Double Dutch: A Tool for Designing Combinatorial Libraries of Biological Systems

Recently, semirational
approaches that rely on combinatorial assembly
of characterized DNA components have been used to engineer biosynthetic
pathways. In practice, however, it is not practical to assemble and
test millions of pathway variants in order to elucidate how different
DNA components affect the behavior of a pathway. To address this challenge,
we apply a rigorous mathematical approach known as design of experiments
(DOE) that can be used to construct empirical models of system behavior
without testing all variants. To support this approach, we have developed
a tool named Double Dutch, which uses a formal grammar and heuristic
algorithms to automate the process of DOE library design. Compared
to designing by hand, Double Dutch enables users to more efficiently
and scalably design libraries of pathway variants that can be used
in a DOE framework and uniquely provides a means to flexibly balance
design considerations of statistical analysis, construction cost,
and risk of homologous recombination, thereby demonstrating the utility
of automating decision making when faced with complex design trade-offs.