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The Joyce Laboratory

Lab Members

Michael Robertson



Michael Robertson, PhD

Staff Scientist
Mar 2009 – present
Ph.D., 2001, U of Texas at Austin
Research: RNA catalyzed RNA replication
E-mail: michaelr@scripps.edu

All life on Earth is believed to be descended from a common cellular ancestor that lived nearly 4 billion years ago, from which the entire diversity of the modern biosphere radiated. Though ancient, this progenitor cell was a sophisticated entity that shared many fundamental biochemical characteristics with modern cellular life. The ultimate ancestor though, is the chemical system that defines the molecular origin of life. The core requirement of such a chemical system was the ability to produce copies of itself (replicate), but what made it the progenitor of all known life was the capability to evolve and adapt. Ribonucleic acid (RNA) is a favored candidate for this first living system based on numerous, but ultimately circumstantial, lines of biochemical evidence. Also, RNA’s genetic/catalytic duality is a simple, elegant solution to the daunting problem of how to start a replicating system from scratch. In such an ‘RNA World,’ catalytically active RNA molecules (ribozymes) produced progeny by making copies of themselves and passing on the occasional mutation, evolving to greater complexity.

The Joyce laboratory has previously developed a replicating genetic system comprised of a matched pair of ribozymes that each catalyze the covalent joining of two smaller RNA substrates (the Lincoln replicase). The substrates are designed such that they form an active copy of their ribozyme partner once joined together (Figure 1). The Lincoln replicase is the first example outside of biology of a genetic system that is autocatalytic (i.e. the products of the reaction catalyze the formation of more product), self-sustained (i.e. no evolved components external to the system are required for its function), and undergoes exponential growth. It is the only model system currently available to study the exponential growth of an RNA population. However, the system in its present form is not capable of evolving novel functions, which limits its general applicability and precludes its designation as a living system.

The focus of current efforts are to improve the efficiency of the replicase with regard to its ability to operate as a large evolving population. The challenge is that as population sizes increase, the absolute amount of any individual component decreases, eventually limiting the ribozyme’s ability to bind specific components efficiently. This limitation is being addressed using directed evolution techniques to improve the ribozyme’s substrate-joining ability under more dilute conditions. The improved version of the replicase will be used to generate a new library of replicases with an encoded domain of random sequence. This library will be used to isolate variants that are able to perform a specific catalytic function while retaining exponential replication activity. Such a result will further demonstrate the viability of a pathway from the simplest RNA-based replicator to the sophistication and diversity of modern life.

Robertson Figure

Figure 1. The replicase reaction scheme. Component ribozymes are depicted in blue or orange and labeled as E or E’, respectively. Substrates are depicted in the color of the full-length ribozyme they form when joined, and labeled as A and B (forms E) or A’ and B’ (forms E’)

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