Synthetic Biology develops after the fierce debates on genetic engineering in the late 1980s and 1990s and in the face of continuing unrest over genetically modified plants (at least in Europe). Therefore, it is only prudent to reflect - and where possible to anticipate - the potential debates that Synthetic Biology is likely to trigger. In fact, the debate on the place of Synthetic Biology in society has been an intrinsic part of the development of Synthetic Biology nearly from the very beginning. Already the “Synthetic Biology 2.0” conference in Berkely (Calif.) in 2006, the second international conference of the community, dedicated entire sessions to the various societal aspects of Synthetic Biology (http://pbd.lbl.gov/sbconf/), and so has “Synthetic Biology 3.0” (2007 in Zürich, http://www.syntheticbiology3.ethz.ch/). By then, it was already the focus of critical attention for a substantial set of NGOs (http://www.etcgroup.org/en/materials/publications.html?id=11), which requested that the development of Synthetic Biology should happen in a broader societal context. In fact, Synthetic Biology has already drawn rather comprehensive critique from NGOs [125].
Overall, it is probably safe to say that the Synthetic Biology community has been very quick to embrace public debate, and this early embrace has already produced a rich variety of materials on some, though not all, aspects that merit a deeper discussion [126, 127].
2.6.1. Synthetic Biology and biosafety
One crucial debate will be whether Synthetic Biology poses a sufficiently new safety risk to the people involved in it and to the wider public to justify novel safety measures. Here, the comparison to genetic engineering, which is thoroughly regulated in Europe (for which the author has first-hand experience), might be useful. As genetic engineering, Synthetic Biology concerns itself with the manipulation of genetic information of living (self-perpetuating) systems. Though currently most examples are limited to bacteria, prominent examples stem already from mammalian cells [128], and there appears to be no reason to assume that Synthetic Biology should not involve plants. Still, the manipulations we have seen so far are neither comprehensive nor fundamentally new, so at the moment it is difficult to see a reason for new rules.
However, what if Synthetic Biology is truly successful and in five years we see a novel bacterium the DNA of which has been entirely de novo synthesized and it consists of a combination of traits that we have not seen before in any other bacterium? And what if the information is encoded in novel 6-base code? In other words, is there a qualitatively new danger in the fact that Synthetic Biology addresses system changes on a large scale and attempts to implement orthogonality in cellular systems? And if so, what is the riskb?
The short answer is that in my view the risks are very small, but some dangers might merit further investigations. Specifically:
a) Regarding Synthetic Biology’s large scale-manipulation perspective: Biological systems are highly non-linear systems and as such characterized by emergentc properties. Therefore, large scale changes might indeed be seen as a potential danger associated with Synthetic Biology that might deserve special attention. On the other hand it has become clear that traits like bacterial toxicity and pathogenicity are traits that can be traced back to molecular mechanisms. These molecular mechanisms have been intensely studied over the last decades, so there is a large body of reference knowledge on the determinants of toxicity and pathogenesis which can guide questions as to the potential impact of novel, complex biological systems. As for example pathogenesis is a complex system property, it should be rather difficult to unintentionally produce a successful pathogenesis phenotype. In summary, I find it difficult to associate a significant risk with the novel dangers that might come from the large-scale manipulation perspective of Synthetic Biology.
b Danger: a theoretically possible bad outcome of a technology; risk: likelihood that the bad outcome materialises
c the arising of novel and coherent structures, patterns and properties during the process of self- organization in complex systems (J. Goldstein (1999), “Emergence as a Construct: History and Issues”, Emergence: Complexity and Organization 1: 49-72
In addition, large scale manipulations might allow addressing biosafety concerns much more effectively: substantial re-design of a genome allows also to thoroughly interfere with the viability of manipulated cells: it is for example easy to imagine how complete metabolic pathways are simply left out of re-designed cells (rather than single genes inactivated), reliably enforcing the external supply of specific nutrients.
b) Regarding the implementation of orthogonality: Where orthogonality requires expanding cellular systems (because specific functions have to be implemented twice, for example once for each orthogonal subsystem), it is highly likely that such systems will depend on the highly regulated environment of the laboratory to prosper, because those cellular systems are unlikely to be more competitive in the natural environment. But what if a cell uses a completely new chemical alphabet for encoding genetic information? Or, perhaps somewhat closer to today’s technical possibilities: what are the chances of survival of a bacterium that has undergone a re-assignment of two codons to unnatural amino acids and whose codon usage has been adapted genome-wide? On the one hand, such a bacterium would most probably contribute to biosafety because transferring DNA would be rather pointless for the bacterium (no other bacterium could read the code). On the other hand, how could a bacteriophage adapted to nature’s classical code attack a bacterial cell that uses a different code? After all, it could no longer produce functional proteins based on its own genetic information. Would that (to any notable extent) upset the “normal” processes that regulate the survival of cells or higher organisms in the environment? In my view, this question remains largely open and should be pursued further – in particular as there is probably still considerable time before we will be able to construct truly “orthogonal” living cells.
2.6.2 Synthetic Biology and biosecurity
In contrast to biosafety, biosecurity – the safety of the population against military or terroristic abuse of biological technologies - has been a very intensely discussed topic in Synthetic Biology. Some of the motivation for this stems from two experiments that have been intensely discussed in the scientific community and from one newspaper article in the British Newspaper “The Guardian”. The experiments involve the re-syntheses of two viruses: The 1918 influenza virus [61] and the polio virus [57]. While the influenza virus was re-constructed to precisely study why the 1918 virus variant had such dramatic effects, the polio-virus was the first genome-reconstruction study of its kind and showed that an infectious agent could be synthesized in vitro. Both experiments sparked concerns about the abuse of de novo DNA synthesis for the design of novel dangerous biological agents. The newspaper article reported that it had been possible for the author of the article to acquire oligonucleotides for re-assembling the smallpox virus without what he felt would be the proper control mechanisms [129]. The other part of the motivation comes from the rapid rise in DNA synthesis capacity (Fig. 3). Together, these reports produced the impression that it might be very
simple in the future for any ill-intending individual to equip him- or herself with the agents required to spread diseases at will.
Even though the reality is much more complex (acknowledging that it is still a major piece of research to assemble kilobases of correct DNA sequence, let alone convert this sequence into a biologically viable entity), this specific scenario is taken seriously [130, 131] and has spurred considerable activities, in particular in the US [132, 133], but also in Europe [134]. Specifically, a number of policy options were identified (such as DNA-sequence providers need to screen orders to detect suspicious sequence requests, owners of DNA synthesizers must register their machines and be licensed, and the competences of Institutional Biosafety Committees need to be expanded [133]), and some of these options have already been endorsed by DNA sequence providers [135].
2.6.3. Synthetic Biology and ethics
Finally, the opportunity to re-synthesize entire genomes to our specifications also harbors the immense attraction to identify the minimum determinants in terms of DNA sequence that are required to allow a cell to replicate in a given environment (see discussion above on minimal genomes). In other words, there is an opportunity to give a rather detailed answer to the question “what is life” [136], even if only for one very specific understanding of the word “life”. Even though this debate is not new at all, the novel experimental opportunities offered in the context of Synthetic Biology will most probably bring this discussion back into public focus.
However, this discussion is only the focus point of what might turn out to be a much wider issue in Synthetic Biology: Synthetic Biology entertains a rather reductionist or utilitarian view of life: Useful cellular systems shall be constructed from well-established, properly documented parts/devices, that are obtained from a central Registry and connected at standardized interfaces, in order to produce novel useful properties. This view will create some unrest and therefore will need some justification. Some of this justification might be provided by the main goals that the Synthetic Biology community embraces, which usually stem from areas where substantial technological progress can be expected to produce substantial beneficial impact on human life (e.g. medicine, chemistry). The remaining justification will most probably depend on the conducting of the Synthetic Biology community – which is overly constructive for the time being.
3. Summary
Synthetic Biology has emerged as an initiative that wants to fundamentally address the properties of living systems that make them difficult to engineer rationally. Though there is no guarantee that this ambition might be successful at the end, the focus on designing biological systems is already producing considerable advances in our understanding of biology and our
concepts for biotechnology. In my view, considerable success in the major fields of Synthetic Biology – orthogonality, coping with evolution, de novo DNA synthesis, an automated synthetic laboratory infrastructure, rational design of parts, devices, and eventually systems – is a prerequisite for biotechnology to turn into the truly pervasive successful industry that it has been predicted to become many times over the last 35 years.
If successful, Synthetic Biology will re-emphasize the role that biotechnology can play in the future development of our society, and this will most probably intensify the discussions around the potential safety-, security-, environmental, and ethical implications of this discipline. The scientific community needs to be prepared for this.