By guest authors Erika Szymanski and Jane Calvert
Whole-genome engineering appears to be moving forward apace. The first synthetic biology effort to build a comprehensively re-designed eukaryotic genome recently made news with seven papers in a special issue of Science (see also ‘Extreme Makeover’). The project – Saccharomyces cerevisiae 2.0, more often called Sc2.0 or “synthetic yeast” – is the first effort to synthesize the genome of a eukaryote. Since eukaryotic genomes are much larger than bacterial genomes, synthetic yeast is being tackled by an international consortium of eleven labs in the UK, United States, Asia, and Australia, and is driving new technologies for working with DNA.
We are social scientists at the University of Edinburgh who have been working closely with the scientists and engineers behind synthetic yeast for the past two years. Just as the scientists observe that this project disrupts standard biological paradigms and provokes new kinds of scientific questions, we find that it generates new questions about the social shape of biology. But we find that these questions tend not to be asked because ethical and safety concerns are often taken to be the only important social dimensions of novel genetics work.[i]
Without dismissing the importance of these concerns, we argue that these are not the only important social questions. Synthetic yeast and other synthetic biology projects don’t just change what happens inside biology labs; they change how humans relate to other organisms, how we define the limits and possibilities of science and engineering, and the shape of future worlds in which we’ll all live together. Consequently, we argue that we need to continue asking questions to understand the scope of what else is being changed when scientists change the genome of “humble” baker’s yeast. Below, we highlight a few of those questions.
Will S. cerevisiae 2.0 be a new species?
A genetic sequence that serves as a “barcode” for identifying species has been deleted from the synthetic yeast genome, and replacement sequences have been designed that allow the synthetic yeast to “morph” species.[ii] The genome also includes sequences borrowed from organisms other than S. cerevisiae. What species, then, will the synthetic yeast be? Many different strategies can be used to determine species in different contexts and for different purposes. In an era of synthetic biology, when species distinctions become important to policy, perhaps the most useful response to the question “what is a species?” is “why are you asking?”
Can evolution be a design tool?
Perhaps the most important design feature of synthetic yeast is the SCRaMbLE tool, a clever acronym for a set of genome-wide changes that make it possible to produce massive genome rearrangements or, as biologists on the project sometimes say, to put “evolution on hyperspeed.”[iii] Given an appropriate signal, the engineered yeast genome will break up into many small segments, which can then reassemble in new ways to produce new “scrambled” genomes. Most of these cells will die, but a few will survive and can be studied. For us, SCRaMbLE draws attention to relationships between evolution and design, a tension at the heart of synthetic biology. Only “designer” chromosomes can be scrambled, but scientists have little control over the outcomes of scrambling. We therefore ask how a randomness-generating tool fits in with the oft-stated aim of synthetic biology to make biology into a rational engineering discipline. Is human control always necessary to achieving design goals? Could design instead be thought of as the result of humans working with the capacities of living things?
What is perfection in synthetic biology?
The team constructing synthetic chromosome V challenged themselves to create a “perfect” version of this chromosome, using the precision genome-editing tool CRISPR to ensure an exact match between the in silico design and the physical chromosome.[iv] Their goal provokes the question: what is “perfection” in synthetic biology? Matching the initial design? Making a cell that functions as intended? Arriving at a solution that “works?” We find this question interesting in part because it implies a response to another of our questions: are synthetic biologists working on or with the yeast? What role does the yeast play in the design? Is the cell an impediment, a co-designer, or an incompletely understood physical material?
What does Sc2.0 tell us about genome engineering?
Much current synthetic biology involves parts- or circuit-based engineering. What differences are involved in engineering at the whole genome scale? Seventeen years ago, Palsson anticipated that “we will move from talking about genetic engineering of single genes, to what may become known as “genome engineering,” where the whole organism is the context of the design”.[v] What does it mean for the whole organism to be the context of the design? If synthetic genomics involves engineering at the level of the whole, do specific organismal characteristics become important in contrast to parts-based synthetic biology? And what is the subject of design and engineering in synthetic biology: the genome, the environment, or both?
Who is a synthetic biologist?
Making synthetic yeast involves microbiologists, geneticists, physicists, programmers, designers, undergraduate students, computer programs, and robots. Who, then, is a synthetic biologist? If synthetic biology is “systematically paving the way for a new era of biology”,[vi] how do disciplinary identities change and what shape does the university take in that era?
How to organize a large, internationally collaborative synthetic biology project?
The Sc2.0 project may herald a new organizational strategy for synthetic biology projects whose size and significance requires the efforts of multiple laboratories across national boundaries. What degrees of congruence and freedom best facilitate such coordinated projects? How are technical and social norms maintained across large distances? How rigid must project standards be for the assembled end product to “work?” And how fluid should standards be to facilitate individual laboratory innovation? These questions particularly interest us for what they imply about the distribution of credit and the parsing of a large international project into PhD and postdoctoral-sized chunks.
Which values guide genome design?
The aim of the Sc2.0 project is not just to copy an existing genome, but to design a new one. While whole-genome sequencing and synthesis are similar in many respects, an important difference is that synthesis requires choices about what to make. These choices, even if they appear to be merely technical, necessarily involve values, which are often wrapped up with expectations about future use, and which can have social, economic, and political consequences. Values therefore play a more substantial role in synthesis than in sequencing. Consequently, we are compelled to ask: how can values be foregrounded and broadly discussed in future attempts to synthesize other genomes?
Jane Calvert and Erika Szymanski are both part of the “Engineering Life” team in Science, Technology and Innovation Studies at the University of Edinburgh in Scotland and they are working on the ERASynBio IESY grant. You can also follow Erika on twitter @ErikaSzymanski, and here is the twitter account for the Engineering Life project: @
[i] For more on how the synthetic yeast project is addressing ethical concerns, see Silva, A, Yang, H, Boeke, JD, & Mathews, DJH. (2015). Freedom and responsibility in synthetic genomes: The synthetic yeast project. Genetics, 200(4), 1021-1028.
[ii] Zhang, W, et al. (2017). Engineering the ribosomal DNA in a megabase synthetic chromosome. Science. 355(6329). DOI: 10.1125/science.aaf3981
[iii] Dymond, J, & Boeke, J. (2012). The Saccharomyces cerevisiae SCRaMbLE system and genome minimization. Bioengineered Bugs, 3(3), 168-171.
[iv] Xie, Z-X, et al. (2017). “Perfect” designer chromosome V and behavior of a ring derivative. Science. 355(6329). doi: 10.1126/science.aaf4704.
[v] Palsson, BO. (2000). The challenges of in silico biology. Nature Biotechnology. 18, 1147-1150.
[vi] Farren Isaacs, quoted in Callaway, E. (2014). First synthetic yeast chromosome revealed. Nature. Doi:10.1038/nature.2014.14941.