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Beyond Containment

Synberc seeks to address biosafety risks before rather than after problems arise. “Beyond Containment” projects deal with cases where accidental release may be anticipated and/or where physical containment of the engineered biological system is not practical to begin with (e.g., in an open pond, or within a human patient).  Projects in risk management are designed to complement specific technical work on designing safer microbial chassis. Aspects of these projects are being conducted in partnership with external partners such as the Woodrow Wilson Center, and the J Craig Venter Institute, among others.

The Environmental Effects of Synthetic Biology: Design, Testing and Demonstration for Biosafety
Projects in Ken Oye’s group  at MIT strive to enable dialog between researchers, regulators and policy makers to proactively identify opportunities for synthetic biology-enabled research that could improve best available technologies for understanding, and mitigating or managing risks associated with environmental deployment. This project is integrated with technical work on safer chassis by Arkin, Church and Knight labs and on cyanobacteria by the Silver lab, and is being conducted in partnership with the Woodrow Wilson Center and US EPA.

In January 2011, Ken Oye and David Rejeski conducted a joint Synberc-Wilson Center exercise with US regulators, South Asian governmental representatives, nongovernmental organizations and technologists at Wilson Center in DC.  Exercises examined the Lumin arsenic biosensor in E.coli and rE.coli chassis as examples of ready-to-roll synthetic biology applications to seed pro-active risk assessment and management. In June 2011, Ken Oye’s group supported a Wilson Center and Silver Lab exercise on proactive risk management in cyanobacteria. A report and analytic summary of the exercises, which includes an outline of open questions identified, has been published on the Wilson Center Synthetic Biology Project Website.

Work in 2012 has centered on data and testing needs for assessment of environmental effects of synthetic biology applications.   These workshops have included developers of specific synthetic biology applications, population geneticists, regulators and insurers, NSF, NGOs, and firms. In June 2012, Ken Oye held a jointly sponsored an MIT and Wilson Center workshop on the Church Lab rE.coli and Silver Lab cyanobacteria. To better prepare nontechnical participants for the workshop, they produced briefing materials on fitness, genetic stability and lateral gene transfer. Workshop participants flagged sources of uncertainty over environmental effects and on evaluating methods of testing for environmental effects, providing a foundation for development of protocols for assessing environmental risks in a regulatory context. A report from the workshop will be released in early 2013.

December 2012 MIT, Woodrow Wilson Center and EPA Meeting on Eukaryotic Algae
Discussions at the June 2012 meeting catalyzed a December 2012 workshop on eukaryotic algae for fuels production, jointly sponsored between the EPA, Wilson Center and MIT. The workshop engaged major firms, the relevant regulatory community, environmental scientists,  and nongovernmental organizations in an assessment of concrete data requirements and measurement issues associated with field release of next generation engineered algae.   There was broad support for the formation of small technical working groups to address specific data and testing issues in greater detail.

The Oye group is now planning a fifth joint workshop on an applications with deliberate rather than incidental release, such as a bioremediation or agricultural or medical applications to occur in summer 2013.

These series of proactive risk management exercises have illuminated key areas of uncertainty and disagreement between stakeholders needing further research and action, and have piloted different workshops designs. Environmental microbiologists have stressed a need for criteria for evaluating fitness, mutation and gene flow. Regulators discussed difficulties in how to assess and certify better chassis. Civil society organizations expressed a need for more accessible information on the nature of technical improvements - which led to development of briefings materials in subsequent workshops. There was general consensus that case-based proactive workshops were effective at identifying issues and the mutual exchange bolstered legitimacy and credibility. Participants felt that there was a strong need for federal research into the design, testing and demonstration for safety. This includes assessing effects of methods of insertion and phylogeny on gene stability and transfer, and how genetic instability impact intrinsic containment approaches (e.g. kill switches). Measurement technologies and standards for gene flow, genetic stability and fitness were highlighted as an area of key need, as well as establishing observational baselines for detection of environmental effects.

These workshops have now led to development of a NSF proposal for a jointly sponsored MIT/Wilson Center project to identify key areas for government supported research to address sources of uncertainty on the environmental implications of synthetic biology. It will include workshops in academic and industrial centers on the East coast and West coast, including many Synberc institutions and partners.

Results from these workshops have been presented in numerous venues and are now being prepared for publication. For example, Oye has presented at the SRA World Congress (June 2012), the International Risk Governance Council  in Lausanne (October 2012) and a conference on risk governance sponsored by Tsinghua University and Chain’s State Council on Science and Technology (January 2013). Todd Kuiken of the Wilson Center will be discussing results of this work at the upcoming co-sponsored Synberc and J Craig Venter Institute (JCVI) workshop on instrinsic containment.

Intrinsic Biocontainment
Mechanisms built into engineered organisms to make them less likely to persist in the environment or to spread their genes have been collectively referred to as “intrinsic biocontainment”. Many scientists are already engaged in developing a variety of different approaches to intrinsic biocontainment, yet an understanding of their comparative properties, as well as their adoption, is not widespread, and funding focused on the topic has been scarce. To begin to build a community of practice around these topics, Drew Endy and Megan Palmer are collaborating with the Policy Office of the J. Craig Venter institute (JCVI) on a Sloan Foundation sponsored project on intrinsic biocontainment.

In February/March 2013 we will be holding a workshop that will bring together ~30 scientists who are pursuing research on intrinsic biocontainment, including many Synberc members. Program managers at several granting agencies will be participating, as well as groups working on regulatory and risk assessment frameworks, including Ken Oye and scholars at the Woodrow Wilson Center. The goals is to better understand the technical status of these mechanisms, the limitations and difficulties that have been encountered, and the possibilities that have been pursued. It will also encourage discussion of new and creative means of intrinsic biocontainment. A summary and any conclusions from this workshop will be compiled and used as a resource for the broader meeting and for any subsequent meetings or activities that may follow. The outcome of workshop will be presented at the Synthetic Biology 6.0 conference in July 2013.

Guide to Regulations and Guidelines for Synthetic Biology
Ken Oye and colleagues have updated the “Guide to United States and European Union Regulations Governing Synthetic Biology.” Areas of regulation not covered by the previous guide, including new Canadian guidelines, are now being added.  A version of this guide will be published in a forthcoming book edited by Markus Schmidt.

Microbial Chassis Safety Engineering
Synberc researchers are pursuing a number of strategies to engineer safer, cost-effective and reliable chassis for synthetic biology. These efforts are closely integrated with projects in proactive risk governance described above.

Development of Synthetic Auxotrophs (Anderson Lab)
Chris Anderson’s group is developing synthetic auxotrophs to mitigate the risks of environmental release.  These organisms are engineered such that their viability is dependent on a chemical that is not found in nature.  Therefore, these organisms cannot survive outside of contained environments to which the synthetic compound has been added. Anderson’s group is producing synthetic auxotrophs via novel protein engineering strategy.  They take a protein critical to the growth of the organism (encoded by an essential gene) and rewires its interactions with the cell such that when two of them bind to each other, the cell detects the event and responds by changing its ability to grow in the presence of toxic compounds.  Using this system, large collections containing billions of variants of the essential gene can be screened for the desired chemical-dependent function. Thus far the Anderson lab has identified easier selection strategies, extensively characterized these methodologies, and are beginning library screening. Chris Anderson will discuss this work at the Synberc and JCVI co-sponsored intrsinsic containment workshop in March 2013.

Cyanobacteria Chassis Engineering (Silver Lab)
Pam Silver’s group is developing cyanobacteria  as a photosynthetic and carbon-fixing chassis for metabolic engineering. Industrial-scale production of products by cyanobacteria requires growth of recombinant microbes in an outdoor environment. In 2011, the Silver lab approached the Practies thrust to help evaluate the current political and regulatory landscape concerning the industrial deployment of engineered cyanobacteria, and identify key scientific and regulatory considerations. This led to the aforementoned series of workshops in 2011 and 2012 lead by Ken Oye in partnership with the Woodrow Wilson Center in which cyanobacteria was was used as a case study to evaluate the potential environmental impact of engineered microbes. A report and analytic summary of the 2011 exercises, which includes an outline of open questions identified, has been published on the Wilson Center Synthetic Biology Project Website. A more detailed report on the safety issues involved in deploying engineered cyanobactera in an industrial context is currently in preparation. Members of the Silver lab will be participating in the Synberc and JCVI co-sponsored intrinsic containment workshop in March 2013.

Toward a Dramatically Reassigned Genetic Code (Church Lab)
George Church’s group is engineering safer chassis from the ground up. MAGE and the SynBIOSIS methodology are being used to reassign of several sense codons genome wide, which they predict will result in an expanded chemical repertoire, genetic isolation, and virus resistance. This genetic isolation is a potentially powerful strategy to prevent the escape of recombinant DNA into the environment. As described above, George Church and Peter Carr have been working closely with Ken Oye’s group and the Woodrow Wilson Center to examine potential frameworks to assess risks of these novel chassis, and how to incorporate this information into engineering safety design, testing and demonstatration. They too will be participating in the Synberc and JCVI co-sponsored intrinsic containment workshop in March 2013.