among those components. Lucy Shapiro’s laboratory at the Stanford University School of Medicine chose a simple organism, a bacterium called Caulobacter crescentus, and set out to under- stand all the integrated processes that this organism needs to function as a living cell. Among these processes are the biochemical circuits that control cell division and differentiation. Four proteins serve as master regulators of these processes, Shapiro and her colleagues have found. Rising and falling quantities of these proteins in particular parts of the cell produce “an exquisite coordination of events in a three- dimensional grid.” Building these circuit diagrams has allowed researchers to identify nodes that control cellular functions and are attractive targets for drugs designed to alter the functioning of cells. Research in Shapiro’s lab, for example, has led to drug develop- ment projects for two new antibiotics and an antifungal agent. Shapiro’s lab members are about half biologists and half physicists and engi- neers. Each has had to learn the language of the others so that they can work together. “You put all these people together and amazing things happen,” Shapiro says. “Now we understand in a completely different way how this bacterial cell works.” SOURCE: Shapiro Lab, Stanford University School of Medicine. Figure 2 R01620 biitmapped fixed image landscape scale below allows one line of caption only

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0 A NEW BIOLOGY FOR THE ST CENTURY subdisciplines of biology to more problem-focused, collaborative and interdis - ciplinary research. Each is important, and many, if not most, biologists have feet in both worlds. So if many biologists already practice the New Biology at some level, what is the role of this report? Its role is to bring attention to the remarkable depth and scope of the emerging New Biology that is as yet poorly recognized, inade- quately supported, and delivering only a fraction of its potential. Consider the newly hired assistant professor in the immunology depart - ment of a medical school who wants to collaborate with an ecologist who studies the impact of changing land use patterns on natural ecosystems and an engineer who models complex networks. Together they hope to develop a biosensor to detect emerging infectious diseases. Where will this group apply for funding? How will that assistant professor’s tenure committee react to a series of publications in engineering and ecology journals? Or consider the physics professor who wants to develop an interdisciplinary course on the physics and chemistry of DNA replication with colleagues from the chemistry and molecular biology departments. Will any of these professors be given credit for contributing to the teaching needs of their own depart - ments? Such a course would likely not count toward degree requirements in any of the three departments. And yet the students who took such a course would be well-prepared to work across disciplinary boundaries no matter which of the three sciences they decided to pursue in depth. Importantly, the New Biologist is not a scientist who knows a little bit about all disciplines, but a scientist with deep knowledge in one discipline and basic “fluency” in several. One implication of this is that not all “New Biolo - gists” are now, or will in the future be, biologists! The physicists who study how the laws of physics play out in the crowded and decidedly non-equilibrium environment of the cell, or the mathematicians who derive new equations to describe the complex network interactions that characterize living systems are New Biologists as well as being physicists or mathematicians. In fact, the New Biology includes any scientist, mathematician, or engineer striving to apply his or her expertise to the understanding and application of living systems. During its deliberations, the committee came to the conclusion that the best way for the United States to capitalize on the new capabilities emerging in the life sciences would be a multi-agency initiative to marshal the necessary resources and provide the coordination to enable the academic, public, and private sectors to address major societal challenges. The challenges laid out in this chapter are analogous to that of placing a man on the moon––the technolo - gies do not all yet exist, there are still fundamental gaps in understanding—but the committee believes that a relatively small investment could reap enormous returns in each of these major societal challenge areas.

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES A NEW BIOLOGY APPROACH TO THE FOOD CHALLENGE: GENERATE FOOD PLANTS TO ADAPT AND GROW SUSTAINABLY IN CHANGING ENVIRONMENTS The United Nations Food and Agriculture Organization has estimated that 923 million people were undernourished in 2007, an increase of 75 million over the 2003–2005 estimate of 848 million (FAO, 2008). Growing enough food worldwide to address this shortfall, as well as providing the higher quality food that will be expected by people living in countries where standards of living are improving, is an enormous challenge. This challenge will be compounded by the changing climatic conditions of the future, which will change the temperature and rainfall patterns of the world’s farmlands, and may also lead to inundation of low-lying fertile land. A better fundamental understanding of plant growth and productivity, as well as of how plants can be conditioned or bred to toler- ate extreme conditions and adapt to climate change, will be key components in increasing food production and nutrition in all areas of agriculture to meet the needs of 8.4 billion people by 2030 (Census Bureau, 2008), while allowing adequate land for energy production and environmental services. Understanding Plant Growth The long-term future of agriculture depends on a deeper understanding of plant growth. Growth—or development—is the path from the genetic instruc - tions stored in the genome to a fully formed organism. Surprisingly little is now known about this path in plants. A genome sequence provides both a list of parts and a resource for plant breeding methods, but does not give the infor- mation needed to understand how each gene contributes to the formation and behavior of individual plant cells, how the cells collaborate and communicate to form tissues (such as the vascular system or the epidermis), and how the tissues function together to form the entire plant. There is simply a lack of fundamen - tal information—we have the parts list for some plants, but not the assembly instructions, so we don’t yet have a useful assembly manual. Understanding at a fundamental and detailed level of the assembly manual of even one plant would be a powerful tool. A recent NRC report, Achieements of the National Plant Genome Initiatie and New Horizons in Plant Biology (National Research Council, 2008), provides a series of recommendations that could serve as the basis for planning a coordinated effort to understand plant growth, including a call to develop “reference genomes.” The report details the benefits of such genomes and outlines the characteristics of desirable reference sequences. The NPGI report recognizes that sequencing is just a first step in understanding plant growth. A fully characterized model plant would provide a scaffold upon which the myriad variations found throughout the plant kingdom could be interpreted and put to use. Here lies the connection between biodiversity and meeting the challenge of revolutionizing our capacity to generate plant varieties

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 A NEW BIOLOGY FOR THE ST CENTURY to meet local needs and conditions. Every plant species, even every local popu - lation of a species, contains unique genetic resources that could contribute to improving the crops we depend on. Assessing and protecting biodiversity is therefore a critical ingredient in meeting the challenge of achieving sustainable food production. Fundamental understanding will require predictive models that include all of the factors that affect growth and development; several technologies that will have to be developed to be applied in parallel to model and crop plants; new methods for live visualization of growing plants and for computational modeling of their growth and development at the molecular and cellular levels; cell-type specific gene expression, proteomic, and metabolomic data; high-throughput phenotyping, both visual and chemical; methods to characterize the dynamics and functions of microbial communities; and ready access to next-generation sequencing methods. The same technologies and measurement techniques will find useful application in energy, environmental, and human health research. The New Biology––integrating life science research with physical science, engineering, computational science, and mathematics––will enable the develop- ment of models of plant growth in cellular and molecular detail. Such predictive models, combined with a comprehensive approach to cataloguing and appre - ciating plant biodiversity and the evolutionary relationships among plants, will allow scientific plant breeding of a new type, in which genetic changes can be targeted in a way that will predictably result in novel crops and crops adapted to their conditions of growth. The goal of predictability is a critical one; genu - ine understanding of plant growth will reduce uncertainty about any possible health or environmental consequences of genetic changes, changes in growth conditions, or in associated microbial or insect communities. The New Biology promises to deliver a dramatically more efficient approach to developing plant varieties that can be grown sustainably under local conditions. Advances in plant breeding and engineering, combined with a more profound and compre - hensive understanding of plant growth and development and more complete knowledge of plant diversity, will make it faster and less expensive to develop plant varieties with helpful characteristics. Genetically Informed Breeding As a result of plant genome sequencing, plant genome analysis, and advances in bioinformatics, it is now possible to recast the principles of highly success- ful traditional plant breeding into a new and accelerated type of plant breed - ing termed “genetically informed breeding.” Previously, the offspring of plant crosses had to be screened after their full life cycle to see which of them had acquired the traits sought by the breeder or farmer. Growing thousands of plant offspring required a lot of time and space, and therefore limited the numbers of offspring that could be analyzed. New quantitative methods—the methods of the

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES New Biology—are being developed that use next-generation DNA sequencing to identify the differences in the genomes of parental varieties, and to identify which genes of the parents are associated with particular desired traits through quantitative trait mapping. Once this is done, the genetic sequence, or geno- type, of millions of offspring can be determined from seeds or seedlings, and only those with the desired trait combinations retained. This will allow a much deeper selection from larger numbers of offspring, hence enormously speeding the overall rate and power of plant breeding. Continued advances in genotyping (including the same next-generation sequencing methods that are contributing to the revolution in medicine, and the same bioinformatics of genetic association studies used in human genomics) and application of novel engineering methods to automatically record the rel - evant traits of growing plants, will greatly accelerate the process of breeding plants with desired characteristics. Transgenics and Genetic Engineering of Crops The advancement of plant genomics will also allow us to engineer crops in another way. By adding genes to the crop DNA from species other than the crop plant of interest, we may be able to capitalize on all of the many molecular mechanisms that can contribute to high crop yields. For example, some plants use an alternate photosynthetic pathway (called C4) that increases carbon fixation in dry environments. If the higher C4 photosynthetic rates could be transferred to crops that normally use conventional C3 photosynthesis, it could increase photosynthetic rates in most of the world’s food crops. Or, manipulat - ing the effects and concentration of hormones could optimize not just growth, but also partitioning of the carbohydrates produced by photosynthesis into grains and other edible parts of the plant. Additional advanced genetic and molecular methods, including those in place and others now being explored, are leading to improvement in the nutritional value of crops, for example by changing the composition of soybean oil to reduce transfat concentrations (Fehr, 2007). Biodiversity, Systematics, and Evolutionary Genomics Research in biodiversity, enhanced by rapid advances in comparative and evolutionary biology, is a critical ingredient in expanding the range of options available for developing new food crops and improving current ones. Informa- tion technology, imaging, and high-throughput sequencing are a few of the technological advances that promise to drive rapid advances in understanding and managing biological diversity. Developing a comprehensive knowledge of plant diversity and greater understanding of evolutionary relationships is the functional equivalent of building a fully stocked parts warehouse with an

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 A NEW BIOLOGY FOR THE ST CENTURY inventory control system that quickly locates exactly the right part. Much of this potential is as yet unrealized because most species on Earth are yet unnamed, indeed undiscovered, and their precise evolutionary relationships are unknown. The field of systematics––the study of the diversity of life and the relationships among organisms––is undergoing a renaissance as a result of adding genomic and computational analysis to the many other ways organisms can be compared. The practical benefits of expanding knowledge in this area are enormous; tap - ping into the vast resources represented by biological diversity will contribute to adapting and improving crops for food and bioenergy, understanding eco - system function, and finding new biologically active chemicals for medical and industrial applications (Chivian & Bernstein, 2008). Crops as Ecosystems All crops grow in a complex environment, characterized by physical parameters like temperature, moisture, and light, and biological parameters including the viruses, bacteria, fungi, insects, birds, and others that interact with the crop plants. Therefore, greater understanding of insect-plant interactions, both beneficial and harmful, offers another route toward increasing crop pro- ductivity. Furthermore, complex microbial communities in the soil, previously difficult to study, play critical roles in providing nutrients and protecting plants from pests and diseases. Understanding these microbial communities in predic - tive detail will also point to new ways to increase plant productivity. Genetic engineering (as well as plant breeding) has been of great importance in improv- ing crop resistance to plant diseases caused by viruses, bacteria, and fungi, and in resistance to herbivores such as insects. Detailed understanding of how plants grow, a comprehensive catalogue of plant diversity and evolutionary relationships, and a systems approach to understanding how plants interact with the microbes and insects in their environments––each of these areas is ripe for major advances in fundamental understanding and none of them can be addressed by any one community of scientists. Molecular and cellular biologists, ecologists, evolutionary biolo - gists, and computational and physical scientists will all be needed. Biomedical researchers with expertise in identifying and growing stem cells, neuroscientists with expertise in how neural networks monitor internal processes and seek out and respond to external signals, environmental engineers with expertise in monitoring and remediating contaminated ecosystems, hydrologists, soil scien - tists and meteorologists who study the physical systems that affect plant growth, private sector researchers with expertise in identifying promising research results and translating them into products––all of these and many others could make critical contributions, if their efforts can be coordinated. The result of this focused and integrated effort will be a body of knowledge, new tools, technologies, and approaches that will make it possible to adapt all

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES sorts of crop plants for efficient production under different conditions, a criti - cal contribution toward making it possible to feed people around the world with abundant, healthful food, adapted to grow efficiently in many different, ever-changing local environments. At the same time, the tools and approaches developed through this effort will enhance the productivity of individual scien - tists around the world, whatever plant or ecosystem they are studying. A NEW BIOLOGY APPROACH TO THE ENVIRONMENT CHALLENGE: UNDERSTAND AND SUSTAIN ECOSYSTEM FUNCTION AND BIODIVERSITY IN THE FACE OF RAPID CHANGE Humans do not exist independently of the rest of the living world. From the most basic requirements of oxygen, clean water, and food, to raw materials like fuel, building material, fiber for clothing, and shelter that have allowed human societies to flourish around the globe, to intangible benefits that enrich the quality of life such as the shade of a tree on a hot day or the inspiration of an eagle in flight, humans are dependent on other organisms. Together, the resources and benefits that are provided by the living world are considered “ecosystem services” (Millennium Ecosystem Assessment, 2005). The amount of services that ecosystems can provide depends, at base, on their productivity: that is, their ability to use energy from the sun to make complex carbon- containing molecules like sugars and starches. Sustaining ecosystems so that their productivity remains high even in the face of rapid climate change is essential to sustaining and enhancing the quality of life of a growing human population. Fundamental advances in knowledge and a new generation of tools and technologies are needed to understand how ecosystems function, measure ecosystem services, allow restoration of damaged ecosystems, and minimize harmful impacts of human activities and climate change. What is needed is the New Biology, combining the knowledge base of ecology with those of organ- ismal biology, evolutionary and comparative biology, climatology, hydrology, soil science, and environmental, civil, and systems engineering, through the unifying languages of mathematics, modeling, and computational science. This integration has the potential to generate breakthroughs in our ability to monitor ecosystem function, identify ecosystems at risk, and develop effective interven - tions to protect and restore ecosystem function. Monitor Ecosystem Services Ecosystem services are varied and some of them are easier to measure than others. The amount of wood in a forest, for example, is easier to measure than the amount of protection a mangrove swamp will provide from coastal flooding. Mea- suring qualities like the impact of ecosystems on air and water quality, or placing

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 A NEW BIOLOGY FOR THE ST CENTURY a value on the carbon that is stored in undisturbed ecosystems, is challenging. Detecting changes in biodiversity and predicting the impact of extinctions on eco- system services is even harder. But if the value of ecosystems is to be appreciated, the impact of human activities understood, and management decisions made on a scientific basis, it is important to develop a methodology and the necessary tools to monitor the state of ecosystems. The New Biology has a great deal to offer in bringing together the necessary expertise and resources to implement a practical ecosystem monitoring system. Monitoring activities are already carried out by several agencies; the Environ - mental Protection Agency measures air and water quality, the National Science Foundation administers the National Ecological Observatory Network and Long Term Ecological Research Network programs, U.S. Geological Survey has the National Water Quality Assessment, the United States Forest Service carries out forest inventories, the Department of Energy and the National Aeronautical and Space Administration administer Ameriflux (which measures ecosystem level exchanges of CO2, water, energy, and momentum across the Americas), and the Department of Agriculture carries out agricultural and soil inventories. Several nonprofit groups also maintain extensive databases of ecological information. However, each of these efforts measures different things, for different reasons, and the parts do not add up to a whole that provides the nation with a compre- hensive understanding of the state of its ecosystems. Ultimately, monitoring is required that is both intensive (covering eco- system services in depth) and extensive (covering all kinds of ecosystems, and at regional and national scales). Current efforts focus on in-depth understand - ing of a few natural ecosystems and crisis intervention in damaged environ - ments with measurements limited to a few key physical air or water quality characteristics. Considerable research has already explored how ecosystem services can be measured. A 2000 NRC report, Ecological Indicators for the Nation (National Research Council, 2000a), recommended a set of national ecological indicators that would measure the extent and status of the nation’s ecosystems, the nation’s ecological capital, and ecological functioning or performance. The years since that report have seen many advances in ecosystem science, technology, and com- putational and mathematical approaches to describing ecosystem function. GIS, GPS, and remote sensing technologies (providing higher resolution and lowered costs) have led to rapid advances in ecology. GPS units are now cheap enough to be part of every ecologist’s toolbox, allowing accurate mapping of species’ distributions against existing maps of geological profiles, hydrological dynamics, and other environmental information. These technological advances have been as important in ecological research as inexpensive high-throughput sequencing has been in molecular, cell, comparative, and evolutionary biology. The Heinz Center for Science, Economics, and the Environment, estab - lished in 1995, pulls together information from all of these sources to produce

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES reports on indicators including two editions, in 2002 and 2008, of the compre - hensive State of the Nation’s Ecosystems (H. John Heinz III Center for Science, Economics, and the Environment, 2002, 2008). The Heinz Center acknowl - edges, however, that the current system is fragmented. A recent article by three Heinz Center directors (O’Malley et al., 2009) contended that— [A] coherent and well-targeted environmental monitoring system will not appear with - out concerted action at the national level. The nation’s environmental monitoring efforts grew up in specific agencies to meet specific program needs, and a combination of lack of funding for integration, fragmented decision-making, and institutional inertia cry out for a more strategic and effective approach. Without integrated environmental information, policymakers lack a broad view of how the environment is changing and risk wasting taxpayer dollars. The article goes on to point out that— [T]here are data gaps for many geographic areas, important ecological endpoints, and contentious management challenges as well as mismatched datasets that make it difficult to detect trends over time or to make comparisons across geographic scales. . . . In The State of the Nation’s Ecosystems 00, only a third of the indicators could be reported with all of the needed data, another third had only partial data, and the remaining 40 indicators were left blank, largely because there were not enough data to present a big-picture view. No single scientific community, federal agency, or foundation can develop and implement a comprehensive set of ecosystem indicators, capable of moni - toring the ecosystem services on which the nation relies. The New Biology approach––coordinating the resources already available and supporting research that integrates biology with physical and earth sciences, engineering, and computation––can be applied to build on such existing resources as the 2000 NRC report and the Heinz Center’s 2002 and 2008 reports to evaluate potential ecological indicators in light of current capabilities and develop an implementable system for monitoring ecosystem function. The goal of a monitoring system is to provide an accurate assessment of the services provided by ecosystems and to indicate when those services are at risk. The next step for the New Biology is to develop the knowledge and means to respond to the information provided by the monitoring system––to minimize the impact of human activities on ecosystem services and, even more impor- tantly, to restore ecosystem function where it has been compromised. Advance Understanding of Ecosystem Restoration Medical doctors follow diagnosis with treatment options. The “medicine” of ecosystem treatment, however, has few arrows in its quiver. We do not currently have the tools needed to manage the biosphere. Between the two

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 A NEW BIOLOGY FOR THE ST CENTURY extremes of, on the one hand, preserving some ecosystems in their pristine state and, on the other hand, carrying out human activities with minimal regard to measuring or predicting their ecological impact, there are few options. The capacity to evaluate human impacts on ecosystem services and to provide options for minimizing or healing those impacts is another potentially valuable contribution of the New Biology. A growing subfield in ecology is restoration, which ultimately holds the key to recovery of ecosystem services in heavily degraded areas (e.g., recovery of watershed function), and perhaps even to mitigation of climate change through designing ecosystems with even greater capacity for removing carbon from the atmosphere.1 Ecological restoration has a role to play in improving crop productivity, reducing energy needs and slowing the loss of biodiversity. The question the New Biology can address is: Once we know that a system is at risk, how do we return it to a state that is more capable of providing ecosystem services? Integrate Basic Knowledge about Ecosystem Function with Problem-Solving Techniques Developing a science of ecosystem restoration will require integration of many fields of knowledge. For example, ecologists rely on soils science and hydrological studies for meaningful ecological niche modeling, which is heavily used in conservation (e.g., reserve design) and in climate change impact studies. Interdisciplinary work is already common as many ecosystem biologists reside in Earth Sciences Departments and institutes, and climate change biologists col- laborate as often with meteorologists as with other biologists. Facilitating these efforts and integrating organismal, agricultural, evolutionary, and comparative biologists, engineers, computational scientists, and others to focus on the ques - tion of ecosystem restoration has the potential to provide treatment options for critical ecosystems. The New Biology could contribute to the development of a field one might call ecosystem engineering, analogous to the MD-PhDs of the biomedical field, grounded in both research and treatment. A NEW BIOLOGY APPROACH TO THE ENERGY CHALLENGE: ExPAND SUSTAINABLE ALTERNATIVES TO FOSSIL FUELS World annual requirements for energy grow at about the same rate as Gross Domestic Product (GDP) and are expected to increase by around 60 percent by 2030. Most of this increase will come from rapidly developing economies like India and China (IEA, 2008). More than three-fourths of the current need is currently met by fossil sources (EIA, 2007). The United States is no exception 1 The July 31, 2009, issue of Science was devoted to this topic.

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES to this pattern, with our high dependence on such carbon-rich fossil fuels as oil, coal, and natural gas for our energy needs. Fossil fuels increase carbon dioxide emissions, which are linked to increased risk of global warming (Houghton & Intergovernmental Panel on Climate Change. Working Group I., 2001). A growing population, desiring a higher standard of living, has put even greater demands on our energy supplies. Thus we face the consequences of burning of high sulfur coal, depletion of petroleum reserves for transportation, and excess CO2 being produced as stored hydrocarbon reserves are depleted. The environ- ment is damaged both by the extraction of these resources and then by the sub- sequent release of the byproducts of their use. Sustainable, efficient, and clean sources of energy are crucial to reducing our dependence on and the depletion of fossil fuels. The New Biology can help propel the sustainable production of biofuels, and the United States could be the leader in this increasingly important industrial sector. Direct conversion of biomass to thermal energy via combustion was our first source of energy. Improvements in biomass combustion continue, as does development of liquid fuels derived from thermochemical conversion of raw cellulose to liquid fuels. The major motivation for producing more biofuels is to reduce dependence on petroleum-based transportation fuel. In 2007, Con - gress passed the Energy Independence and Security Act (Public Law 110-140). Among other things, the legislation included the Renewable Fuel Standard (RFS) program, which calls for the volume of renewable fuel required to be blended into gasoline from 9 billion gallons in 2008 to 36 billion gallons by 2022. In 2007, the United States consumed 176 billion gallons of fuel for trans - portation, so 36 billion gallons of renewable fuel (assuming equivalent energy content per unit volume) would cover roughly 20 percent of our transportation fuel needs (Bureau of Transportation Statistics, 2009). The RFS further stipu - lates that a substantial fraction of the biofuel must be advanced or cellulose- based fuels, rather than ethanol derived from corn. In fact, technology is not currently available to meet the RFS, but the New Biology offers the possibility of advancing the fundamental knowledge, tools and technology needed to achieve it. Making efficient use of plant materials— biomass––to make biofuels is a systems challenge, and this is where the New Biology can make a critical contribution. At its simplest, the system consists of a plant that serves as the source of cellulose and an industrial process that turns the cellulose into a useful product. There are many points in the system that can be optimized: choosing the right crops as sources of biomass, engineering these crops so that they grow with a minimum of energy, fertilizer, and water input and produce cellulose that is easy to ferment, and engineering enzymes that are efficient at digesting the cellulose. The optimization of each of these steps depends on the others, so maintaining a view of the whole system is important. Each of these steps involves a large number of choices. Which plants can produce the most biomass with the least input of fertilizers and water and the

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0 A NEW BIOLOGY FOR THE ST CENTURY least impact on the land needed to grow food and sustain ecosystem services? How can those plants be modified to produce biomass even more efficiently or produce cellulose that is easier to digest? How can that biomass be converted to fuel? What enzymes and metabolic pathways have evolved in microbes that could be adapted for biomass conversion? How can the fermentation process be optimized to produce the most fuel at lowest cost? Work in all of these areas is underway in laboratories and companies, but the New Biology approach can tackle this challenge in a comprehensive way, bringing together expertise from many different scientific communities, federal agencies, and the private sec - tor to generate the advances in fundamental knowledge and translational and developmental research needed to provide innovative solutions. Identifying and Optimizing Sources of Biomass for Biofuel Today, the United States leads the world in the volume of biofuels pro - duced, and nearly all U.S. biofuel today is made by using fermentation to convert starch from corn into ethanol. More than 30 percent of the U.S. corn crop is used for ethanol production (USDA, 2009). As a result of the applica - tion of biotechnology to agriculture, per-acre corn yields are increasing at 2 to 3 percent per year (Egli, 2008). Grain alone, however, will not allow dramatic expansion of biofuel production, and must be supplemented, and ultimately replaced, with other sources of biomass. Development of energy crops that are direct sources of fermentable sugars, such as sugarcane or sweet sorghum, or sources of cellulosic materials, such as switchgrass, miscanthus, or agricultural and forestry byproducts, is an important priority. The same fundamental knowl- edge, tools, and technologies developed in the New Biology approach to the food challenge would be directly applicable here: understanding plant growth; advancing genetically informed breeding, transgenics and genetic engineering; advancing biodiversity, systematics and evolutionary genomics; and under- standing crops as ecosystems. Thus, both the agriculture and energy research communities will be stakeholders in the effort to transform plant breeding capabilities. Identifying and Optimizing Microbial Biocatalysts Ethanol is a first-generation biofuel, produced via fermentation of sugars by wild-type yeast. Ethanol has limitations, such as low energy density, high vapor pressure, and water solubility. By combining recent advances in technolo- gies such as high-throughput sequencing, automated gene expression measure - ment, and metabolic engineering, future generations of biofuels are now within reach. Advanced biofuels targets include higher alcohols, long-chain fatty acids and derivatives, even olefinic and alkane derivatives––all products that can be made by microorganisms, with subsequent chemical processing in some cases.

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES For each fuel molecule, microbial hosts are being selected, metabolic pathways are being identified, and using recombinant methods, organisms are being engineered to deliver biofuels at acceptable rates and yields. The challenge for advanced biofuels is to be able to produce fuel more cheaply than using yeast to ferment starch or sugar into ethanol. Again, the unique contribution the New Biology can add to these existing efforts is the coordination of efforts to discover, characterize, and engineer microbes so that they serve as factories for high production rates, with efforts to engineer production systems that maximize those microbes’ productivity, for example by continuously adjusting levels of nutrients and end-products. These optimized systems will allow next- generation biofuels to compete with gasoline at prevailing prices. Approaching Biofuel Production as a Systems Challenge Clearly, the road to meeting the U.S. Renewable Fuel Standard consists of multiple steps, steps that are interdependent. An integrated approach that includes scientists and engineers expert at each step is essential. The combined efforts of plant scientists, microbiologists, ecologists, chemical and industrial process engineers, molecular biologists, geneticists, and many others are needed to develop and optimize the biomass-to-biofuel system. Combining the strengths of these communities does not necessarily mean bringing these experts into the same facility. Indeed, advancing communication and informatics infrastructures make it easier than ever to assemble a virtual collaboration. The New Biology Initiative proposed in this report would provide the resources to attract the best minds from across the scientific landscape to the problem, ensure that innovations and advances are swiftly communicated, and provide the tools and technologies needed to succeed. A coordinated effort to optimize the conversion of biomass to biofuel would create knowledge and technologies that would have an immediate and direct impact on other sectors, including therapeutics and industrial materials, which can also be produced in this way (Box 2.2). A NEW BIOLOGY APPROACH TO THE HEALTH CHALLENGE: UNDERSTANDING INDIVIDUAL HEALTH The New Biology approach to the environmental challenge aims to make it possible to monitor ecosystem function and restore that function when it is compromised. The goal of a New Biology approach to health is similar––to make it possible to monitor each individual’s health and treat any malfunction in a manner that is tailored to that individual. In other words, the goal is to provide individually predictive surveillance and care. In both cases, reaching these goals means understanding how the interactions of myriad components are related to overall system function.

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 A NEW BIOLOGY FOR THE ST CENTURY BOX 2.2 Biomass to Biomaterials and Biosynthesis of Chemicals and Therapeutics Liquid transportation fuels represent by far the largest-volume opportunity for renewable products made by living organisms from biomass. Chemicals and materials made from petroleum account for about 10 percent of total U.S. oil consumption. The same fermentation-based technology that is being developed for biofuels can also be harnessed to replace petroleum-based materials and make many other useful products. Microbes can also be engineered to produce chemicals, industrial enzymes, and therapeutics at industrial scales. Insulin was the first material produced using an engineered organism, in the 1980s. Many pharmaceutically active proteins, antibiotics, vitamins, and amino acids for food and animal feed followed. Microorganisms are now widely used to produce industrial enzymes for many uses. Fermentation-based large-scale (>10 ktons/year) production of chemicals and materials is an emerging opportunity. For example, lactic acid, produced by bacteria, can be polymerized into a substance that has useful properties in both fiber and molded form. Large-volume production of propanediol (PDO), using an engineered E. coli host, was commercialized in 2007. PDO is used in applications ranging from deicing fluids to personal care prod- ucts. BioPDO is also an important component of poly (trimethylene terephthalate), a polymer with true engineering properties. We can now foresee a range of such chemical building blocks as succinic acid, dodecanedioic acid, and p-hydroxybenzoic acid being made from biomass via fermentation (Pacific Northwest National Laboratory, 2009). At present, medical decision-making is often based on probabilities. For example, high cholesterol levels are associated with heart disease and early- stage cancers metastasize at a predictable rate. But some individuals with high cholesterol do not develop heart disease, and metastasis of a given tumor type occurs with frightening speed in some individuals and not at all in others. Each individual has a unique set of genes and a unique environmental history, yet the relationship of all of this variation to health is uncertain. Understanding the relationship of an individual’s genetic makeup and environmental history to that individual’s health risks, disease susceptibility, and response to treatment is a chal- lenge well beyond current capabilities. Critical to improving that understanding is a quantum leap in our ability to understand the functioning of and interactions among complex networks, or systems of interconnected components. The Genotype-Phenotype Challenge It seems likely that it will soon be economically feasible to determine the full genome sequence of every individual. An individual’s genetic make-up, or

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES genotype, is directly related to his or her phenotype (i.e., the various traits of an individual that can be observed or measured). Because genetic sequences serve as the blueprints for all biological processes, genetic variation affects the functioning of all of the networks that underlie human health. As if the challenge of understanding the connection between an individual’s genome sequence and health were not difficult enough, two additional factors add further layers of complexity. First, feedback from the environment affects how the genetic blueprint is executed. For example, individuals who live at high altitudes, where the air holds less oxygen, produce more red blood cells. All individuals have the genetic potential for this adaptation, but it only occurs under particular environmental circumstances. Diet, exercise, exposure to sun - light, chemicals, viruses, and bacteria––all of these and much more can affect the connection between genotype and phenotype. Furthermore, new kinds of gene regulation continue to be discovered, including epigenetic mechanisms (mechanisms that change gene expression without changing the underlying gene sequence) and mechanisms like small, interfering RNA, in which short RNA fragments regulate expression or translation. The second layer of complication recently added to the challenge of under- standing the genotype-phenotype connection is the discovery that our own human genes are not the only genetic material affecting our health. Humans are intimately associated with a complex microbial community—the microbiome. Rapidly accumulating discoveries of the many essential roles of this microbial consortium are redefining our understanding of human health and making it clear that a true understanding of human health must take into account not only the human genome, but also the genomes of each human’s microbial com - munity. For example, differences in the microbiomes of twins has been shown to be associated with obese versus lean physiological states (Turnbaugh et al., 2009). The normal, healthy human body contains ten times more microbes than human cells, and these microbes carry out many essential functions. The microbes in the human intestine synthesize essential amino acids and vitamins, and digest complex carbohydrates (Backhed et al., 2005). Genomic and other new technologies are now making it possible for life scientists to characterize the human microbiome and the factors that influence the distribution, func - tion, and evolution of our microbial partners. Recognizing the importance of the microbiome means assessing how these evolutionarily ancient microbial partnerships influence health and predisposition to diseases. In other words, the connection of genotype to phenotype must include not only the human genome, but also the genomes of the microbes that live in and on us. The important influence of viruses on the genotype-phenotype connection must also be taken into account, from their role in cancer (for example, HIV and Kaposi’s sar- coma, human papilloma virus and cervical cancer) to the role that the immune response to persistent viruses plays in the development of autoimmune and other chronic diseases. Understanding the role of microbes and viruses in

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 A NEW BIOLOGY FOR THE ST CENTURY human health is a major challenge, but it also holds the promise of providing new intervention points for prevention, diagnosis, and treatment of disease. A growing body of evidence suggests that many diseases, including types 1 and 2 diabetes, coronary artery disease, and glioblastoma, typically result from small defects in many genes, rather than catastrophic defects in a few genes (Altshuler et al., 2008). It is likely that many different combinations of genetic changes, acting in the context of particular environmental influences (for exam - ple, a viral infection), can produce the same disease, so that understanding how genes work together in regulatory networks, and how those networks are affected by external factors, will be crucial to untangling the intricate web of interactions associated with a particular disease phenotype. Large-scale studies that associate genotype to phenotype are rapidly iden - tifying many, many genetic variations (both human and microbial) and environ- mental factors that are associated with specific diseases. The key word in that sentence is “associated.” While some of these variations may have a direct role in causing disease, there is currently a substantial gap between discovering an association and uncovering a causal mechanism. But ultimately, if health care is to move from treatment based on statistical likelihood to treatment based on each individual’s specific circumstances––in other words, truly personal - ized medicine––the chasm between genotype and phenotype will have to be bridged. This is a challenge that is beyond the scope of any single Institute at the NIH. Indeed, it is a challenge that will demand a New Biology-driven research community empowered by scientific and technical resources from across the federal government, the broad community of scientists, and the private sector. Unraveling the genotype-phenotype connection will require combining increasingly sophisticated genotype-phenotype associations with experimentation, modeling, systems analyses, and comparative biology. Understanding Networks Between the starting point of an individual’s gene sequences and the end- point of that individual’s health is a web of interacting networks of staggering complexity. Recent advances are enabling biomedical researchers to begin to study humans more comprehensively, as individuals whose health is determined by the interactions between these complex structural and metabolic networks. On the path from genotype to phenotype, each network is interlocked with many others through intricate interfaces, such as feedback loops. Study of the complex networks that monitor, report, and react to changes in human health is an area of biology that is poised for exponential development. These networks consist of circuits of interacting genes, gene products, metabolites, and signals that function together much like electronic integrated circuits. Unlike electronic circuits, however, almost all of the components of living networks are constantly changing, with results that ripple through all of the other networks. Tools and

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES methodologies are being developed that can detect, synthesize, and process complex biological information at a network level, image cellular events in real time, delineate how proteins interact, and access single sites within the DNA library of the cell. Computational and modeling approaches are beginning to allow analysis of these complex systems, with the ultimate goal of predicting how variations in individual components affect the function of the overall sys - tem. Many of the pieces are identified, and some circuits and interactions have been described, but true understanding is still well beyond reach. Combining fundamental knowledge with physical and computational analysis, modeling and engineering, in other words, the New Biology approach, is going to be the only way to bring understanding of these complex networks to a useful level of predictability. Such complex events as how embryos develop or how cells of the immune system differentiate (that is, the actual processes by which an individual’s phenotype––the appearance and characteristics of the individual––come into being) must be viewed from a global yet detailed perspective because they are composed of a collection of molecular mechanisms that include junctions that interconnect vast networks of genes. It is essential to take a broader view and analyze entire gene regulatory networks, and the circuitry of events underlying complex biological systems. Data obtained from mutational, chemical genetic or imaging analyses of organisms such as Drosophila, C. elegans, Arabidopsis, mouse, sea urchin, and other species will continue to uncover rich sets of inter- actions between gene products that comprise such regulatory networks. Analy - sis of developing and differentiating systems at a network level will be critical for understanding complex events of how tissues and organs are assembled. These studies have obvious import in regenerative medicine. Similarly, networks of proteins interact at a biochemical level to form complex metabolic machines that produce distinct cellular products. Under- standing these and other complex networks from a holistic perspective offers the possibility of diagnosing human diseases that arise from subtle changes in network components. Perhaps the most complex, fascinating, and least understood networks involve circuits of nerve cells that act in a coordinated fashion to produce learning, memory, movement, and cognition. These studies can be approached both experimentally, at the cellular level, as well as at the whole brain level via functional imaging approaches. In addition, recent computational approaches allow modeling of neurobiological systems that provide valuable predictive information. Understanding networks will require increasingly sophisticated, quanti - tative technologies to measure intermediates and output, which in turn may demand conceptual and technical advances in mathematical and computational approaches to the study of networks.

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 A NEW BIOLOGY FOR THE ST CENTURY Studying Complex Systems Directly in Humans Work in model organisms, as discussed earlier, is immensely produc- tive because fundamental developmental and metabolic pathways have been conserved throughout evolution and are shared among many organisms. In fact, model organisms are increasingly useful as genomics makes it possible to understand the differences and similarities among organisms at an ever more detailed level. Advances in imaging, high-throughput technologies, and compu- tational biology increasingly make it possible to relate model system informa - tion directly to the study of complex systems in the human. New technologies and sciences that allow, for example, comprehensive comparisons of genomes and gene expression will enable much more sophisticated associations between genotype and phenotype. Another approach to the genotype-phenotype challenge is to survey the “read-out” from the genome: that is, the collection of proteins and metabo - lites that are the end-products of gene activities. Technologies for charac - terizing proteomes (all the proteins in a sample) and metabolomes (all the metabolites in a sample) are less capable and more expensive than sequencing technologies. But they are increasingly being used to generate profiles from body fluids, such as blood, sweat, and urine, which contain the products and byproducts of metabolic processes that reflect a composite of an individual’s genomic activity together with that of his or her particular microbiome. These profiles can be used, for example, to design tailor-made drugs (i.e., drugs that would take into account differences in how individuals break down and assimilate a given pharmaceutical). Ultimately, high-throughput assessment of the metabolome could provide a remarkably precise picture of the overall activities within and on the human body and critical insights into the rela - tionship of “composite genotype” to phenotype. Achieving those insights, however, will require new technologies to measure proteins and metabolites, massive collections of samples from healthy and sick individuals, and novel mathematical and computational tools, and concepts to discern the patterns associated with health and disease. Such a task dwarfs the complexity of the Human Genome Project. A Systems Approach to the Genotype-Phenotype Challenge Unraveling the genotype-phenotype connection will require that the efforts of biomedical researchers be complemented and supplemented by the skills and different approaches of engineers, mathematicians, and physical and com - putational scientists. The efforts of scientists nurtured by separate institutes of the NIH will need to be joined by those supported by NSF and DOE, for example, who study non-human organisms and who create and support vari- ous multi-user facilities. Agencies like the National Institute of Standards and Technology could add interdisciplinary expertise in the development of mea -

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 HOW THE NEW BIOLOGY CAN ADDRESS SOCIETAL CHALLENGES surement technologies, pharmaceutical companies their extensive databases, and nonprofit disease research foundations their refined expertise. By providing the framework for these communities to work together to address the challenge of understanding the genotype-phenotype connection, the New Biology can accelerate fundamental understanding of the systems that underlie health and the development of the tools and technologies that will in turn lead to more efficient approaches to developing therapeutics (Box 2.3). And just as with sequencing technology, the technological and conceptual breakthroughs that emerge from these efforts could revolutionize the capacity and sophistication of all biological research. INTERCONNECTED PROBLEMS, INTERCONNECTED SOLUTIONS The future holds truly imposing challenges for humankind: efficiently improving the sustainable productivity of diverse food crops, producing sus - tainable substitutes for fossil fuels, monitoring and restoring ecosystem ser- vices, and understanding and promoting human health. The New Biology described in this report, if properly nurtured and supported, has the potential to contribute to real progress in meeting these challenges and many tools and approaches will be shared for all four problem areas. The projected impacts are significant, from both a societal and economic perspective. Furthermore, the importance of the challenges to which the New Biology will contribute ensure BOX 2.3 Developing Therapeutics to Prevent, Treat, and Cure Disease The future of therapeutics lies in the application of new technologies as tools for detecting and treating diseases. Therapeutic efforts will also benefit from an increased understanding of networks. Therapeutics that focus on a single driver may miss both the critical role played by other genes as well as the ease with which a malignant cell, for instance, may utilize alternative parts of the larger network to side-step the drug’s effect, and thus continue to thrive. Similarly, adverse side effects can result when intervention in one network causes unforeseen changes in others. Complicated as these networks are, we are now in a position to study the response of complex systems to a range of perturbagens (both natural mutations and introduced chemicals), providing an important opportunity to probe the pattern of interactions and refine the model. This approach may also identify underappreci- ated network pressure points—possible drug targets or biomarkers that are less evident in traditional linear models.

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 A NEW BIOLOGY FOR THE ST CENTURY that students, and the American public, will be inspired to help, and will be drawn in to science and science education. The United States cannot afford to wait for others to create these life science-based solutions. As a nation, we must lead these efforts.