Design by Directed Evolution

The stunning array of features and functions exhibited by proteins in nature should convince most scientists of the power of evolutionary design processes. Natural selection acting on populations over long periods of time has generated a vast number of proteins ideally suited to their biological functions. When we try to recruit these remarkable molecular machines for new taskssfrom serving as industrial catalysts to being used as additives for laundry detergentsswe find that they are often not so well suited. (The chemist is not terribly impressed with a synthesis requiring a reactor the size of a football field simply because the enzyme functions in water and the substrate does not dissolve, nor is she pleased with a catalyst shut down by the products of its own reaction.) Evolution is usually the culprit: proteins are optimized, and often highly specialized, for specific biological tasks. Most protein reengineering efforts have been by socalled rational design. The filtering effect of scientific publication (successes get published, failures mostly do not) might lead one to believe that we can, with reasonable probability of success, identify and modify the amino acids responsible for key properties such as an enzyme’s substrate preference, stability, or activity in a nonnatural environment. In reality, we are far from being able to do this reliably. This is true even for the relatively small number of enzymes for which considerable structural and mechanistic data are available. Admitting ineptitude in rational design, however, frees us to consider other approaches which are hardly irrational. An alternative and highly effective design strategy can be found by looking to the processes by which all these proteins came about in the first place. My research has been devoted to recreating in the laboratory the key processes of evolution and doing it in such a way that we can design scientifically interesting and technologically useful molecules. The challenge is to collapse the time scale for evolution from millions of years to months or even weeks.