On futures

I’m at the Exploratory Round Table Conference in Shanghai, which is ostensibly a forum to discuss what directions synthetic biology will take into the future. As with most such forums, it frequently devolves into a discussion of what synthetic biology is (or is not). I am as happy to engage in such silly discussions as anyone else, especially given that I think synthetic biology is a buzzword rather than a discipline.

Arguments aside, it has been very good to see my friend Pam Silver here, and to hear her perspectives on the issue. As with many measured individuals (as opposed to zealots such as myself) she argues for a middle ground in which the good is maximized and the bad is minimized. In her view, the excitement and interest (at all levels) generated by the buzzword justify its use. More importantly, she sees the science and engineering that have arisen to be most useful for testing hypotheses about the nature of living systems. It is with Pam in mind that I submit to you two extreme futures:

The organism was one they really needed. And so it was good that it had been possible to synthesize this organism from the ground up. The years that had been required to painstakingly make and standardize the biological parts that comprised its critical circuits had been well-spent. These parts were robust, and worked consistently in a variety of genetic and environmental backgrounds. More importantly, though, they worked together in ways that were entirely predictable, allowing circuits with chemical and regulatory properties to be strung together and tested on the BioCAD prior to even laying them into carbon. This was especially true given the minimal chassis (UniOrg) that was being used, where there was little chance for unanticipated interactions or cross-talk (not that these were a problem even for the more Natural hosts, given the orthogonal building blocks and genetic elements that were being incorporated into the key pathway). The chemical and logical schemes may not have been ones that Nature would have ever chosen or even thought of, but the systematic characterizations that had been carried out over the years had shown that circuit and even organismal construction was indeed the sum of the parts (as it must be). The in silico testing had even revealed a feedback loop in genetic noise that might eventually lead to evolutionary loss of part of the key pathway, but this was quickly smoothed out by some nifty codon optimization and destructuring of mRNAs. Now the genome was spinning out on the Forge and its coat simultaneously crafted. A quick injection of starter materials (which degraded even as the organism’s new complement of proteins and self-sustaining metabolism came on-line), and life was breathed into the critical beast. Mankind was saved.

The organism was one they really needed. And so it was good that they understood where and how that critical bug delta could be changed. The microorganism had been retrieved from the Pharoah’s tomb itself, sequence had been acquired on the fly, the genome automatically annotated with precision, and the interactome and regulatory networks plotted based on analogy and a bit of extrapolation. The homology mapping from the vast repository of structural proteomics data and PhPh (phylo-physics)-based computational modeling had helped a great deal. Of course, it didn’t do quite what they needed, but it was close enough, with its thermo- and salt-tolerances almost perfectly balanced. It was just a matter of giving it a few new tricks. The synthetic pathway was laid carefully on top of the existing network, with a series of heterologous gene insertions scattered at key sites throughout the genome, and a few mutational changes to the bug’s own regulatory factors and signal transduction cascades. The changes were carried out quickly in parallel, and growth characterizations provided estimates of the fitness landscape surrounding each perturbation. This knowledge fedback onto the designs, and enhanced the ever-upgraded predictive evolutionary algorithms. Ultimately, genome editing of the bug by homologous recombination and targeted gene repair (the orthogonal operon that made the changes vanishing once the transfers had been effected) guided the critical beast to its new application. Mankind was saved.

Of course, both futures are open to us, and a good engineer will choose the pieces of these futures that allows her to save Mankind.

Or are they? We live in a world of limited resources and extraordinary competition. There is more than a little bit of ‘follow the zeitgeist’ where science is involved. The truly novel idea can be lost in the stampede towards perceived novelty. Perhaps this is ultimately not about which future is best, but about what type of scientific infrastructure produces the best future.

Choose wisely.


- originally posted on Tuesday, October 19th, 2010