Mysteries in a Minimal Genome

The history of the field of total synthesis demonstrates that there is value in constructing novel products from simpler building blocks, a value that extends beyond that of the products themselves. “New synthetic methods are often incorporated into the synthetic schemes towards the target, and the exercise of the total synthesis becomes an opportunity for the invention and discovery of new chemistry,” writes K. C. Nicolaou and colleagues. The maturation of the field of total synthesis has provided a bounty of useful medicines and materials. But in tandem with the achievement of progressively more elaborate syntheses came paradigm-shifting insight into the nature of chemical bonds and bond-forming reactions. Many see synthetic biology as poised to follow a similar path as synthetic chemistry. Building living things from simple and well-characterized parts can provide useful technologies such as microbial fuel factories, immune cells engineered to selectively attack cancer, living tissues, and novel materials. However, synthetic biology also promises to yield new and fundamental biological insights. Through their efforts to build new life forms, synthetic biologists will reveal what works, what does not work, and in the process ask, “why?” The synthesis of a minimal functional genome from simple chemical precursors (rather than copied from an existing biological template) has stood as a practical and symbolic milestone in synthetic biology, since the genome encodes the complete instruction set for life. The first synthetic genome was viralthat of the hepatitis C virus (HCV), encompassing 9600 bases and completed in 2000. In 2008, Craig Venter and colleagues synthesized the first cellular genome, that of Mycoplasma genitalium, spanning 580,000 bases and encoding 525 genes. In 2010, Venter’s team synthesized an even larger cellular genome, that of Mycoplasma mycoides, and proved its functionality by transplanting it into the cell body of Mycoplasma capricolum, thereby morphing the cell into the M. mycoides species as it read and rebooted itself from the new genetic instructions. This genome, JCVI-syn1.0, also contained watermark sequences, modifications to its genetic code that spelled out names and quotations, but were biologically inert. However, this genome, from a functional perspective, was identical to the genome from which it was derived. In an important recent milestone for the field of synthetic biology, Venter and colleagues completed the synthesis of another synthetic genome called JCVI-syn3.0, which is JCVI-syn1.0 distilled to a minimal necessary set of components. The goal of identifying a minimal genome emerged as genome sequencing technologies came online in the 1990s. A minimal genome promises to provide a genetic chassis upon which more complex cell behaviors and functions can be constructed, for example, the capacity to produce fuels.