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IDR Team Summary 4

Designing communities of cells: how do we create communication and collaboration between cells to allow for specialization and division of labor?

CHALLENGE SUMMARY

Synthetic biology often focuses on engineering individual strains of microbial or other organisms to implement novel behaviors or metabolic functions in a cell autonomous manner. This approach, while powerful, appears to overlook one of the most basic aspects of biological systems: the ability of different species or cell types to interact with one another in order to generate behaviors that would be less feasible or impossible with a single genotype. In natural ecosystems, consortia of multiple species are commonplace, and many, perhaps most, species are non-culturable in isolation, requiring signals or nutrients from other species to grow. Some metabolic functions may be more efficient when divided between strains, compared to when implemented in a single genotype. Thus, multi-genotype/multi-cell type systems provide an opportunity for specialization and optimization not possible with homogeneous cultures. Two examples of such optimization include the ability to compartmentalize different biosynthetic reactions in different cells that are chemically incompatible with each other, and the ability to create coherent structures that are dramatically larger than the size limit imposed by the dimensions of a cell.

Nevertheless, polycultures present a number of unique challenges compared to monocultures, such as engineering ecological stability (preventing one genotype from taking over the population). Signaling between cells and populations is crucial to organize multiple populations. Clearly, expanding synthetic biology to polyculture systems will require better understanding and control of basic ecological principles, signaling systems, determinants



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IDR Team Summary 4 Designing communities of cells: how do we create communication and collaboration between cells to allow for specialization and division of labor? CHALLENGE SUMMARY Synthetic biology often focuses on engineering individual strains of microbial or other organisms to implement novel behaviors or metabolic functions in a cell autonomous manner. This approach, while powerful, appears to overlook one of the most basic aspects of biological systems: the ability of different species or cell types to interact with one another in order to generate behaviors that would be less feasible or impossible with a single genotype. In natural ecosystems, consortia of multiple species are com- monplace, and many, perhaps most, species are non-culturable in isolation, requiring signals or nutrients from other species to grow. Some metabolic functions may be more efficient when divided between strains, compared to when implemented in a single genotype. Thus, multi-genotype/multi-cell type systems provide an opportunity for specialization and optimization not possible with homogeneous cultures. Two examples of such optimization include the ability to compartmentalize different biosynthetic reactions in different cells that are chemically incompatible with each other, and the ability to create coherent structures that are dramatically larger than the size limit imposed by the dimensions of a cell. Nevertheless, polycultures present a number of unique challenges com- pared to monocultures, such as engineering ecological stability (preventing one genotype from taking over the population). Signaling between cells and populations is crucial to organize multiple populations. Clearly, expanding synthetic biology to polyculture systems will require better understanding and control of basic ecological principles, signaling systems, determinants 

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 SYnTHETIc BIoloGY of evolutionary stability, population synchronization, and the constraints inherent in complex metabolic pathways. In addition, problems inherent to all synthetic biology projects, such as uncertainty about the effects of a synthetic circuit on host growth rate, or uncertainty in biochemical param- eters, could be even more challenging in the polyculture context. Here we will discuss the key issues, opportunities, and challenges that we will face in efforts to make use of the “parallelism” inherent in polycul- ture systems. Key Questions • How can one engineer self-synchronizing populations, that behave coherently, despite cell-cell variability? • How do we achieve effective cell communication over multiple length and time scales. For example, what are strategies for cell communica- tion to nearest neighbors, over several cell layers and across an entire culture? How do we design cells to self-organize into defined three-dimensional structures (Example: organs). Temporally, how do we synchronize cell cycles or metabolic states? • What kinds of metabolic processes are best carried out through the cooperative action of distinct strains, rather than consolidated in a single cell? Are there advantages to spreading out metabolic functions even when the individual pathways involved are chemically compatible with each other? (Example: Chris Voigt’s research, www.voigtlab.ucsf.edu.) • What are optimal strategies for engineering ecological systems that maintain programmable population fractions? How can such a system be made ecologically and evolutionarily stable (i.e., robust to invasion by “cheaters”)? (Example: Alexander van Oudenaarden’s research, http://web. mit.edu/biophysics; and Wenying Shou’s COSMO, see reading reference below.) What applications might exist for controlled multi-population systems? • Trojan horses: How do we engineer organisms that can invade and flourish in natural populations while altering the behavior of the affected organism/ecosystem in a controlled and desirable manner? (Example: Bruce Hay’s work on making elements that invade and spread through mos- quito populations while making them resistant to malaria, www.its.caltech. edu/~haylab.)

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 IdR TEam SUmmaRY  Reading Basu S, Gerchman Y, Collins CH, Arnold FH, and Weiss R. A synthetic multicellular system for programmed pattern formation. nature 2005;434:1130-1134: http://www.nature. com/nature/journal/v434/n7037/full/nature03461.html. Accessed online 28 July 2009. Brenner K, Karig DK, Weiss R, and Arnold FH. Engineered bidirectional communication mediates a consensus in a microbial biofilm consortium. Proc natl acad Sci USa 2007;104;17300-17304: http://www.pnas.org/content/104/44/17300.full. Accessed online 28 July 2009. Chen CH, Huang H, Ward CM, Su JT, Schaeffer LV, Guo M, and Hay BA. A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila. Science 2007;316:597-600: http://www.sciencemag.org/cgi/content/full/316/5824/597. Accessed online 28 July 2009. Gore J, Youk H, and van Oudenaarden A. Snowdrift game dynamics and facultative cheating in yeast. nature 2009;459:253-256: http://www.nature.com/nature/journal/v459/ n7244/full/nature07921.html. Accessed online 28 July 2009. Shou W, Ram S, and Vilar JM. Synthetic cooperation in engineered yeast populations. Proc natl acad Sci USa 2007;104:1877-1882: http://www.pnas.org/content/104/6/1877. full. Accessed online 28 July 2009. IDR TEAM MEMBERS • Patrick Cirino, Pennsylvania State University • Cynthia Collins, Rensselaer Polytechnic Institute • James Glazier, Indiana University • Kerwyn Huang, Stanford University • Oleg Igoshin, Rice University • Michel Maharbiz, University of California, Berkeley • Robert Nerem, Georgia Institute of Technology • Ann Reid, American Society for Microbiology • Claudia Schmidt-Dannert, University of Minnesota • Samuel Sia, Columbia University • Mercedes Talley, W.M. Keck Foundation • Douglas Weibel, University of Wisconsin-Madison • Ron Weiss, Massachusetts Institute of Technology • Olga P. Kuchment, University of California, Santa Cruz

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0 SYnTHETIc BIoloGY IDR TEAM SUMMARY By olga P. kuchment, Graduate Science Writing Student, University of california, Santa cruz Fixing a broken spine would be a routine operation if we could per- suade bone, muscle, neurons, and other players to work together predictably and on cue. But though diverse communities of cells working together are common in nature, many mysteries remain about how they communicate constructively, and how best to work with them to encourage cellular com- munities to do things on command. An Interdisciplinary Research (IDR) team comprising scientists in biochemistry, chemistry, computer science, and chemical, biological, and electrical engineering arrived at the 2009 National Academies Keck Futures Initiative Conference on Synthetic Biology to consider how synthetic biol- ogy might best harness the power of cellular collaboration. They considered the following: Synthetic biology often focuses on putting into action novel behaviors in independent cells. But in biological systems, different species or cell types interact to generate behaviors that would be difficult or impossible otherwise. Many, perhaps most, species cannot survive in isolation, requiring signals or nutrients from other species to grow. The team discussed how research could best use such behaviors. They also discussed navigating the challenges unique to poly-cultures, in addition to the inherent challenges of all synthetic biology projects. The team members at first proposed seemingly opposite approaches to the task of designing and engineering communities of cells. Some wanted first to ask what useful systems, machines, organs, or instruments could be built. Others wanted to first consider the properties of interacting pieces: cell types from complex organisms, microbes, enzymes, and structural mol- ecules. Discussion ran the gamut of complexity and abstraction. The team developed a framework for tackling the problem, and then proposed specific ways that cell communities could be used to clean up waste, improve health, keep plants fed, and explore the Earth or other plan- ets in the next years and decades.

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 IdR TEam SUmmaRY  Why Study and Build Cell Communities? Cells do certain things well only in company: using hundreds of senses to navigate through life, differentiating from each other, and performing certain types of chemical reactions. The “company” sometimes includes multicellular organisms or organs. Or it can entail several strains of single cells working together, such as the yeast and bacteria that help humans digest food. Or it might consist of cells all of the same strain, such as bioluminescent ocean bacteria that produce light only when many cells congregate. Such communities hold frequent “town-hall meetings” to decide what to do, “talking” with each other and testing for a multitude of organisms and substances that a single cell could not detect. They emit light, repair parts, replicate themselves, or spawn off portions to do distinct tasks. Dif- ferent strains of bacteria are known to produce food to sustain each other, or work together to carry out multi-step chemical reactions. Working with these cellular companies could fill many gaps in under- standing biological systems, team members argued. For instance, it is still not clear how these groups of cells arise in nature and what they need to stay together. Seemingly fragile components form surprisingly robust communi- ties and emerge as symbionts. There are breaks in our knowledge about how such communities age, how they repair themselves, how their constituents interact to reach a common goal, and why one community flourishes while another flounders. What Kinds of Things Might Be Built? Communities of cells might help build tiny devices, organic irrigation systems, or textiles. They might help deliver antibiotics or help people grow hair. The group members split into three teams to discuss several practical applications in depth. Some team members considered the many applications of groups of different species of microbe living in close contact in seawater, in the soil, or elsewhere, known as bacterial consortia. In these consortia, the popula- tion of different types of cells changes cyclically over time, but most of the component organisms never disappear entirely. These consortia could be used as “bucket brigades” to synthesize biofu- els or to break down toxic waste, with different strains carrying out sequen- tial reaction steps. They could form better probiotics, restoring microbial

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 SYnTHETIc BIoloGY balance to the human gut and helping prevent obesity. Or, they could aid plant digestion, conferring drought resistance. Engineered consortia could serve as models of natural systems. They may also help educate the public about synthetic biology. School children could observe, for instance, how a consortium breaks down sugars at different temperatures and on different timescales. Another idea is a “land and pond rover” based on the somewhat bizarre life cycle of the well-studied slime mold dictyosthelium discoideum, Dicty for short. A Dicty’s individual cells arise from spores scattered in the soil. These cells eat soil bacteria until the bacteria become scarce. The Dicty cells then coalesce into a slug and crawl toward light, heat, and humidity. When the “slug” finds a suitable resting place, its cells change, it develops a stalk and a hat, and eventually produces spores. The team members predicted that during the next two years, Dicty- like slugs could be commissioned to search for arsenic or gold, then grow into their easily-visible mushroom-like form when they find the substances. During the next fifty years, researchers could engineer these cells to com- municate over larger distances, to detect a larger variety of materials and The life cycle of a Dicty. © Copyright, Mark Grimson and Larry Blanton, Electron Microscopy Laboratory, Department of Biological Sciences, Texas Tech University.

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 IdR TEam SUmmaRY  collect samples, and to spawn off slugs to test for various things, including living organisms. They could test for biodiversity, profiling the cells they find and collecting samples. The team considered building artificial organs. Engineered to be hypoallergenic, these could allow for a mass production of personalized organs. Their novel and broad functions could also be useful for medical testing. In a single artificial organ, one might screen potential drugs for both toxicity and permeability. For instance, group members proposed the idea of a “kliver,” a kidney- liver hybrid. An independent “kliver” could help filter bio-compounds out of drinking water. It could conceivably grow from an easily-shipped sample of a few cells that would regenerate when needed. One could also imagine how a riff on both organs’ detox capabilities and the liver’s ability to syn- thesize proteins could benefit a human body. How Would We Build Them? Having proposed the applications, the team considered anew whether what they envision would actually be possible. Potential building blocks might be mammalian and microbial cells and their products, such as slime, fibers, small molecules and proteins. The cells might be engineered to hold new electrical, mechanical, and chemical powers. For instance, their genetic circuits might allow the use of a laser or radio-waves to communicate with each other. The cells might be further changed and molded externally and internally, by engineering their environment and by synthetic parasites designed to accomplish specific cellular changes. When placed together, the building blocks might be designed to be- come even more aware of each other, to communicate even more effectively. They might be taught to recognize invaders. The different cell populations might be designed to fluctuate, with the different components feeding off each other’s byproducts and helping keep each others’ populations in check. Cells would be programmed to degrade their organs and DNA if they began to invade other organisms or the environment. A genetic “kill switch” aims to stop contamination or infection. The communities would be capable of things that singletons are not: They could generate force, specialize, rearrange, build large structures, spawn, and move as a collective. They would use these behaviors toward the overall goal.

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 SYnTHETIc BIoloGY Moving Forward The group decided that the field is ready to move forward, and that enough building blocks exist to begin work on the applications they sug- gested. Starting work would teach researchers about any additional re- quirements. The group members foresee building and exploring different architectures as an important challenge when moving toward their goals. They agreed to start work on simple proof-of-principle systems, but also to start moving from “toys to products”—creating commercial products to bring tangible benefits to society. They wondered what the first commercial product to employ communities of cells would be.