Useful Construction

Drew Endy is an assistant professor in the biological engineering division and cofounder of Massachusetts Institute of Technology's synthetic biology working group.

Creation implies an act that is based on some combination of perfect knowledge, unlimited power, and infinite resources. Gods create. Engineers on the other hand, from structural to electrical and now biological, are always constrained by (1) an imperfect understanding of raw materials, (2) limited abilities to manipulate these materials, and (3) a budget. As a result, engineers construct. The art of engineering is to reliably construct useful and beautiful artifacts despite our limits.

In synthetic biology, there is now tremendous excitement about constructing fully functioning cells from scratch. Unlike past scientific research - for example, sequencing of the human genome - the race to construct synthetic cells has no finish line. Instead, synthetic cells will be judged on their elegance of design, functional prowess, and safety features, all characteristics that can be continuously improved. For comparison, would you want to drive your car across the world's first "minimal" bridge?

As one or more of the remarkably diverse approaches to construct synthetic cells succeed, the resulting organisms will define the "power supplies and chassis" of our future synthetic biological systems. A biological engineer working today cannot predict which approaches are likely to produce the dominant cellular platforms for future synthetic biology. But, consider the following possibilities:

Escherichia coli
The common E. coli, today's favorite bacterial chassis, is being heavily re-engineered to improve its properties and function. for example, fred blattner, Gy￶rgy P￲sfai, and colleagues are constructing a reduced E. coli genome, removing cryptic prophages, transposons, and other genetic elements of "ill repute." The resulting changes produce a genome that doesn't mutate as much as the natural cell. As a second example, George Church and colleagues are working to recode the E. coli genome in order to implement a new genetic code. Alternative genetic codes should facilitate protein production and engineering and could eventually improve genetic safety - for example, by enabling orthogonal DNA programs executable only inside the synthetic cell.

Mycoplasmas
At least two groups are working to construct "minimal" cells from some of the smallest known natural bacteria, the Mycoplasmas. On the next page, scientists J. Craig Venter, Hamilton Smith, and Clyde Hutchison explain their goal of rebuilding and then extending the genome of the slow-growing, human pathogen, Mycoplasma genitalium. A less well-known example is engineer Thomas F. Knight, Jr.'s work to understand and rebuild the genome of Mesoplasma florum. Although the M. florum genome is slightly larger than M. genitalium's, M. florum grows as fast as E. coli and is a biosafety level 1 organism, which means that it is not known to cause disease in healthy people. Choosing such a potential cellular chassis for synthetic biological systems appears nearly as rational as choosing a small transparent worm - caenorhabditis elegans - to study development, as Sydney Brenner did in June of 1963.

Artificial Cells & Virtual Machines
As described throughout this issue, many groups are working to construct synthetic cells from raw materials. It's exciting to imagine using such cells as platforms for operating our future synthetic biological systems. By only including components of known function, it may be easier to avoid issues of component crosstalk and compatibility. A more modest approach, however, involves the idea that "virtual machines" can be engineered inside existing cells to isolate and insulate the operation of our synthetic biological systems. In computer programming, "virtual machines" provide environments for running software independent of the underlying details of the computer itself. For example, Java is a language for programming any computer, so long as that computer can provide a Java Virtual Machine. The first synthetic biology Virtual Machines might only include the T7 RNA polymerase - an enzyme that can transcribe genes in nearly any organism - coupled to orthogonal ribosomes, but could eventually involve a synthetic organelle, which installs inside any natural organism to provide a common and independent biological operating system.

Regardless of which approaches work first, our ability to design and build novel genomes and cells will directly aid our study of nature's designs, and enable the construction of useful synthetic biological systems.