A priority paper for the societal and ethical aspects of synthetic biology

As synthetic biology develops into a promising science and engineering field, we need to have clear ideas and priorities regarding its safety, security, ethical and public dialogue implications. Based on an extensive literature search, interviews with scientists, social scientists, a 4 week long public e-forum, and consultation with several stakeholders from science, industry and civil society organisations, we compiled a list of priority topics regarding societal issues of synthetic biology for the years ahead. The points presented here are intended to encourage all stakeholders to engage in the prioritisation of these issues and to participate in a continuous dialogue, with the ultimate goal of providing a basis for a multi-stakeholder governance in synthetic biology. Here we show possible ways to solve the challenges to synthetic biology in the field of safety, security, ethics and the science–public interface.     

Freedom and Responsibility in Synthetic Genomics: The Synthetic Yeast Project

First introduced in 2011, the Synthetic Yeast Genome (Sc2.0) Project is a large international synthetic genomics project that will culminate in the first eukaryotic cell (Saccharomyces cerevisiae) with a fully synthetic genome. With collaborators from across the globe and from a range of institutions spanning from do-it-yourself biology (DIYbio) to commercial enterprises, it is important that all scientists working on this project are cognizant of the ethical and policy issues associated with this field of research and operate under a common set of principles. In this commentary, we survey the current ethics and regulatory landscape of synthetic biology and present the Sc2.0 Statement of Ethics and Governance to which all members of the project adhere. This statement focuses on four aspects of the Sc2.0 Project: societal benefit, intellectual property, safety, and self-governance. We propose that such project-level agreements are an important, valuable, and flexible model of self-regulation for similar global, large-scale synthetic biology projects in order to maximize the benefits and minimize potential harms.     

Interactive learning and action: realizing the promise of synthetic biology for global health

The emerging field of synthetic biology has the potential to improve global health. For example, synthetic biology could contribute to efforts at vaccine development in a context in which vaccines and immunization have been identified by the international community as being crucial to international development efforts and, in particular, the millennium development goals. However, past experience with innovations shows that realizing a technology’s potential can be difficult and complex. To achieve better societal embedding of synthetic biology and to make sure it reaches its potential, science and technology development should be made more inclusive and interactive. Responsible research and innovation is based on the premise that a broad range of stakeholders with different views, needs and ideas should have a voice in the technological development and deployment process. The interactive learning and action (ILA) approach has been developed as a methodology to bring societal stakeholders into a science and technology development process. This paper proposes an ILA in five phases for an international effort, with national case studies, to develop socially robust applications of synthetic biology for global health, based on the example of vaccine development. The design is based on results of a recently initiated ILA project on synthetic biology; results from other interactive initiatives described in the literature; and examples of possible applications of synthetic biology for global health that are currently being developed.     

Social and ethical checkpoints for bottom-up synthetic biology, or protocells

An alternative to creating novel organisms through the traditional “top-down” approach to synthetic biology involves creating them from the “bottom up” by assembling them from non-living components; the products of this approach are called “protocells.” In this paper we describe how bottom-up and top-down synthetic biology differ, review the current state of protocell research and development, and examine the unique ethical, social, and regulatory issues raised by bottom-up synthetic biology. Protocells have not yet been developed, but many expect this to happen within the next five to ten years. Accordingly, we identify six key checkpoints in protocell development at which particular attention should be given to specific ethical, social and regulatory issues concerning bottom-up synthetic biology, and make ten recommendations for responsible protocell science that are tied to the achievement of these checkpoints.     

Shaping the science–industry–policy interface in synthetic biology

Current advances in the emerging field of synthetic biology and the improvements in key technologies promise great impacts, not only on future scientific development, but also on the economy. In this paper we will adopt the triple helix concept for analyzing the early stages of a new field of science and innovation, namely synthetic biology. Synthetic biology is based on the creation and assembly of parts in order to create new and more complex structures and functions. These features of synthetic biology raise questions related to standardization and intellectual property, but also to security and public perception issues that go beyond the classical biotechnology discussions. These issues concern all involved actors in the synthetic biology field and affect the interrelationship between science, industry and policy. Based on the results of the recently finished EU FP-6 funded project TESSY (http://www.tessy-europe.de), the article analyzes these issues. Additionally, it illustrates the setting of clear framework conditions for synthetic biology research and development and the identification and definition of common goals for the future development of the field which will be needed for efficient science–industry–policy interaction. It was shown that it will be crucial to develop approaches that consider the needs of science and industry, on the one hand, and comply with the expectations of society, on the other hand. As synthetic biology is a global activity, the involvement of national decision-makers in international initiatives will further stimulate the development of the field.     

Intellectual property rights in synthetic biology: an anti-thesis to open access to research?

Synthetic Biology is a surging area of contemporary life science based research that is rapidly evolving by virtue of its multidisciplinary composition and applications. Biology never before has seen such a gold rush and demonstrated potential for knowledge based economy. The area of synthetic biology is in a nascent and tender stage, however issues pertaining to open access to research versus the monopolistic intellectual property regime (specifically patents) have already started raising concerns in the emerging bio-based economy. The present study critically analyses the comparative benefits as well as lacunas of open access to research and patenting issues. It is noteworthy that both approaches for synthetic biology development have to co-exist in order to optimally benefit the society at large.     

合成生物学伦理、法律与社会问题探讨

合成生物学是以基因组学、系统生物学知识和分子生物学技术为基础,综合了科学与工程的一门新兴交叉学科。它使生命科学和生物技术研发进入了以人工设计、合成自然界中原本不曾出现的人造生命体系,以及对这些人工体系进行体内、体外优化,或利用这些人造生命体系研究自然生命规律为目标的新时代。然而,合成生物学研究在迅速发展、表现出巨大潜力和应用前景的同时,也引发了社会各界对相关社会、伦理、安全,以及知识产权等问题的重视与讨论。就世界各国针对合成生命对传统意义上生命概念的挑战、合成生物学产品存在的潜在风险危害、合成生物学研究的风险评估与监管等问题进行回顾综述和相关探讨。     

A day of systems and synthetic biology for non‐experts

From understanding ageing to the creation of artificial membrane‐bounded ‘organisms’, systems biology and synthetic biology are seen as the latest revolutions in the life sciences. They certainly represent a major change of gear, but paradigm shifts? This is open to debate, to say the least. For scientists they open up exciting ways of studying living systems, of formulating the ‘laws of life’, and the relationship between the origin of life, evolution and artificial biological systems. However, the ethical and societal considerations are probably indistinguishable from those of human genetics and genetically modified organisms. There are some tangible developments just around the corner for society, and as ever, our ability to understand the consequences of, and manage, our own progress lags far behind our technological abilities. Furthermore our educational systems are doing a bad job of preparing the next generation of scientists and non‐scientists.     

A primer to ‘bio-objects’: new challenges at the interface of science, technology and society

Biotechnological and life science innovations do not only lead to immense progress in diverse fields of natural science and technical research and thereby drive economic development, they also fundamentally affect the relationship between nature, technology and society. Taken this seriously, the ethical and societal assessment of emerging biotechnologies as for example synthetic biology is challenged not only to constrain on questions of biosafety and biosecurity but also to face the societal questions within the different fields as an interface problem of science and society. In order to map this vague and stirring field, we propose the concept of bio-objects to explore the reciprocal interaction at the interface of science and society serious as well to have the opportunity to detect possible junctions of societal discontent and unease before their appearance.     

‘Bio-nano interactions: new tools,insights and impacts’: summary of the Royal Society discussion meeting

Bio-nano interactions can be defined as the study of interactions between nanoscale entities and biological systems such as, but not limited to, peptides, proteins, lipids, DNA and other biomolecules, cells and cellular receptors and organisms including humans. Studying bio-nano interactions is particularly useful for understanding engineered materials that have at least one dimension in the nanoscale. Such materials may consist of discrete particles or nanostructured surfaces. Much of biology functions at the nanoscale; therefore, our ability to manipulate materials such that they are taken up at the nanoscale, and engage biological machinery in a designed and purposeful manner, opens new vistas for more efficient diagnostics, therapeutics (treatments) and tissue regeneration, so-called nanomedicine. Additionally, this ability of nanomaterials to interact with and be taken up by cells allows nanomaterials to be used as probes and tools to advance our understanding of cellular functioning. Yet, as a new technology, assessment of the safety of nanomaterials, and the applicability of existing regulatory frameworks for nanomaterials must be investigated in parallel with development of novel applications. The Royal Society meeting ‘Bio-nano interactions: new tools, insights and impacts'' provided an important platform for open dialogue on the current state of knowledge on these issues, bringing together scientists, industry, regulatory and legal experts to concretize existing discourse in science law and policy. This paper summarizes these discussions and the insights that emerged.     

Aequorin-expressing yeast emits light under electric control

In this study, we show the use of direct external electrical stimulation of a jellyfish luminescent calcium-activated protein, aequorin, expressed in a transgenic yeast strain. Yeast cultures were electrically stimulated through two electrodes coupled to a standard power generator. Even low (1.5 V) electric pulses triggered a rapid light peak and serial light pulses were obtained after electric pulses were applied periodically, suggesting that the system is re-enacted after a short refraction time. These results open up a new scenario, in the very interphase between synthetic biology and cybernetics, in which complex cellular behavior might be subjected to electrical control.     

Knowledge-making distinctions in synthetic biology

Synthetic biology is an increasingly high-profile area of research that can be understood as encompassing three broad approaches towards the synthesis of living systems: DNA-based device construction, genome-driven cell engineering and protocell creation. Each approach is characterized by different aims, methods and constructs, in addition to a range of positions on intellectual property and regulatory regimes. We identify subtle but important differences between the schools in relation to their treatments of genetic determinism, cellular context and complexity. These distinctions tie into two broader issues that define synthetic biology: the relationships between biology and engineering, and between synthesis and analysis. These themes also illuminate synthetic biology's connections to genetic and other forms of biological engineering, as well as to systems biology. We suggest that all these knowledge-making distinctions in synthetic biology raise fundamental questions about the nature of biological investigation and its relationship to the construction of biological components and systems.     

The synthetic biology puzzle: a qualitative study on public reflections towards a governance framework

Synthetic biology is currently one of the most debated emerging biotechnologies. The societal assessment of this technology is primarily based on contributions by scientists and policy makers, who focus mainly on technical challenges and possible risks. While public dialogue is given, it is yet rather limited. This study explores public debates concerning synthetic biology based on a focus group study with citizens from Austria and Germany and contextualises the analysed public views with content from policy reports and previous empirical studies on public engagement. The findings suggest that discussants favoured a gradual implementation process of synthetic biology, which is receptive to questions about the distribution of possible benefits. The discussed topics correspond in many ways with content from policy reports and former investigations, yet the emphasis of the discussions was different for many aspects.     

Do-it-yourself biology: challenges and promises for an open science and technology movement

The do-it-yourself biology (DIYbio) community is emerging as a movement that fosters open access to resources permitting modern molecular biology, and synthetic biology among others. It promises in particular to be a source of cheaper and simpler solutions for environmental monitoring, personal diagnostic and the use of biomaterials. The successful growth of a global community of DIYbio practitioners will depend largely on enabling safe access to state-of-the-art molecular biology tools and resources. In this paper we analyze the rise of DIYbio, its community, its material resources and its applications. We look at the current projects developed for the international genetically engineered machine competition in order to get a sense of what amateur biologists can potentially create in their community laboratories over the coming years. We also show why and how the DIYbio community, in the context of a global governance development, is putting in place a safety/ethical framework for guarantying the pursuit of its activity. And finally we argue that the global spread of DIY biology potentially reconfigures and opens up access to biological information and laboratory equipment and that, therefore, it can foster new practices and transversal collaborations between professional scientists and amateurs.     

合成生物学及其在生物技术中的应用进展

合成生物学是一门21世纪生物学的新兴学科,它着眼生物科学与工程科学的结合,把生物系统当作工程系统"从下往上"进行处理,由"单元"(unit)到"部件"(device)再到"系统"(system)来设计,修改和组装细胞构件及生物系统.合成生物学是分子和细胞生物学、进化系统学、生物化学、信息学、数学、计算机和工程等多学科交叉的产物.目前研究应用包括两个主要方面:一是通过对现有的、天然存在的生物系统进行重新设计和改造,修改已存在的生物系统,使该系统增添新的功能.二是通过设计和构建新的生物零件、组件和系统,创造自然界中尚不存在的人工生命系统.合成生物学作为一门建立在基因组方法之上的学科,主要强调对创造人工生命形态的计算生物学与实验生物学的协同整合.必须强调的是,用来构建生命系统新结构、产生新功能所使用的组件单元既可以是基因、核酸等生物组件,也可以是化学的、机械的和物理的元件.本文跟踪合成生物学研究及应用,对其在DNA水平编程、分子修饰、代谢途径、调控网络和工业生物技术等方面的进展进行综述.     

Programmable control of bacterial gene expression with the combined CRISPR and antisense RNA system

A central goal of synthetic biology is to implement diverse cellular functions by predictably controlling gene expression. Though research has focused more on protein regulators than RNA regulators, recent advances in our understanding of RNA folding and functions have motivated the use of RNA regulators. RNA regulators provide an advantage because they are easier to design and engineer than protein regulators, potentially have a lower burden on the cell and are highly orthogonal. Here, we combine the CRISPR system from Streptococcus pyogenes and synthetic antisense RNAs (asRNAs) in Escherichia coli strains to repress or derepress a target gene in a programmable manner. Specifically, we demonstrate for the first time that the gene target repressed by the CRISPR system can be derepressed by expressing an asRNA that sequesters a small guide RNA (sgRNA). Furthermore, we demonstrate that tunable levels of derepression can be achieved (up to 95%) by designing asRNAs that target different regions of a sgRNA and by altering the hybridization free energy of the sgRNA–asRNA complex. This new system, which we call the combined CRISPR and asRNA system, can be used to reversibly repress or derepress multiple target genes simultaneously, allowing for rational reprogramming of cellular functions.     

Microbial interventions are an easier alternative to engineer higher organisms

Advances in synthetic biology have made microbes easier to engineer than ever before. However, synthetic biology in animals and plants has lagged behind. Since it is now known that the phenotype of higher organisms depends largely on their microbiota, we propose that this is an easier route to achieving synthetic biology applications in these organisms.

A transition from reading to writing biology has blurred the lines between basic science and engineering creating the field of synthetic biology. With an ever‐expanding genetic toolbox, we now manipulate natural biological systems to optimize our anthropocentric activities. From the synthesis of complex aromatic compounds, to the production of safer vaccines, a problem identified may find its solution lying in the metabolism of a single cell. Initially, synthetic biology was largely focused on the production of such commodities at the industrial scale, not only to maximize profitability, but also to minimize energy and resource consumption. Consequently, this paradigm shift has come to alter the notion of a factory by many orders of magnitude and to create a new bridge between the built and natural world, as we employ nature’s evolutionary machinery to address our modern endeavours.Growth of the genetic toolbox and maturation of synthetic biology as a field has led to speculation about increasingly ambitious applications of writing biology with implications beyond biosynthesis. To date, most applications have been developed using microbes because they are less complex, more well understood and easier to manipulate. Single‐celled organisms can be optimized for production of complicated organic molecules; however, other exploits of genetic engineering will target more ambitious feats and thus require engineering of more than a large monoculture of microbes. Applications of synthetic biology outside of the bioreactor can address such issues as health and longevity, challenges in industrial agriculture and farming, the degradation of natural habitats and the reclamation of limited natural resources.Scope and scale of these applications provide obvious obstacles to the development of effective biotechnologies, but a more immediate limitation to realizing these technologies is the relative lack of genetic tools and insights which would allow the tinkering and rewiring of more complex organisms such as animals and plants. However, because of the natural intimate interactions between higher eukaryotes and microbes and the effect of these on phenotype, it is our vision that a faster, more tractable route to the engineering animal and plant phenotypes is via engineering their microbiomes.     

One-pot DNA construction for synthetic biology: the Modular Overlap-Directed Assembly with Linkers (MODAL) strategy

Overlap-directed DNA assembly methods allow multiple DNA parts to be assembled together in one reaction. These methods, which rely on sequence homology between the ends of DNA parts, have become widely adopted in synthetic biology, despite being incompatible with a key principle of engineering: modularity. To answer this, we present MODAL: a Modular Overlap-Directed Assembly with Linkers strategy that brings modularity to overlap-directed methods, allowing assembly of an initial set of DNA parts into a variety of arrangements in one-pot reactions. MODAL is accompanied by a custom software tool that designs overlap linkers to guide assembly, allowing parts to be assembled in any specified order and orientation. The in silico design of synthetic orthogonal overlapping junctions allows for much greater efficiency in DNA assembly for a variety of different methods compared with using non-designed sequence. In tests with three different assembly technologies, the MODAL strategy gives assembly of both yeast and bacterial plasmids, composed of up to five DNA parts in the kilobase range with efficiencies of between 75 and 100%. It also seamlessly allows mutagenesis to be performed on any specified DNA parts during the process, allowing the one-step creation of construct libraries valuable for synthetic biology applications.     

Programming living sensors for environment,health and biomanufacturing

Synthetic biology offers new tools and capabilities of engineering cells with desired functions for example as new biosensing platforms leveraging engineered microbes. In the last two decades, bacterial cells have been programmed to sense and respond to various input cues for versatile purposes including environmental monitoring, disease diagnosis and adaptive biomanufacturing. Despite demonstrated proof-of-concept success in the laboratory, the real-world applications of microbial sensors have been restricted due to certain technical and societal limitations. Yet, most limitations can be addressed by new technological developments in synthetic biology such as circuit design, biocontainment and machine learning. Here, we summarize the latest advances in synthetic biology and discuss how they could accelerate the development, enhance the performance and address the present limitations of microbial sensors to facilitate their use in the field. We view that programmable living sensors are promising sensing platforms to achieve sustainable, affordable and easy-to-use on-site detection in diverse settings.