Jack W. Szostak
Professor of Chemistry and Chemical Biology, Harvard University
Dept. of Molecular Biology, and Ctr. for Computational & Integrative Biology
Origins of life, self-replicating systems.
Our work is focused on the synthesis of simple living systems from non-living components, as a means of studying the origin of life. The unifying principle of biology is Darwinian evolution, so in our view the synthesis of life is essentially equivalent to the synthesis of a supra-molecular assemblies that are capable of evolving autonomously. We think that this can be accomplished by combining two types of replicating system – one encoding genetic information, and one maintaining spatial localization. A self-replicating genetic system could in principle be based on molecules such as RNA, DNA, or any of a number of structurally related molecules which have the ability to transmit coded information through the replication of complementary strands. We are now exploring a variety of chemical strategies for the spontaneous replication of such nucleic acids. A self-replicating system of spatially localized compartments could in principle be based on lipid vesicles. We have recently identified multiple distinct pathways by which fatty acid vesicles can be made to grow and divide solely under the influence of chemical and physical forces.
Vesicle growth occurs when pre-formed vesicles are fed with new lipid in the form of micelles, or in a variety of competitive scenarios in which some vesicles grow at the expense of neighboring vesicles. Remarkably, in all cases initially spherical vesicles grow into long thin filamentous vesicles. Division can be mediated by gentle shear forces acting on these thread-like vesicles, or as a result of a cascade of photochemically triggered reactions. Our efforts on this front are now devoted to understanding the mechanistic details of these processes. In a prebiotic scenario, the replication of encapsulated genetic materials such as RNA must be driven by chemical and physical processes, without enzymes. We have recently found simple and robust conditions that allow for the nonenzymatic copying of RNA sequences containing all four nucleotides. We continue to explore the chemistry of nonenzymatic RNA replication through mechanistic reaction kinetics, structural, and computational approaches. Finally, the interactions between the genetic and membrane components of a protocell pose numerous interesting problems. We have recently found that suitably activated nucleotides can spontaneously cross fatty acid membranes, and can then take part in template copying reactions in the protocell interior. Nucleic acid molecules replicating inside replicating vesicles should begin to evolve spontaneously due to the strong selection for better protocell replication. By pursuing the development of spontaneously replicating and evolving molecular assemblies in the laboratory, we hope to uncover constraints on the origin of life on earth, and perhaps to find explanations for some of the universal aspects of current biological life.
Adamala K and Szostak JW. Non-enzymatic RNA copying inside fatty acid vesicles. Science, 2013; 342:1098-1100.
Prywes N, Blain JC, Del Frate F and Szostak JW. Nonenzymatic copying of RNA templates containing all four letters is catalyzed by activated oligonucleotides. eLife, 2016; 5:e17756.
Walton T and Szostak JW. A highly reactive imidazolium-bridged dinucleotide intermediate in nonenzymatic RNA primer extension. J. Am. Chem. Soc., 2016; 138:11996-12002.
Li L, Prywes N, Tam CP, O’Flaherty DK, Lelyveld VS, Izgu EC, Pal A, and Szostak JW. Enhanced nonenzymatic RNA copying with 2-aminoimidazole-activated nucleotides. J. Am. Chem. Soc. 2017; 139:1810-1813.
Zhang W, Tam C-P, Walton T, Fahrenbach AC, Birrane G, and Szostak JW. Insight into the mechanism of nonenzymatic RNA primer extension from the structure of an RNA-GpppG complex. Proc. Natl. Acad. Sci. USA, 2017; 114:7659-7664.
Simches Research Center, Room 7215
185 Cambridge Street, Boston, MA 02114