The Surprising Chemistry of Nonenzymatic RNA Replication

Marshall W. Nirenberg Lecture | Friday, May 1, 2026 | 2:00 to 3:00 p.m. ET

Jack W. Szostak, PhD

University Professor

The University of Chicago

jwszostak@uchicago.edu

Website

Jack Szostak is a biologist of Polish British descent, Nobel Prize laureate, university professor at the University of Chicago, former professor of genetics at Harvard Medical School, and Alexander Rich Distinguished Investigator at Massachusetts General Hospital, Boston. Szostak has made significant contributions to the field of genetics. His achievement helped scientists to map the location of genes in mammals and to develop techniques for manipulating genes. His research findings in this area are also instrumental to the Human Genome Project. He was awarded the 2009 Nobel Prize for Physiology or Medicine, along with Elizabeth Blackburn and Carol W. Greider, for the discovery of how chromosomes are protected by telomeres.

Summary

Once the ability of life to evolve in a Darwinian sense had become firmly established, life was free to adapt, diversify, and flourish, eventually giving rise to all the varieties of life we see around us today. However, during the origin of life, there were no protein polymerases or even ribozymes to catalyze the replication of the genetic material. Our work and many prior studies have shown that nonenzymatic primer extension proceeds with an error rate that is too high to allow for the evolution of even a small ribozyme. One solution to this conundrum arises from the observation that primer extension following most mismatches is very slow. In the context of the virtual circular genome (VCG) model for primordial replication, this stalling effect results in oligonucleotides with a terminal mismatch being diluted out, while correctly extended oligos continue to take part in the replication cycle. 

Learning Objectives: 

• How could RNA have replicated prior to the evolution of ribozyme or protein polymerases?
• What factors might mitigate the high error rate of nonenzymatic RNA copying chemistry?