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Synthetic Biology Synthetic Biology © NATALIMIS / Fotolia 2nd Interim report of the German Central Committee on Biological Safety June 2018 Az. 46012 Contents Summary ............................................................................................... 3 Zusammenfassung ............................................................................... 5 1 Introduction ..................................................................................... 7 1.1 What is Synthetic Biology ........................................................................................ 7 1.2 Aim of the report .....................................................................................................10 2 Research approaches in Synthetic Biology ................................ 11 2.1 Synthesis of genes and genomes ...........................................................................12 2.2 Design of genetic signalling circuits ........................................................................17 2.3 Metabolic engineering ............................................................................................22 2.4 Minimal cells: Genome reduction and production of protocells ...............................25 2.5 Xenobiology ...........................................................................................................30 3 Research trends and social discussion ...................................... 34 4 References .................................................................................... 35 2 Summary Summary In this report, Synthetic Biology is considered a scientific concept in which engineering practice is applied to the construction of novel biological systems and cells at the genetic, biochemical, and physiological level. Synthetic Biology goes far beyond classical biology as it no longer aims at the description and analysis of organisms, but at the design of living entities for novel applications. Such entities process information, alter chemicals, generate materials and structures, produce energy, and maintain and regulate specific biochemical pathways. With the help of Synthetic Biology, researchers wish to produce novel pharmaceuticals, vaccines, or food additives. Synthetic Biology can help relieve pressure from natural resources, improve human health or provide alternatives to fossil-based fuels. Finally, Synthetic Biology allows a basic research approach to study what living is all about. Since the beginning of the 21st century, the number of scientific publications related to Synthetic Biology has raised from about 500 p.a. to 4000 p.a. in 2017. The progress so far has been summarized in this report along with a discussion on safety considerations for the five major fields that are generally agreed to be part of Synthetic Biology: synthesis of artificial genes and genomes, metabolic engineering incl. bio-factories, design of genetic signalling circuits, cells with minimal genomes and protocells, and xenobiology. As most of the research approaches in Synthetic Biology generate genetically modified organisms (GMOs), their potential risk can be assessed with existing methodologies as outlined in the German Genetic Engineering Act, the European Directives 2001/18/EC and 2009/41/EC and the Cartagena Protocol on Biosafety to the Convention on Biological Diversity. The insertion of synthesized genes or genomes causing genetic modifications that cannot occur naturally by mating and/or natural recombination creates a GMO. The same applies to the introduction of new or alternative metabolic pathways into a cells' genome. The installation of genetic signalling circuits that sense a specific input and react by a distinct output creates a GMO, as well as the downsizing of an organisms' genome to produce a minimal cell only possessing the essential genes needed to survive. Another approach with a similar goal is to create cells from chemical components together with a minimum of genetic information, the so-called protocells. Research concerning protocells is still at the beginning. If replicating protocells will be achieved, they would have no natural counterpart that could serve as a basis for a risk assessment relying on the known risk potential of naturally occurring donor and recipient organisms. Concerning xenobiology, researchers try to establish bio-orthogonal systems that do not, or to a lesser extent, interact with natural organisms. Orthogonality can be reached by introducing xenonucleic acids or by 3 Summary expansion of the genetic code, e.g. allowing the insertion of non-canonical amino acids into polypeptides. Since such approaches are based on the genomic introduction of novel tRNAs or aminoacyl-tRNA synthetase genes, these organisms are considered GMOs. In summary, the research approaches currently pursued in Synthetic Biology in Germany as well as worldwide involve no specific risks for biological safety other than those already being assessed for “conventional” genetic engineering by applying the GenTG and other international regulations. 4 Zusammenfassung Zusammenfassung In diesem Bericht wird die Synthetische Biologie als ein wissenschaftliches Konzept betrachtet, in dessen Rahmen diverse, u. a. ingenieurwissenschaftliche Methoden dafür verwendet werden, auf genetischer, biochemischer und physiologischer Ebene neue biologische Systeme und Zellen zu konstruieren. Die Synthetische Biologie geht dabei über die klassische Biologie hinaus, indem Organismen nicht mehr nur analysiert und charakterisiert werden, sondern lebende Einheiten für neue Anwendungen konstruiert werden. Solche Einheiten verarbeiten Informationen, modifizieren Chemikalien, erzeugen Materialien und Strukturen, produzieren Energie und unterhalten und regulieren spezifische biochemische Stoffwechselwege. Mit Hilfe der Synthetischen Biologie versuchen Forscher, neue Pharmazeutika, Impfstoffe oder Lebensmittelzusatzstoffe zu produzieren. Die Synthetische Biologie kann dabei helfen, natürliche Ressourcen zu entlasten, die menschliche Gesundheit zu verbessern und Alternativen zu fossilen Brennstoffen zu liefern. Auch für die Grundlagenforschung ist die Synthetische Biologie wertvoll, da sie neue Wege der Erforschung des Ursprungs und der Basis des Lebens eröffnet. Seit Beginn des 21. Jahrhunderts ist die Anzahl der wissenschaftlichen Publikationen, die sich mit Synthetischer Biologie beschäftigen, von etwa 500 pro Jahr auf 4000 pro Jahr im Jahr 2017 angestiegen. Die aktuellen Entwicklungen auf dem Gebiet der Synthetischen Biologie werden in diesem zweiten Bericht der ZKBS zusammengefasst und die Sicherheitsaspekte der fünf Hauptforschungsfelder diskutiert, die generell als Teil der Synthetischen Biologie angesehen werden: Die Synthese künstlicher Gene und Genome, die Erstellung maßgeschneiderter Stoffwechselwege inklusive Bio-Fabriken, die Konzeption genetischer Schaltkreise, das Erzeugen von Zellen mit Minimalgenomen und von Protozellen sowie die Xenobiologie. Da die meisten Forschungsansätze in der Synthetischen Biologie gentechnisch veränderte Organismen (GVO) generieren, kann deren potenzielles Risiko mit den bereits existierenden Methoden bewertet werden. Diese finden sich im deutschen Gentechnikgesetz (GenTG), den europäischen Richtlinien 2001/18/EC und 2009/41/EC sowie dem Cartagena-Protokoll über die biologische Sicherheit zum Übereinkommen über die biologische Vielfalt. Das Einfügen synthetisierter, künstlicher Gene und Genome führt zu genetischen Veränderungen, die nicht auf natürlichem Weg durch Kreuzen und/oder natürliche Rekombination entstehen können, und generiert einen GVO. Dasselbe trifft auf das Einfügen neuer oder alternativer Stoffwechselwege in das Genom einer Zelle zu. Das Einbringen genetischer Signalwege in Zellen, sodass diese ein spezifisches Signal wahrnehmen und 5 Zusammenfassung mit einer definierten Antwort reagieren können, erzeugt ebenfalls einen GVO. Dies gilt auch für das Verkleinern des Genoms eines Organismus mit dem Ziel eine Minimalzelle zu erzeugen, die nur noch die für das Überleben essenziellen Gene aufweist. Ein ähnliches Ziel, aber mit anderer Herangehensweise, verfolgt die Herstellung sogenannter Protozellen, die aus chemischen Bestandteilen und einem Minimum genetischer Information aufgebaut werden. Die Forschung zu Protozellen befindet sich noch in den Anfängen. Sollte es eines Tages gelingen, replizierende Protozellen herzustellen, würde für diese kein natürliches Vorbild existieren. Dementsprechend kann die auf einem Vergleich mit natürlich vorkommenden Spender- und Empfängerorganismen basierende Risikobewertung nicht angewendet werden. In der Xenobiologie versuchen Forscher bio-orthogonale Systeme zu etablieren, die nicht bzw. nur in einem geringen Ausmaß, mit natürlichen Organismen interagieren. Orthogonalität kann durch das Einbringen von Xenonukleinsäuren erreicht werden oder durch eine Erweiterung des genetischen Codes, die z. B. den Einbau nicht- kanonischer Aminosäuren in Polypeptide erlaubt. Da diese Ansätze darauf basieren, Gene für neue tRNAs oder Aminoacyl-tRNA-Synthetasen in das Genom zu inserieren, handelt es sich bei den entstehenden Organismen ebenfalls um GVO. Zusammenfassend birgt die derzeitige Forschung zur Synthetischen Biologie sowohl in Deutschland als auch weltweit keine anderen Risiken für die biologische Sicherheit, als solche, die bereits mithilfe des GenTG und anderer internationaler Regulierungen für „konventionelle“ gentechnische Veränderungen bewertet werden. 6 Introduction 1 Introduction 1.1 What is Synthetic Biology For millennia, humans have been
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