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.     

Synthetic biology as a source of global health innovation

Synthetic biology has the potential to contribute breakthrough innovations to the pursuit of new global health solutions. Wishing to harness the emerging tools of synthetic biology for the goals of global health, in 2011 the Bill & Melinda Gates Foundation put out a call for grant applications to “Apply Synthetic Biology to Global Health Challenges” under its “Grand Challenges Explorations” program. A highly diverse pool of over 700 applications was received. Proposed applications of synthetic biology to global health needs included interventions such as therapeutics, vaccines, and diagnostics, as well as strategies for biomanufacturing, and the design of tools and platforms that could further global health research.     

Building momentum for systems and synthetic biology in India

Biological systems are inherently noisy. Predicting the outcome of a perturbation is extremely challenging. Traditional reductionist approach of describing properties of parts, vis-a-vis higher level behaviour has led to enormous understanding of fundamental molecular level biology. This approach typically consists of converting genes into junk (knock-down) and garbage (knock-out) and observe how a system responds. To enable broader understanding of biological dynamics, an integrated computational and experimental strategy was formally proposed in mid 1990s leading to the re-emergence of Systems Biology. However, soon it became clear that natural systems were far more complex than expected. A new strategy to address biological complexity was proposed at MIT (Massachusetts Institute of Technology) in June 2004, when the first meeting of synthetic biology was held. Though the term ‘synthetic biology’ was proposed during 1970s (Szybalski in Control of gene expression, Plenum Press, New York, 1974), the usage of the original concept found an experimental proof in 2000 with the demonstration of a three-gene circuit called repressilator (Elowitz and Leibler in Nature, 403:335–338, 2000). This encouraged people to think of forward engineering biology from a set of well described parts.     

The art of trans-boundary governance: the case of synthetic biology

Synthetic biology raises few, if any, social concerns that are distinctively new. Similar to many other convergent technologies, synthetic biology’s interface across various scientific communities and interests groups presents an incessant challenge to political and conceptual boundaries. However, the scale and intensity of these interfaces seem to necessitate a reflection over how corresponding governance capacities can be developed. This paper argues that, in addition to existing regulatory approaches, such capacities may be gained through the art of trans-boundary governance, which is not only attentive to the crossing and erosion of particular boundaries but also adept in keeping up with the dynamics among evolving networks of actors.     

Evolving cell models for systems and synthetic biology

This paper proposes a new methodology for the automated design of cell models for systems and synthetic biology. Our modelling framework is based on P systems, a discrete, stochastic and modular formal modelling language. The automated design of biological models comprising the optimization of the model structure and its stochastic kinetic constants is performed using an evolutionary algorithm. The evolutionary algorithm evolves model structures by combining different modules taken from a predefined module library and then it fine-tunes the associated stochastic kinetic constants. We investigate four alternative objective functions for the fitness calculation within the evolutionary algorithm: (1) equally weighted sum method, (2) normalization method, (3) randomly weighted sum method, and (4) equally weighted product method. The effectiveness of the methodology is tested on four case studies of increasing complexity including negative and positive autoregulation as well as two gene networks implementing a pulse generator and a bandwidth detector. We provide a systematic analysis of the evolutionary algorithm’s results as well as of the resulting evolved cell models.     

Design-driven, multi-use research agendas to enable applied synthetic biology for global health

Many of the synthetic biological devices, pathways and systems that can be engineered are multi-use, in the sense that they could be used both for commercially-important applications and to help meet global health needs. The on-going development of models and simulation tools for assembling component parts into functionally-complex devices and systems will enable successful engineering with much less trial-and-error experimentation and laboratory infrastructure. As illustrations, I draw upon recent examples from my own work and the broader Keasling research group at the University of California Berkeley and the Joint BioEnergy Institute, of which I was formerly a part. By combining multi-use synthetic biology research agendas with advanced computer-aided design tool creation, it may be possible to more rapidly engineer safe and effective synthetic biology technologies that help address a wide range of global health problems.     

Co-evolution of physical and social sciences in synthetic biology

Emerging technologies research often covers various perspectives in disciplines and research areas ranging from hard sciences, engineering, policymaking, and sociology. However, the interrelationship between these different disciplinary domains, particularly the physical and social sciences, often occurs many years after a technology has matured and moved towards commercialization. Synthetic biology may serve an exception to this idea, where, since 2000, the physical and the social sciences communities have increasingly framed their research in response to various perspectives in biological engineering, risk assessment needs, governance challenges, and the social implications that the technology may incur. This paper reviews a broad collection of synthetic biology literature from 2000–2016, and demonstrates how the co-development of physical and social science communities has grown throughout synthetic biology’s earliest stages of development. Further, this paper indicates that future co-development of synthetic biology scholarship will assist with significant challenges of the technology’s risk assessment, governance, and public engagement needs, where an interdisciplinary approach is necessary to foster sustainable, risk-informed, and societally beneficial technological advances moving forward.     

Systems and synthetic biology approaches to cell division

Cells proliferate by division into similar daughter cells, a process that lies at the heart of cell biology. Extensive research on cell division has led to the identification of the many components and control elements of the molecular machinery underlying cellular division. Here we provide a brief review of prokaryotic and eukaryotic cell division and emphasize how new approaches such as systems and synthetic biology can provide valuable new insight.     

Synthetic biology, patenting, health and global justice

The legal and moral issues that synthetic biology (SB) and its medical applications are likely to raise with regard to intellectual property (IP) and patenting are best approached through the lens of a theoretical framework highlighting the “co-construction” or “co-evolution” of patent law and technology. The current situation is characterized by a major contest between the so-called IP frame and the access-to-knowledge frame. In SB this contest is found in the contrasting approaches of Craig Venter’s chassis school and the BioBricks school. The stakes in this contest are high as issues of global health and global justice are implied. Patents are not simply to be seen as neutral incentives, but must also be judged on their effects for access to essential medicines, a more balanced pattern of innovation and the widest possible social participation in innovative activity. We need moral imagination to design new institutional systems and new ways of practising SB that meet the new demands of global justice.     

Engineering chromatin states: Chemical and synthetic biology approaches to investigate histone modification function

Patterns of histone post-translational modifications (PTMs) and DNA modifications establish a landscape of chromatin states with regulatory impact on gene expression, cell differentiation and development. These diverse modifications are read out by effector protein complexes, which ultimately determine their functional outcome by modulating the activity state of underlying genes. From genome-wide studies employing high-throughput ChIP-Seq methods as well as proteomic mass spectrometry studies, a large number of PTMs are known and their coexistence patterns and associations with genomic regions have been mapped in a large number of different cell types. Conversely, the molecular interplay between chromatin effector proteins and modified chromatin regions as well as their resulting biological output is less well understood on a molecular level. Within the last decade a host of chemical approaches has been developed with the goal to produce synthetic chromatin with a defined arrangement of PTMs. These methods now permit systematic functional studies of individual histone and DNA modifications, and additionally provide a discovery platform to identify further interacting nuclear proteins. Complementary chemical- and synthetic-biology methods have emerged to directly observe and modulate the modification landscape in living cells and to readily probe the effect of altered PTM patterns on biological processes. Herein, we review current methodologies allowing chemical and synthetic biological engineering of distinct chromatin states in vitro and in vivo with the aim of obtaining a molecular understanding of histone and DNA modification function. This article is part of a Special Issue entitled: Molecular mechanisms of histone modification function.     

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.     

研究生细胞分子生物学教学探索

为了培养具有科研思雏、德才兼备的研究生,在细胞分子生物学的教学中,从与人类生活及疾病相关的问题入手,以近年诺贝尔生理学或医学奖获奖相关工作为主线,要求学生阅读指定文献并自己查阅相关文献,采用启发式或讨论式等多种方式开展教学,让学生在学习过程中经历了文献查阅、综述撰写、会议报告的制作等过程,使学生掌握了基础理论,增强了发现问题的意识,培养了解决问题的能力,提高了学术交流的技能。从而使学生的道德修养和综合素质有了显著提高,为今后从事科学研究工作奠定了良好的基础。     

Development of GRAS strains for nutraceutical production using systems and synthetic biology approaches: advances and prospects

Nutraceuticals are food substances with medical and health benefits for humans. Limited by complicated procedures, high cost, low yield, insufficient raw materials, resource waste, and environment pollution, chemical synthesis and extraction are being replaced by microbial synthesis of nutraceuticals. Many microbial strains that are generally regarded as safe (GRAS) have been identified and developed for the synthesis of nutraceuticals, and significant nutraceutical production by these strains has been achieved. In this review, we systematically summarize recent advances in nutraceutical research in terms of physiological effects on health, potential applications, drawbacks of traditional production processes, characteristics of production strains, and progress in microbial fermentation. Recent advances in systems and synthetic biology techniques have enabled comprehensive understanding of GRAS strains and its wider applications. Thus, these microbial strains are promising cell factories for the commercial production of nutraceuticals.     

Creating parts that allow for rational design: Synthetic biology and the problem of context-sensitivity

The parts-based engineering approach in synthetic biology aims to create pre-characterised biological parts that can be used for the rational design of novel functional systems. Given the context-sensitivity of biological entities, a key question synthetic biologists have to address is what properties these parts should have so that they give a predictable output even when they are used in different contexts. In the first part of this paper I will analyse some of the answers that synthetic biologists have given to this question and claim that the focus of these answers on parts and their properties does not allow us to tackle the problem of context-sensitivity. In the second part of the paper, I will argue that we might have to abandon the notions of parts and their properties in order to understand how independence in biology could be achieved. Using Robert Cummins’ account of functional analysis, I will then develop the notion of a capacity and its condition space and show how these notions can help to tackle the problem of context-sensitivity in biology.     

Consensus statement understanding health and malnutrition through a systems approach: the ENOUGH program for early life

Nutrition research, like most biomedical disciplines, adopted and often uses experimental approaches based on Beadle and Tatum’s one gene—one polypeptide hypothesis, thereby reducing biological processes to single reactions or pathways. Systems thinking is needed to understand the complexity of health and disease processes requiring measurements of physiological processes, as well as environmental and social factors, which may alter the expression of genetic information. Analysis of physiological processes with omics technologies to assess systems’ responses has only become available over the past decade and remains costly. Studies of environmental and social conditions known to alter health are often not connected to biomedical research. While these facts are widely accepted, developing and conducting comprehensive research programs for health are often beyond financial and human resources of single research groups. We propose a new research program on essential nutrients for optimal underpinning of growth and health (ENOUGH) that will use systems approaches with more comprehensive measurements and biostatistical analysis of the many biological and environmental factors that influence undernutrition. Creating a knowledge base for nutrition and health is a necessary first step toward developing solutions targeted to different populations in diverse social and physical environments for the two billion undernourished people in developed and developing economies.     

Modelling and simulation techniques for membrane biology

One of the most important aspects of Computational Cell Biology is the understanding of the complicated dynamical processes that take place on plasma membranes. These processes are often so complicated that purely temporal models cannot always adequately capture the dynamics. On the other hand, spatial models can have large computational overheads. In this article, we review some of these issues with respect to chemistry, membrane microdomains and anomalous diffusion and discuss how to select appropriate modelling and simulation paradigms based on some or all the following aspects: discrete, continuous, stochastic, delayed and complex spatial processes.     

Priorities for mental health research in Europe: A survey among national stakeholders' associations within the ROAMER project

Within the ROAMER project, funded by the European Commission, a survey was conducted with national associations/organizations of psychiatrists, other mental health professionals, users and/or carers, and psychiatric trainees in the 27 countries of the European Union, aiming to explore their views about priorities for mental health research in Europe. One hundred and eight associations/organizations returned the questionnaire. The five most frequently selected research priorities were early detection and management of mental disorders, quality of mental health services, prevention of mental disorders, rehabilitation and social inclusion, and new medications for mental disorders. All these areas, except the last one, were among the top ten research priorities according to all categories of stakeholders, along with stigma and discrimination. These results seem to support the recent argument that some rebalancing in favor of psychosocial and health service studies may be needed in psychiatric research.