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Synthetic Biology Building on Nature's Inspiration: Interdisciplinary Research Team Summaries Conference Summary Cassandra Brooks Synthetic biology is an innovative and growing field that unites engineering and biology. It builds on the powerful research that came about as a result of recombinant DNA technology and genome sequencing and appears to be one of the most important extensions of that work—a perfect example of science building on what came before. The goal of synthetic biologists is nothing short of building a biological system from the ground up. By definition, synthetic biology is an interdisciplinary enterprise comprising biologists of many specialties, engineers, physicists, computer scientists, and others. It promises a fundamentally deeper understanding of how living systems work and the capacity to recreate them for medicine, public health, and for the environment, including renewable energy. By building synthetic biological systems, scientists seek an unprecedented level of insight and knowledge about how various parts of biological systems function in isolation and as whole organisms or even whole ecosystems. The National Academies Keck Futures Initiative in 2009 focused on Synthetic Biology to generate new ideas about how to program and control both simple and complex biological systems. The possibilities synthetic biology offer are clear but challenges are significant because, as one participant said, “We cannot yet program cells the way we can program computers,” and that is what needs to happen. To explore the engineering, scientific and social aspects of synthetic biology, researchers, as well as individuals from funding, industry, and government agencies who participated in the Futures Initiative on Synthetic
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Synthetic Biology Building on Nature's Inspiration: Interdisciplinary Research Team Summaries Biology joined one of 12 Interdisciplinary Research (IDR) teams comprising about a dozen leading researchers whose job was to think creatively, outside the proverbial “box” about how to move the field forward. IDR teams 1a and 1b each discussed new foundational technologies and tools required to make biology easier to engineer. The teams came up with many clever ideas, including creating a “smart Web-cam” that could be inserted into a cell to observe and record cellular processes without disturbing the cell’s function. They also explored creating a futuristic “photocopying machine” that could copy cells, tissues, organelles and whole organisms. This would allow synthetic biologists to efficiently produce useful products in large quantities. The group also stressed the importance of increasing the number of cell types with open protocols. For example, access to thermophilic bacteria that live in extremely hot environments for carrying out reactions at high temperatures would lead to innovative avenues of research. IDR team 2 was asked to consider whether there are ethical considerations unique to synthetic biology. After much deliberation, the team of scientists and bioethicists concluded that synthetic biology does not pose any unique problems when compared to previous cutting edge advances in science. Yet, they warned, this new field does deserve the same level of careful attention and monitoring devoted to previous technologies. They recommended that synthetic biology should borrow from the existing regulatory framework to protect the public while allowing the science to move forward. IDR teams 3a and 3b asked how synthetic biology could lead to an understanding of the principles underlying natural genetic circuits and to the discovery of new ways to make use of that knowledge. Half of the group approached the problem by asking if a failed or noisy synthetic circuit could help scientists better understand natural circuits and locate missing genes, proteins or chemical reactions. The group proposed a noise “decomposer” that could track the randomness in zebrafish stem cells as they become the various parts of the animal. Moreover, they proposed assembling a “deviance library” where a scientific failure (i.e., a synthetic circuit that intentionally produces caffeine in E. coli but arsenic in staphylococcus) could lead to another’s deliberate design. The other half of the group debated how synthetic biology could be used to answer fundamental biological questions such as how proteins assemble, bind to DNA and regulate transcription. They also suggested borrowing techniques from electrical engineering: for example, sending the
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Synthetic Biology Building on Nature's Inspiration: Interdisciplinary Research Team Summaries equivalent of a pulse or oscillating wave into a biological circuit and then devising ways to measure the output. By finding tools to precisely disturb natural systems, scientists could gain tremendous insight into how these systems operate. IDR team 4 tackled how cellular collaboration and communication could be used in synthetic biology for specialization and division of labor. The team proposed specific ways that cell communities could be used to clean up waste, improve health, keep plants fed and watered, and even explore Earth or other planets in the future. One clever idea proposed was a “land and pond rover” based on the life cycle of the slime mold Dictyostelium discoideum, or Dicty for short. The team proposed that mobile Dicty-like slugs could be engineered to search for arsenic or gold and then sprout into their readily visible mushroom-like form to indicate where hazardous or valuable materials are located. IDR team 5 thought about why human-designed biological circuits and devices are fragile and inaccurate relative to their natural counterparts. To kick off the discussion, they considered whether the rigidity of engineered systems is the source of fragility. Although biology is noisy, it works well and should not be considered an undesired element when engineering biological systems. Instead synthetic biologists should consider how to engineer biological robustness, including redundancy, plasticity, adaptability and flexibility. In the end they worried that “the inherent complexity of biological systems defies reliable engineering.” Despite this, the team came up with some theoretical tools for constructing more robust systems. They suggested that the equivalent of a biological wind tunnel could be used to carefully examine each genetic circuit in a one-at-a-time way to test its strengths and flaws. In contrast, the researchers also proposed a “rapid comparison” approach. This entailed bombarding combinatorial circuits into the cell and then assessing which was most robust. IDR team 6 pondered how genomics could be leveraged to develop coherent approaches for rapidly exploring the biochemical diversity in and engineering of new model organisms, to augment studies that currently rely on well studied organisms. They decided that the most pertinent problem is figuring out ways to most efficiently and effectively search the biosphere for new genes and to elucidate their specific functions. Because genetic diversity is presumed to correlate with biodiversity, the team recommended sampling soil from different ecological zones throughout the world. Once regions of highest diversity are found, biopropsecting efforts could be focused on
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Synthetic Biology Building on Nature's Inspiration: Interdisciplinary Research Team Summaries those regions. This should include toxic waste sites, where an organism’s ability to deal with toxins could potentially be exploited to clean up other polluted environments. IDR teams 7a and 7b each investigated how to move beyond genetics to use chemical and physical approaches to synthetic biology. Half of the team explored means for developing new tools to exploit the evolution of biological systems and use that knowledge to renew systems that are failing. They identified several goals based on orthogonal functions, meaning those entirely separate from and not interacting with existing biological functions. These included generating cells that include macromolecules with new and desirable functions, programming new molecules to encode information, designing sub-cellular pathways that are separate from the cell’s machinery, and engineering molecular interactions with organic or engineered devices. The other half of the team focused on creating biotic and abiotic devices that could act on the host cell without altering its DNA, which would offer research an incredible advantage over current techniques of genetic engineering. First, the team proposed building simpler synthetic transporter proteins that, when injected into cells, could stimulate a desired response immediately. Moreover, the transporter would be designed to self-destruct after completing its task in order to “do no harm.” Second, they proposed building a cellular radio that could be inserted into a cell and remotely controlled with incredible power and precision. The radio could theoretically be used to produce heat, mechanical vibrations, or hydrolysis. The heat, for example, could be used to destroy cancer cells. IDR team 8 considered the role of evolution in synthetic biology. They pointed out the necessity of developing methods to accelerate evolution and get a desired result faster, but also having a kill switch for these evolutionary processes once the experiment was finished. Yet, this will only be possible by engineering strains of bacteria in which the mutation rate can be controlled, making it significantly more reliable and malleable. IDR team 9 focused on explaining synthetic biology to the public and on encouraging young scientists to enter the field. The team worked to define some of the educational, institutional and communication barriers that may inhibit the progress of synthetic biology. They concluded that part of the solution is to train young scientists in new ways, break
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Synthetic Biology Building on Nature's Inspiration: Interdisciplinary Research Team Summaries down divisions in academic institutions, and to improve general science communication. As all the groups gathered on the final day of the conference to present their ideas, it became clear that most individuals were both challenged and inspired. During the final large group discussion, many participants commented that the conference changed the way they will do their research, will inspire their teaching, foster new collegial connections and bolster existing ones.
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