Jack W. Szostak
Department of Genetics, Harvard Medical School
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. Growth occurs when pre-formed vesicles are fed with new lipid in the form of micelles, or when osmotically swollen vesicles grow at the expense of relaxed neighboring vesicles. Division can be mediated by extrusion through small pores in filters, or, in a more prebiotically realistic scenario, by gentle shear forces acting on thread-like vesicles. Our efforts on this front are now devoted to understanding the mechanistic details of these processes. The interactions between the genetic and membrane components of a protocell pose numerous interesting problems, including the means by which externally synthesized nucleotides could enter the protocell. 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 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.
Szostak JW, Bartel DP, Luisi PL. (2001) Synthesizing life. Nature 409: 387-390.
Hanczyc, M.M., Fujikawa, S.M., and Szostak, J.W. (2003) Experimental Models of Primitive Cellular Compartments: Encapsulation, Growth and Division. Science 302: 618-622.
Chen, I.A., Roberts, R.W., and Szostak, J.W. (2004) The emergence of competition between model protocells. Science 305: 1474-76.
Mansy, S.S., Schrum, J.P., Krishnamurthy, M., Tobé, S., Treco, D., and Szostak, J.W. (2008) Template-directed Synthesis of a Genetic Polymer in a Model Protocell. Nature 454: 122-5.
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