In response to a request from the U.S. Department of Energy and the National Science Foundation, the National Research Council convened an ad hoc committee to create a roadmap for accelerating the advanced manufacturing of chemicals using biological systems. The committee was charged to “develop a roadmap of necessary advances in basic science and engineering capabilities, including knowledge, tools and skills,” while “working at the interface of synthetic chemistry, metabolic engineering, molecular biology and synthetic biology” and “considering when and how to integrate non-technological insights and societal concerns into the pursuit of the technical challenges.” The full statement of task can be found in Box 1-1. While the central focus of this report and roadmap is on industrial biotechnology, many of the roadmap goals, conclusions, and recommendations herein will also benefit other sectors, including health, energy, and agriculture.
In its 2012 National Bioeconomy Blueprint, the Obama Administration defined the bioeconomy simply as “one based on the use of research and innovation in the biological sciences to create economic activity and public benefit.” It went on to observe that “[t]he U.S. bioeconomy is all around us,” with new bio-based chemicals, improved public health through improved drugs and diagnostics, and biofuels that reduce our dependency on oil.1
Bio-based product markets are already significant in the United States—representing more than 2.2 percent of gross domestic product, or more than $353 billion in economic activity in 2012.2 While biotechnology has had its greatest economic impact, to date, in human health and in agriculture, bio-based chemicals are neither entirely new, nor are they a historic artifact. Current global bio-based chemical and polymer production is already estimated to be about 50 million tons each year, and bioprocessing techniques (such as fermentation, baking, and tanning) have been used throughout much of human industrial history.
Agilent Technologies estimates that U.S. business-to-business revenues from industrial biotechnology alone reached at least $125 billion in 2012.2b Bio-based chemical applications accounted for about $66 billion of that activity with biofuels adding another $30 billion. Lux Research estimates that industrial chemicals made through synthetic biology currently represent a $1.5 billion market and that this likely will expand at a 15 to 25 percent annual growth rate for the foreseeable future.3 Based on a 2009 Organisation for Economic Co-operation and Development (OECD) analysis, a recent U.S. Department of Agriculture (USDA) report indicates that, this year, bio-based chemicals will comprise greater than 10 percent of the chemical market.4
Despite this impressive recent and projected growth, the manufacturing of chemicals using biological synthesis and engineering could expand even faster. Today, many of the chemicals being produced are selected, in part, because well-established chemical syntheses toward them already exist. In many cases, bio-based routes are often not even considered. Yet the addition of bio-based routes to chemicals could open the door to making and marketing chemicals that cannot presently be made at scale or may allow the use of new classes of feedstocks. This report examines the technical, economic, and societal factors that limit the adoption of bioprocessing in the chemical industry today and that, if surmounted, would markedly accelerate the advanced manufacturing of chemicals via industrial biotechnology and the benefits that would accrue.
The advanced manufacturing of chemicals through biology can help address global challenges related to energy, climate change, sustainable and more productive agriculture, and environmental sustainability. For example, these processes may help reduce toxic by-products, greenhouse gas emissions, and fossil fuel consumption in chemical production. Lowered costs, increases in production speed, flexibility of manufacturing plants, and increased production capacity are among the many potential benefits that the increased industrialization of biology may bring to producers and consumers of chemical products that have not been previously available at scale.
The genetics underlying the natural world are being illuminated by DNA sequencing, the cost of which is declining rapidly.5 The first human genome (3.2 billion base pairs [bp]) was sequenced in 2001 at a cost of $2.7 billion.6 Nine years later 1,000 human genomes (3.2 trillion bp) were sequenced, and in 2014 the company Illumina released the HiSeq X, promising a $1,000 human genome.7 Databases of sequences have rapidly grown; as of 2013, there were 160 million sequences from 300,000 organisms.8 This growth has built an enormous potential catalogue of natural “parts”—functional units of DNA—from which high-value chemical pathways can be discovered or created.
The past decade has seen an explosion in the technologies to compose, read, write, and debug DNA. This has rapidly increased the scale and sophistication of genetic engineering projects, and in the near term this will lead to more complex chemical structures and composite nanomaterials, which require precise control over dozens of genes. Examples of this include mining drug candidates from the human microbiome, pesticides from environmental samples, and the production of metal nanoparticles for electronics and medical devices. In the longer term, one can imagine organisms designed from the ground up for consolidated bioprocessing and automated product assembly that requires multiple steps to synthesize relevant industrial chemicals.
The ability to compose, or decide the sequence of, DNA has lagged behind our ability to read and write it. The most valuable functions require many genes and complex regulatory control over how much, when, and where they are turned on. Synthetic biologists pursue the creation of important tools to solve this problem, including genetic circuits, precision gene regulation parts, and computer-aided design to systematically recode multigene systems. Although it is possible to synthesize entire genomes, we are far from being able to write them from scratch from the bottom up. The current state of the art is the top-down “editing” of existing genomes using technologies such as MAGE9 and CRISPR/Cas910 to introduce incremental changes in an otherwise natural genome. Similarly, genome-scale design tools have begun to emerge to control flux through metabolic pathways.
The applications of synthetic biology in human health and agriculture have advanced more quickly than the manufacturing of chemicals. As a result, groundwork has been laid for the manipulation of genes and
proteins to beneficial purposes and for the scaling of bioprocesses to large volumes. For human health applications, therapeutic proteins are more structurally complex than the small molecules that make up most important industrial chemicals. Their synthesis, however, is directly related to the DNA chosen for expression; simple overexpression in the right host of as little as a single gene produces the product of interest.
Agricultural applications of biotechnology involve the introduction and regulation of a small number of genes. Typically, one or two genes are introduced to confer each desired property (e.g., herbicide tolerance, insect resistance, or disease resistance). Agricultural uses are complicated by the need to express the genes in the tissues of a plant, without adverse phenotypic responses such as slower growth or reduced yield. That transgenic plants are grown in an open environment increases the scope of regulatory controls.
In contrast to health and agriculture applications, synthesis of a chemical product requires the coordination of the expressions of many genes. Biologically produced chemicals are the result of a series of enzyme-catalyzed reactions, with each enzyme encoded by at least one gene. In total, the expression of as many as dozens of genes must be regulated to affect a chemical synthesis. This complexity of the pathways involved creates a systems-level challenge that requires systems-oriented solutions. Biological engineering seeks to take advantage of the tools of recombinant DNA technology while applying systems and network analyses to the challenge of engineering more productive host organisms. These principles have already been successfully applied to generate highly efficient and productive fermentation processes for a number of products. Early successes include, for example, the production of industrial enzymes, artemisinin, lactic acid, 1,3-propanediol, isoprenoids, and alcohol-based biofuels.
Based on these early successes, and powered by the rapidly developing science, use of industrial biology to produce a broad range of chemical products is likely to continue to accelerate. The growth of this field will enable the use of biology to produce high-valued chemical products that cannot be produced at high purity and high yield through traditional chemical synthesis. The future may also include a large number of high-volume chemicals, where biology represents a better synthetic pathway (cheaper and greener) than the conventional chemical synthesis.
In the future production of chemicals, industrial chemical synthesis will frequently take advantage of both biosynthesis and traditional chemical synthetic steps, employing each so as to optimize the overall synthetic pathway.
Achieving a future where biosynthesis and traditional chemical synthesis are equally viable candidates in the industrial production of chemicals requires closing several scientific, technical, and societal gaps. This report identifies feedstock design and use, fermentation and processing, enabling chemical transformations, and governance and societal factors as critical areas in its roadmap and recommendations. Scientific and engineering challenges remain, particularly in the areas of feedstocks, enabling transformations, and the development of an integrated design toolchain.
Today, the feedstock for biomanufacturing chemicals is fermentable sugars from starch. The starch, in turn, derives from grains such as corn. The continued expansion of biomanufacturing chemicals will require additional feedstocks from nongrain sources. Cellulosic biomass holds great promise as a feedstock, but there are still many challenges associated with using recalcitrant cellulosic material in industrial biotechnology. While much current attention is focused on different forms of biomass, there is also significant active work in facilitating the use of syngas, methane, and carbon dioxide in manufacturing.
One of the major engineering considerations is related to fermentation and processing that is required for production of biological systems. Fermentation can be facilitated in many ways, but it typically represents a large capital expense that must be overcome in order to begin production. To mitigate this capital expense, the ability to scale up processes is a critical step. While fermentation is typically conducted batchwise or in “fed batch mode,” developments such as continuous fermentation, continuous product removal, and cell-free processing are needed for rapid improvement.
Further research and development is needed to facilitate chemical transformations. The dramatic advances in synthetic biology are at the heart of chemical manufacturing via biological synthesis and engineering. Continued progress is needed in both the organismal “chassis” and the metabolic pathways of the microorganisms used in chemical manufacturing. In addition, the number and range of microorganisms “domesticated” for industrial use will need to increase with the diversity of products manufactured.
A number of governance and societal factors will also influence the rate of industrialization of biology. Governance starts with the establishment of industry norms and standards that are needed for industrial biology value chains to be established and for economic exchange to occur. Such standards are needed in areas such as (1) read/write accuracy for DNA; (2) DNA “part” performance specifications; (3) data and machine standards across “-omics” technologies; and (4) organism performance in terms of production rates, titers, and yields.
Beyond standards, an updated regulatory regime is needed to speed the safe commercialization of new host organisms, new metabolic pathways, and new chemical products. Such regimes must be harmonized across national boundaries, enabling rapid, safe, and global access to new technologies and products. It must be recognized that ultimately it is society that confers the right to operate new technologies. Efforts are needed to inform the public of the nature of industrial biotechnology and of its societal benefits, and to make sure that public concerns are communicated effectively.
Finally, a roadmap should be an evergreen document. A mechanism is needed to maintain this roadmap, to sustain the momentum, and to ensure that the complex network of technical, economic, and societal factors is progressing in harmony as we build the industrial biology ecosystem.
The vision of the future put forth herein is one where biological synthesis and engineering and chemical synthesis and engineering are on par with one another for chemical manufacturing. The current capabilities of traditional chemical manufacturing are vast, but limit the types of chemicals that can be produced at scale (see Chapter 3). Furthermore, the core petroleum-based feedstock is a limited resource and diversification of feedstocks will provide even greater opportunity for the chemical manufacturing industry.
The recommendations and roadmap goals outlined throughout this report were all conceived in the context of this vision and are designed with the understanding that, in order for the industrialization of biology to be fully realized, the use of biological and chemical routes must be thought of as equals. That does not imply that each would be used interchangeably, but rather that biological options would be considered in the same way individual chemical reactions are considered when developing a synthetic route. The following conclusions, recommendations, and roadmap goals given in Tables S-1 and S-2 are aligned to help achieve this major goal.
There are many areas of science and engineering that must be advanced to accelerate the industrialization of biology. The roadmap items and categories are all in the context of the core technical conclusion: Biomanufacturing of chemicals is already a significant element of the national economy and is poised for rapid growth during the next decade. Both the scale
and scope of biomanufacturing of chemicals will expand and will involve both high-value and high-volume chemicals. Progress in the areas identified in this report will play a major role in achieving the challenge of increasing the contribution of biotechnology to the national economy. While the roadmap is clearly designed to push forward industrial biotechnology, there are many aspects of fundamental research that are needed, and described in this report, that can be applied broadly to other fields, such as health, energy, and agriculture.
The technical roadmap is broken down into six main categories that follow along the production model outlined in the chemical manufacturing flowchart (Figure 1-1). They are:
- Feedstocks and Pre-Processing;
- Fermentation and Processing;
- Design Toolchain;
- Organism: Chassis;
- Organism: Pathways; and
- Test and Measurement.
Each category contains a set of conclusions (Table S-1) leading to Roadmap Goals (Figure S-1) that would represent a step change in the field. It is important to note that not all roadmap goals are geared toward all manufacturing sectors. For example, the roadmap goals for feedstocks assume that feedstock cost is a major component of overall production costs, as it is for fuels or other high-volume chemicals. In order to be competitive with current manufacturing costs, the cost of feedstocks needs to be reduced and choice of feedstocks diversified. Similarly, reducing the quantity of process water used in bioprocessing will not only reduce costs, but also serve to create a more environmentally friendly production process. This too, will focus largely on high-volume materials.
By contrast, the roadmap goals for organism (chassis and pathways) and design toolchain will benefit lower-volume, higher-value chemicals, including pharmaceuticals, where one may have to rely on developing newer pathways to generate higher value. Much of the basic research that will be invested herein not only will be applicable to industrial biotechnology, but also will have implications for health, energy, and agriculture as well.
The following recommendation is central to the success of the proposed roadmap: In order to transform the pace of industrial biotechnology by enabling commercial entities to develop new biomanufacturing processes, the committee recommends that the National Science Foundation, U.S. Department of Energy, National Institutes of Health, National Institute of Standards and Technology, U.S. Department of Defense,
and other relevant agencies support the scientific research and foundational technologies required to advance and to integrate the areas of feedstocks, organismal chassis and pathway development, fermentation, and processing as outlined in the roadmap goals.
In addition to the technical roadmap, recommendations, and conclusions, a number of nontechnical insights and societal concerns are important to ensuring the success of this roadmap. In light of this issue and to better enable implementation of the technical goals set forth, a series of recommendations relating to Economic, Education and Workforce, and Governance issues are shown in Table S-2. As an example, this and many other reports discuss the bioeconomy and its contribution to the overall economy on several occasions; however, the term “bioeconomy” is poorly defined and can lead to confusion. A formal, quantitative measure of the bioeconomy would allow all stakeholders to speak on the same terms and focus on enabling technical solutions. It would also provide a benchmark for measuring improvement in the industrial biotechnology sector.
TABLE S-1 Technical Conclusions
|Feedstocks and Pre-Processing|
|Fermentation and Processing|
|Test and Measurement|
TABLE S-2 Nontechnical Insights and Societal Concerns
|Recommendations: Education and Workforce|
Consideration of the educational and workforce needs as the bioeconomy expands the needs of industry and academia will change as well. It is important that the broader stakeholder community come together to determine future needs and strengthen partnerships broadly. Finally, as with any growing field, a series of governance challenges have emerged. First, engagement with the public will be a key factor in the acceptance of the technology and the conveying industries right to operate, as has been started with many groups in the United Kingdom and United States. Secondly, key government stakeholders will have to address and ensure that governance needs are being met, and continually assess whether the correct stance is being taken. Finally, in order for the community to work
together, the development of fact-based standards will be an important step forward.
Biomanufacturing of chemicals is already a significant element of the national economy, and it is poised for rapid growth during the next decade. Both the scale and scope of biomanufacturing of chemicals will expand and will involve both high-value and high-volume chemicals. High-value chemicals will benefit from the specificity of biological synthesis, leading to high-purity products, produced at high yield via pathways that minimize by-product formation. Large-volume chemicals must be produced in a cost efficient manner, taking advantage of cheap, abundant carbon sources, while minimizing the capital costs for the production facilities.
However, the realization of the promise of the industrialization of biology for chemical manufacturing can only be achieved through a sustained effort among multiple stakeholders. The next decade will be critical to the realization of the promise. Therefore, the Committee recommends that the relevant government agencies consider establishment of an ongoing road-mapping mechanism to provide direction to technology development, translation, and commercialization at scale.
As outlined in Chapter 5, a road-mapping activity, maintained in an evergreen fashion, could serve as a catalyst for many of the roadmap goals and recommendations in this report and could foster productive collaborations among diverse stakeholder groups. Examples are provided illustrating how this approach could be applied.