This project will continue work on the chemical synthesis of polymers that can both carry information in their sequence and replicate that information chemically without using enzymes. These experiments are inspired by the desire to understand the emergence of information carrying molecules such as RNA during the origin of life on earth. Basic chemical principles are used to design simple variants of RNA and DNA that may be capable of chemical replication, such as a family of nucleic acids in which the hydroxyl nucleophile is replaced with an amino group, which is a stronger nucleophile. This change, coupled with the use of more active leaving groups as well as nucleobases that enhance duplex stability, should lead to faster chemical copying of template sequences. The project will also explore ways in which replication may be accelerated through the use of simple catalysts, or through localization to mineral surfaces or membrane vesicles.
With this award, the Organic and Macromolecular Chemistry Program and the Genes and Genome Systems Cluster program are supporting the research of Professor Jack W. Szostak of the Department of Molecular Biology at Massachusetts General Hospital. Professor Szostak's research is aimed at understanding the origin of life on the early earth, a topic that has always attracted great public interest. Because this work explores the connection between chemistry and biology at a very fundamental level, it is also of great interest to students, and will help to attract young people to the chemical sciences.
Modern cells use complex, highly evolved enzymes to direct the rapid and accurate copying of their set of DNA molecules. The first cells lacked such enzymes, raising the question of how their genetic material was copied. Decades of effort by many laboratories has enabled the partial copying of certain short templates, but chemically driven copying remains too inefficient to explain the replication of the genetic material of primitive cells. We set out to study the chemical copying of molecules closely related in structure to DNA and RNA in an effort to learn general principles controlling the chemical copying of genetic materials, with the goal of eventually applying these lessons to RNA replication. Our experiments have shown that in order to be copied efficiently, the strand to be copied (known as the template strand) must be held in the correct shape, which is the shape adopted by an RNA strand in an RNA double-helix. We have also shown that in certain model systems, very simple chemical changes can lead to greatly increased copying accuracy. For example, replacing the oxygen at position 2 of thymidine with sulfur results in formation of a stronger A:T base-pair, a weaker G:T wobble pair, and therefore enhanced accuracy in template copying. These and other advances are bringing us closer to demonstrating self-replication in simple model systems. We are now in the process of seeing whether these advances apply to an all RNA system. Broader implications The origin of life has been the subject of scientific studies for over a century, and a subject of speculation and myth for millennia. Systematic scientific studies of the many steps involved in the transition from chemistry to biology on the early life are necessary, in order to build up a reasonable, natural explanation for the origin of life. Our studies, supported by this grant, have begun to provide clues to chemical replication pathways for both RNA and certain closely related nucleic acids, bringing us closer to a chemical explanation for the origin of life.
