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Rational design: best route for synthetic biology?

Wyss Institute Core Faculty member Pam Silver and Senior Staff Scientist Jeffrey Way

In an issue of Nature (vol. 509, issue 7499), Wyss Institute Core Faculty member Pamela Silver and Senior Staff Scientist Jeffrey Way argue that rational design can be used to predictably engineer new biological systems. The goal in rational design is to harness our understanding of biology – which has exploded in the last few decades, they say – to build a library of well understood and characterized modular, biological parts, such as genes and proteins, whose functions are well understood and use these parts to assemble new biological systems with predictable and reliable outcomes.

“In the early days of synthetic biology, scientists envisioned building biological systems in the same way that we build computers and engineer physical systems,” Way said. “While the engineering mindset has been very useful in propelling synthetic biology, we have also learned that we need to accept Nature on its own terms and take advantage of the parts and tools that Nature has given us, with all of their wonderful idiosyncrasies.”

One illustration of the rational design approach is the recent work by Silver, Way, Wyss Core Faculty member Jim Collins, and members of their labs, in which they used a well characterized genetic switch from a virus to engineer bacteria to remember chemical stimuli that they experienced as they pass through the mouse gut. These authors also recently described the evolution of the synthetic biology ‘ideology’ as it has evolved over the past 10 years in an invited Cell review.

Since the development of molecular biology and recombinant DNA, there has been an explosion of knowledge in reductionist biology – breaking down biological systems into the parts that make them up – that now enables us to create new organisms that represent huge leaps from what Nature has provided us,” Silver said. Way also suggested that the lay public, who has funded basic biological research for the last 50 years, would likely side with a rational design strategy that leverages the fruits of that research.

In a counter point of view in the same issue of Nature, Frances Arnold and Joseph Meyerowitz of the California Institute of Technology make the case for directed evolution, which harnesses the power of evolution to direct the design of synthetic organisms and relies on high throughput gene editing tools. In this approach, reflected in the research done by Wyss Core Faculty member George Church as well as by Arnold and her colleagues, genes within a cell pool are randomly mutated in a series of rounds – with unpredictable outcomes — to eventually produce cells that exhibit a desired trait or function. These cells are then subjected to new rounds of mutation and screening until the desired new function is achieved.

Perhaps, writes Arnold and Meyerowitz, the answer will be in a combined approach: “Evolutionary engineering is not incompatible with rational design; in fact, the two are highly complementary.”


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