The Origins of Life
The complexity of modern biological life has long made it difficult to understand how life could emerge spontaneously from the chemistry of the early earth. The key to resolving this mystery lies in the simplicity of the earliest living cells. Through our efforts to synthesize extremely simple artificial cells, we hope to discover plausible pathways for the transition from chemical evolution to Darwinian evolution. We view the two key components of a primitive cell as a self-replicating nucleic acid genome, and a self-replicating boundary structure. We have uncovered simple and robust pathways for the coupled growth and division of primitive cell membranes, and have made significant experimental progress towards the synthesis of self-replicating nucleic acids. Recently, we have begun to investigate potential routes for the emergence of coded peptide synthesis from the chemistry of the RNA World. We are also interested in model systems that may provide a route to artificial life with a biochemistry that is distinct from that of existing biology.
References
- Szostak JW. The Narrow Road to the Deep Past: In Search of the Chemistry of the Origin of Life. Angew. Chemie Int. Ed. Engl., 2017; 56:11037-11043.
- Joyce GF, and Szostak JW. Protocells and RNA Self-Replication. Cold Spring Harbor Perspectives in Biology. 2018; 10(9). pii: a034801.
Nonenzymatic RNA Replication
The RNA genomes of the first cells are thought to have emerged from the nonenzymatic replication of short RNA strands. Several recent developments have enhanced our ability to copy RNA templates by primer extension. Through thermodynamic and kinetic studies, we demonstrated an important catalytic role for activated downstream nucleotides and oligonucleotides. We subsequently showed that this catalytic effect was due to the formation of a covalent imidazolium-bridged dinucleotide intermediate in primer extension. Mechanistic studies then led to the identification of 2-aminoimidazole as a superior nucleotide activating moiety. Our kinetic and crystallographic studies have provided insight into the mechanism of this key reaction, and to improvements in RNA copying chemistry that are both more prebiotically plausible and more accurate, efficient, and general.
Prebiotic chemistry is likely to have given rise not only to ribonucleotides, but also to related compounds with variations in the chemistry of the nucleobase and sugar components. Oligomers of such nucleotides would also have had significant heterogeneity in their backbone structure. Surprisingly, we find that ribonucleotides are typically more effective than likely alternatives in nonenzymatic template copying reactions. Our findings suggest a model for the transition from early heterogeneous nucleic acids to a more homogeneous form that is closer to modern RNA.
Going beyond simple template copying to multiple cycles of replication remains a key challenge. We have recently proposed the Virtual Circular Genome model for primordial RNA replication. This model avoids any requirement for specific primers, as well as problems related to the replication of the ends of linear sequences. We are currently working towards establishing a viable experimental system for nonenzymatic RNA replication based upon this model
References
- Fahrenbach AF, Giurgiu C, Tam CP, Li L, Hongo Y, Aono M and Szostak JW. Common and Potentially Prebiotic Origin for Precursors of Nucleotide Synthesis and Activation. J. Am. Chem. Soc., 2017; 139:8780-8783.
- Zhang W, Walton T, Li L, Szostak JW. Direct observation of nonenzymatic primer extension by X-ray crystallography. eLife, 2018; 7:e36422.
- Kim S, Zhang W, O’Flaherty D, Zhou L, Rondo-Brevetta V, Szostak JW. A model for the emergence of RNA from a prebiotically plausible mixture of ribonucleotide arabinonucleotides and 2′-deoxynucleotides. J. Am. Chem. Soc., 2020; 142:2317-2326.
- Zhou L, Ding D, Szostak JW. The virtual circular genome model for primordial RNA replication. RNA, 2021; 27:1-11.
Model Protocells
Very primitive cells may have consisted of a self-replicating nucleic acid genome, encapsulated within a self-replicating cell membrane. We have recently described robust pathways for the coupled growth and division of primitive cell membranes composed of fatty acids, which were likely to have been available prebiotically. Fatty acid membranes are remarkably permeable to charged small molecules such as nucleotides, which can be added to the outside of fatty acid vesicles so that RNA copying can proceed inside the vesicles. However, a major unresolved problem is that fatty acid vesicles are destroyed by the high concentrations of divalent cations such as Mg2+ that are required for RNA copying. This problem can be overcome by chelating the Mg2+ with citrate, but the search for a more plausible solution continues.
References
- Budin I, Prywes N, Zhang N, and Szostak JW. Chain-length heterogeneity allows for the assembly of fatty acid vesicles in dilute solutions. Biophys. J., 2014; 107:1582-90.
- O’Flaherty D, Kamat NP, Mirza FN, Li L, Prywes N, and Szostak JW. Copying of mixed sequence RNA templates inside model protocells. J. Am. Chem. Soc., 2018; 140:5171-5178.
- Kindt J, Szostak JW, Wang A. Bulk self-assembly of giant, unilamellar vesicles. ACS Nano., 2020; 14:14627-14634.
The Origins of Translation
In modern biology, the ribosomal synthesis of proteins makes use of aminoacylated RNAs as substrates. Therefore, aminoacylated RNAs must have existed before the evolution of the primordial ribosome. However, the spontaneous chemical generation of such substrates is inefficient, and aminoacylated RNAs are unstable due to hydrolysis. We are searching for potential roles for aminoacylated RNAs that may have been important prior to the evolution of coded peptide synthesis. Recently we showed that aminoacylated RNAs can rapidly assemble into chimeric amino acid-bridged ribozymes that retain their native enzymatic activity. This potential role for RNA aminoacylation could have driven the evolution of aminoacyl-RNA synthetase ribozymes that were both sequence and amino acid specific, thereby setting the stage for the evolution of coded peptide synthesis.
References
- Radakovic A, Wright T, Lelyveld V, Szostak JW. A Potential Role for Aminoacylation in Primordial RNA Copying Chemistry. Biochemistry, 2021; 60:477-488.
- Radakovic A, DasGupta S, Wright TH, Aitken HRM, and Szostak JW. Nonenzymatic assembly of active chimeric ribozymes from aminoacylated RNA oligonucleotides. Proc. Natl. Acad. Sci. USA, 2022. Published online 2022 Feb 15; 119(7):e2116840119.
McGill University
B.S. (Cell Biology)
1972
Cornell University
Ph.D (Biochemistry)
1977
Cornell University
Research Associate (Biochemistry)
1979
Harvard Medical School
Assistant Professor, Sidney Farber Cancer Institute and Department of Biological Chemistry
1983
Harvard Medical School
Associate Professor, Dana Farber Cancer Institute and Department of Biological Chemistry
1984
Massachusetts General Hospital
Associate Molecular Biologist, Department of Molecular Biology
1987
Harvard Medical School
Associate Professor, Department of Genetics
1987
Harvard Medical School
Professor, Department of Genetics
Massachusetts General Hospital
Professor, Department of Molecular Biology
Howard Hughes Medical Institute
Investigator
Massachusetts General Hospital
Alex Rich Distinguished Investigator, Department of Molecular Biology
Harvard University
Professor of Chemistry and Chemical Biology, Faculty of Arts and Sciences
University of Chicago
Visiting Professor
University of Chicago
Professor
Imbach-Townsend Award, IS3NA
2020
Dewey-Kelley Award, Dept. of Chemistry, University of Nebraska-Lincoln
2020
Fellow of the Royal Society
2019
Walker Prize, Museum of Science, Boston MA
2019
Westheimer Prize, Dept. of Chemistry and Chemical Biology, Harvard University
2019
Wheland Medal, Dept. of Chemistry, University of Chicago
2018
Doctorate honoris causa, University of Sherbrooke, PQ, Canada
2017
Doctorate honoris causa, University of Buenos Aires
2016
Doctorate honoris causa, University of British Columbia
2014
Butcher Award, University of Colorado Boulder
2013
IUBMB Medal
2013
Fellow, American Academy of Cancer Researchers
2013
Fellow, National Academy of Inventors
2012
Honorary Professor, Sichuan University
2012
Member, American Philosophical Society
2012
Fellow of the Royal Society of Chemistry (U.K.)
2011
Harold C. Urey Medal, International Society for the Study of the Origin of Life
2011
Doctorate honoris causa, McGill University
2011
Member, Cambridge Scientific Club
2010
Delphi Idea Wisdom Award, National and Kapodistrian University of Athens
2010
Fellow, American Society of Microbiology
2010
Nobel Prize in Physiology or Medicine
2009
H.P. Heineken Award in Biochemistry and Biophysics
2008
Andrew Braisted Award Lectureship in Chemical Biology, UCSF/Berkeley
2007
Fellow, AAAS
2006
Albert Lasker Award for Basic Medical Research
2006
Visiting Fellow, Brasenose College and Astor Lecturer, Oxford University
2005
Harrison Howe Award, American Chemical Society, Rochester section
2003
Genetics Society of America Medal
2000
Fellow, New York Academy of Sciences
1999
Fellow, American Academy of Arts and Sciences
1999
Member, National Academy of Sciences
1998
Hans Sigrist Prize, University of Bern, Switzerland
1997
Louis Vuitton-Moet Hennesey 'Vinci of Excellence' Award
1996
Dolman Lectures and Award, University of British Columbia
1996
National Academy of Sciences Award in Molecular Biology
1994
National Research Council of Canada Postdoctoral Fellowship
1978
Andrew D. White Fellowship, Cornell University
1975
Penhallow Prize in Botany, McGill University
1972
Walter W. Ross III Memorial Scholarship
1971
McGill University Scholarship
1971
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