2013 : WHAT *SHOULD* WE BE WORRIED ABOUT?

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Senior Lecturer in Behavioural Biology School, University of Bristol
A Synthetic World

Synthetic biology is lego-land for natural scientists. We take nature's building blocks apart, and piece them back together again in a way that suits us better. We can combine genetic functions to reprogramme new biological pathways with predictable behaviours. We have spent the last decade imagining how this will improve society and the environment. We are now realizing these dreams. We can make yogurt that mops up cholera; we can manufacture yeast to power our cars; and can engineer micro-organisms to clean-up our environment. Very soon, we will be using living organisms to mimic electrical engineering solutions—bio-computers that are programmed to follow logic gates in the same way as computers do; we will have materials stronger than steel made from animal products. Could this be the end of landfill? There is no doubt that synthetic biology is going to revolutionise our lives in the 21st century.

I worry about where synthetic biology is going next, and specifically what happens when it gets out of the lab into the natural world and into the public domain.

Biological engineering started outside the lab—we've been modifying plants and animals since the advent of agriculture, about 12,000 years ago, through breeding and artificial selection for domestication: we've ensnared yeast and bacteria to make beer, wine and cheese; we've tamed wild wolves to be man's best friend; we've cajoled grass to be a high nutrient source. Synthetic biology is a new packaging that describes how we've got an awful lot better at manipulating natural systems to suit our whims. A 'plug and play' approach is being developed (e.g. BioBricks) to facilitate manipulations at the molecular level. In the future, tried-and-tested genetic modules may slotted together by non-experts to create their own bio-engineered product. Our children's children could be getting bio-lego for Christmas to build their own synthetic pet!

Synthetic biology has tremendous commercial potential (beyond the lego!), and is estimated to be worth over $10 billion by 2016. Currently, progress is focused on small things, like individual gene networks or micro-organisms. But there is potential too for the larger, more charismatic organisms, specifically the fluffy and endangered ones. These species capture the interests of the public, business and entrepreneurs. This is what I am worried about.

We can make a new whole organism from a single stem cell (e.g. Dolly and co). We can uncover the genome sequence, complete with epigenetic programming instructions, for practically any extant organism within a few weeks. With this toolkit, we could potentially recreate any living organism on the planet; animal populations on the brink of extinction could be re-stocked with better, hardier forms. We are a stone's throw away from re-creating extinct organisms.

The woolly mammoth genome was sequenced in 2008, and Japanese researchers are reputedly cloning it now, using extant elephant relatives as surrogate mothers. Synthetic biology makes resurrecting extinct animals so much more achievable, because any missing genomic information could be replaced with a 'plug and play' genetic module. A contained collection of resurrected animals is certainly wow-factor, and might help uncover their secret lives and explain why they went extinct. But as Hollywood tells us, even a 'Jurassic Park' cannot be contained for long.

There are already attempts to re-create ancient ecosystems through the re-introduction of the descendants of extinct megafauna (e.g. Pleistocene Park in Russia), and synthetic woolly mammoths may complete the set. Could synthetic biology could be used to resurrect species that 'fit better' or present less of a threat to humans? A friendly mammoth perhaps? Extinct, extant, friendly or fierce, I worry about the impact of bio-synthetic aliens being introduced to a naïve and vulnerable environment, becoming invasive and devastating native ecosystems. I worry that if we can recreate any animal, why should we even bother conserving any in the first place?

Synthetic biology is currently tightly regulated, along the same lines as GMOs. But when biosynthetic products overflow into the natural world, it will be harder to keep control. Let's look at this from the molecular level, which arguably we have more control over than the organism or ecosystem level. We can shuffle the genes and whole genomes to create something that nature did not get round to creating. But a biological unit does not exist in isolation: Genes, protein complexes, cells, all function in modules—a composite of units, finely tuned by evolution in a changeable environment to work together.

Modules may be swapped around, allowing plasticity in a system. But there are rules to 'rewiring'. Synthetic biology relies on a good understanding of these rules. Do we really understand the molecular rules enough to risk releasing our synthetic creations into natural ecosystems? We barely understand the epigenetic processes that regulate cell differentiation in model organisms in controlled lab conditions: how do we deal with the epigenome in a synthetic genome, especially one destined to exist in an environment very different to its original one, 10,000 years ago?

Ecology is the play-dough of evolution—ecosystem components get pushed and pulled, changing form, function and relationships. We might be able to create a bio-unit that looks and performs perfectly in the lab, but we cannot control how ecology and evolution might rewire our synthetic unit in an ecosystem, nor can we predict how that synthetic unit might rewire the ecosystem and its inhabitants. Molecular control mechansims are engineered into microorganisms used to clean up toxic spills in the environment, preventing them evolving and spreading. Can we put a 'stop evolving' switch on more complex organisms? How do we know they won't evolve around this? And what happens if (when) they interbreed with native species? What the disruption of the engineered modules or transfer to other organisms might lead to is unimaginable.

To sum up, I worry about the natural world becoming naturally unnatural.