Literature

Natural proteins are remarkable materials, and immense efforts have been devoted to engineering proteins for use in biotechnology applications. Two methodologies have been used: Darwinian blind searches (inspired by evolutionary theory) and rational design (requiring an understanding of the principles of protein structure and function). In their review paper, Leisola and Turunen point out that "some impressive practical achievements have been done using directed evolution methodologies". The analogy here is not with natural selection, but with the artificial selection of desired traits. It should be noted that "the starting point is always a functional protein". These are not engineered from scratch, but promising materials are chosen in order to improve existing properties. The authors raise questions about this approach. "In view of the very substantial challenges remaining and the considerable effort expended thus far, we should pause to ask what things are most impeding our progress." They identify three significant obstacles: lack of a theory for structure design, lack of a general approach for sequence design, and over-reliance on the Darwinian methodology. The problem is that the directed evolution methodology does not focus on understanding the way proteins work. "Thus, we are still missing general theories that would help us to design novel enzymes without a need to use methods that are based on a random search in the local sequence space." "In spite of the progress, we still do not have a general theory on how a sequence produces a specific structure and how a structure determines a function. Therefore, a blind Darwinian search within a known protein scaffold is often used to modify proteins. Unfortunately, blind searches have hard resource limits whereas insight has not. Therefore, in the long run, blind searches are of limited value in compensating our present ignorance."
This is a very interesting conclusion. It illustrates the central theme of Michael Behe's new book: that there are limits to what Darwinian processes can do. Tweaking existing materials is feasible, but if you want to go further than that, you need a rational design methodology. Darwinian mechanisms can be used to explain the adaptation of proteins, but it is unwarranted extrapolation to think that the same mechanisms explain the origins of those proteins.

Protein engineering: opportunities and challenges
Matti Leisola and Ossi Turunen
Applied Microbiology and Biotechnology, 75(6), July 2007, 1225-1232.

Abstract: The extraordinary properties of natural proteins demonstrate that life-like protein engineering is both achievable and valuable. Rapid progress and impressive results have been made towards this goal using rational design and random techniques or a combination of both. However, we still do not have a general theory on how to specify a structure that is suited to a target function nor can we specify a sequence that folds to a target structure. There is also overreliance on the Darwinian blind search to obtain practical results. In the long run, random methods cannot replace insight in constructing life-like proteins. For the near future, however, in enzyme development, we need to rely on a combination of both.