Nature Reviews Molecular Cell Biology | AOP, published online 12 March 2014; doi:10.1038/nrm3767 PERSPECTIVES computer-aided-design (CAD), safety sys- VIEWPOINT tems, integrating models, genome editing and accelerated evolution. Synthetic biology Realizing the potential of synthetic is less like highly modular (or ‘switch-like’) electrical engineering and computer science biology and more like civil and mechanical engineer- ing in its use of optimization of modelling of whole system-level stresses and traffic flow. George M. Church, Michael B. Elowitz, Christina D. Smolke, Christopher A. Voigt and Ron Weiss Michael B. Elowitz. At the most general level, synthetic biology expands the subject Abstract | Synthetic biology, despite still being in its infancy, is increasingly matter of biology from the (already enor- providing valuable information for applications in the clinic, the biotechnology mous) space of existing species and cellular industry and in basic molecular research. Both its unique potential and the systems that have evolved to the even larger challenges it presents have brought together the expertise of an eclectic group of space of non-natural, but feasible, species scientists, from cell biologists to engineers. In this Viewpoint article, five experts and systems. Although we started with circuits to carry out the simplest kinds of discuss their views on the future of synthetic biology, on its main achievements in dynamic behaviours, synthetic approaches basic and applied science, and on the bioethical issues that are associated with the can be applied broadly to all types of bio­ design of new biological systems. logical functions from metabolism to multi­ cellular development. Synthetic biology allows us to figure out what types of genetic An increasing number of publications For instance, insight gained from systems circuit designs are capable of implement- and institutions are dedicated to biology investigations of natural processes ing different cellular behaviours, and what synthetic biology. From the initial focus on the leads to improved designs of synthetic sys- trade-offs exist between different designs, by design of synthetic genetic circuits, how has tems, and the creation of small artificial building and testing these circuits in living the field expanded and evolved? And how networks helps to analyse hypo­theses on the cells. We can thus use forward design instead does synthetic biology today relate to other function of natural ones. Computational of (or rather in addition to) more traditional disciplines such as systems biology and modelling tools have become essential for reverse engineering approaches, effectively mathematical modelling? the design of artificial networks and are also ‘building to understand’34. Beyond the many finding application in other areas of biology important immediate applications, I think it Ron Weiss. Synthetic biology was seeded that require advanced observation and corre- is this transformation in the way of thinking when bacterial cells were programmed with lation. Finally, synthetic biology researchers about, and working with, biological systems basic circuits — a ‘toggle switch’, an oscillator are developing an ever-growing appreciation that stimulates the imagination of so many and cell–cell communicatio­n. The focus has for biological complexity, which requires people and explains the rapid growth of evolved from small transcriptional regula- interdisciplinary research, new circuit design the field. tory networks into complex multicellular principles and programming paradigms to The fundamental questions that are at the systems that are embedded in a variety of overcome barriers such as metabolic load, heart of synthetic biology overlap consider- organisms such as yeast, mammalian cells crosstalk, resource sharing and gene expres- ably with systems biology, as both fields and plants, using non-transcriptional logic, sion noise (and sometimes actually utilize seek to understand principles of genetic including microRNAs, protein phosphoryla- these barriers to create more robust systems). circuit design, and I expect that these fields tion and DNA editing. Detailed and precise will cross-stimulate each other and become characterization and predictable part compo- the creation of small artificial increasingly difficult to disentangle in sition have become essential for the efficient the future. creation of sophisticated multi-input logic networks helps to analyse functions, composite states and analogue hypotheses on the function Christina D. Smolke. Both synthetic circuit­s. This has led to varied and improved of natural ones. biolog­y and systems biology represent interfaces for cellular sensors and actuators fundamental shifts in approaches from the along with advancements such as subcellular fields they grew out of. Synthetic biology compartmentalization of logic operations. George M. Church. In my view, synthetic emphasizes engineering principles and Synthetic biology complements systems biology was never focused on ‘genetic cir- methodology in designing, constructing biology: the former is based on forward engi- cuits’, but rather on biology rapidly matur- and characterizing biological systems from neering and the latter on reverse engineering. ing as an engineering discipline, including traditional genetic engineering research; NATURE REVIEWS | MOLECULAR CELL BIOLOGY ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved PERSPECTIVES systems biology represents a shift in studying Mathematical modelling is a tool that writing genomes progresses, the new chal- integrated components from the more tra- enables quantitative predictions or the lenges lie in system design and selection ditional reductionist approach taken in bio- understanding of data. It is applicable to for new functions, and efficient replication logical research. Computational modelling is both areas, as are other tools such as mass and production. Additional challenges an important tool in both fields but used to spectroscopy to measure protein levels arise from how to anticipate, simulate and achieve different objectives. In systems biol- or transfection methods to move DNA improve highly diverse or personalized ogy, computational models are used to make into cells. technologies and their impact on comple­x predictions about the behaviour of a system, physiological and ecological system­s9 whereas modelling is used to direct design in (discusse­d below). synthetic biology. Synthetic biology is an Synthetic biology has expanded and engineering discipline — there is M.B.E. We have come a long way as a field: evolved substantially from its initial rather a desire to build things that do we have built several generations of oscil- narrow focus to appreciate and use more lators35-38 and genetic switches4,39 that work fully the diversity of mechanisms found in not yet exist. with diverse cellular components and natural biological systems. For example, regulatory mechanisms, and which interact early work focused largely on transcription with endogenous gene circuits40. Complex factor-based regulatory networks designed What have been the main achievements metabolic pathways have been engineered to exhibit dynamic behaviour (such as of synthetic biology so far in basic to produce useful products, and signallin­g oscillator and ‘toggle switch’ behaviours)1, research, and what are the challenges to be met? pathways have been rewired to alter their whereas designs now routinely incorporate dynamic behaviours in predictable ways. other levels of regulation, including RNA- R.W. Over the past decade or so, synthetic However, synthetic biology remains based regulators, post-translational modifi- biology has helped to transform the bio- extremely primitive owing both to technical cations and molecular scaffolds2. As another logical sciences into a true engineering dis- challenges and, even more, to fundamen- example, mutation and evolution were cipline. Notable achievements include the tal inadequacies in our understanding of widely viewed as an obstacle to system per- creation of a registry of composable parts, biologica­l circuit design. formance and something to be minimized, revolutionary advances in gene synthesis On the technical side, synthesizing whereas newer approaches are beginning technologies and faster and more efficient genetic circuits and transferring them to exploit this unique aspect of biological modular DNA assembly methods. By into cells remains far too slow and idio­ systems and to design for evolution and integrating these rapidly developing tech- syncratic, especially in animal cells. How- adaptation3. nologies with computational modelling ever, several new methods, such as those approaches, a synthetic biologist can now based on the CRISPR system, are extremely Christopher A. Voigt. The early ambition­s engineer biological systems top-down in a encouraging. in the field were around the creation of (somewhat) predictable manner. On the fundamental side, we still have cells that could go through a series of What is critically lacking, however, with little understanding of how circuit designs programmed tasks; for example, Adam respect to mammalian synthetic biology can function effectively in cells and tissues Arkin envisioned an engineered bacterium (an area that my laboratory is currently and much to learn from natural examples. that could move through the human body most focused on), are ‘real-world’ applica- In particular, one of the greatest challenges