About

Jack W. Szostak is a University Professor in the Department of Chemistry at The University of Chicago, with research interests spanning chemical biology, biophysics, organic chemistry, and physical chemistry. His work primarily focuses on understanding the origins of life, particularly how life could have emerged spontaneously from early Earth chemistry. Szostak's research involves synthesizing simple artificial cells to uncover plausible pathways for the transition from chemical evolution to Darwinian evolution, emphasizing the roles of self-replicating nucleic acid genomes and boundary structures such as primitive cell membranes. His laboratory has made significant progress in the synthesis of self-replicating nucleic acids, the coupled growth and division of primitive cell membranes, and investigating routes for the emergence of coded peptide synthesis from the RNA World. Szostak's work also explores model systems that could lead to artificial life with biochemistries different from those of existing biology, including the development of models like the Virtual Circular Genome for primordial RNA replication. His contributions extend to understanding nonenzymatic RNA replication, the formation and stability of protocells, and the potential roles of aminoacylated RNAs in early peptide synthesis. Szostak's extensive career includes positions at Harvard Medical School, Massachusetts General Hospital, and McGill University, along with numerous awards and honors, including the Nobel Prize in Physiology or Medicine in 2009.

Research topics

• Chemistry
• Biology
• Biochemistry
• Computational biology
• Genetics

Selected publications

• Mg2+ Catalyzes Nonenzymatic RNA Primer Extension through a Concerted Outer-Sphere Mechanism

  ChemRxiv · 2026-03-22

  articleOpen accessSenior author

  The nonenzymatic replication of the primordial genetic material was an essential stage in the origin of life. One intensively studied model for this process is the template-directed extension of an RNA primer with imidazolium-bridged dinucleotide substrates. This reaction is catalyzed by divalent metal ions such as Mg 2+ , but the mechanism of catalysis remains poorly understood. We have utilized classical molecular dynamics (MD) together with hybrid quantum mechanics/molecular mechanics (QM/MM) to investigate the catalytic role of Mg 2+ . We used these approaches to compute the free energy landscape along key reaction coordinates, and to quantify the impact of Mg 2+ coordination at each step of the primer extension reaction. The presence of Mg 2+ in the reaction center significantly lowers the pKa of the nucleophilic 3′-OH group and reduces the probability of O2′ attack. Based on the energetics of potential reaction pathways, our results suggest a preferred mechanism in which Mg 2+ becomes outer sphere coordinated to the oxygen of the 3′-hydroxyl group of the extending primer, followed by concerted proton transfer and nucleophilic attack on the phosphate of the incoming nucleotide. Our results demonstrate the dual structural and electronic roles of Mg 2+ in catalysis and provide insights that may inform the search for metal ion chelators that further enhance nonenzymatic primer extension.

  PublisherDOI

• Conditioning as a route to stereotyped behavior in growing populations

  ArXiv.org · 2026-05-13

  articleOpen access

  Biological systems perform complex multi-step processes in a reproducible way despite underlying stochasticity. The standard explanation is micromanagement by molecular machinery that recognizes and corrects specific errors. Here we study conditioning, a qualitatively different strategy in which attempts failing a coarse criterion are destroyed and do not leave a physical record. The surviving, i.e., conditioned, ensemble is narrower and therefore more ordered. We model conditioning through stochastic resets in a ''socks-before-shoes'' model of a growing population, where $n$ actions must be completed in any order to replicate and any replication attempt not finished by a threshold time is discarded. We find that resets impose hierarchical temporal ordering of the $n$ actions without microscopic control over which action happens when. When disorder carries a sufficient time penalty, this ordering is free: the fastest-growing population is automatically the most ordered, with no direct selection for order required. Save points, at which verified progress is preserved across resets, allow conditioning to scale to complex multi-step processes. Conditioning provides a minimal route to reliable behavior, requiring only a clock rather than molecular machinery that recognizes specific errors. For the right class of processes, it pays for itself.

  PublisherOA PDF

• Influence of Phosphate Activation Chemistry on the Selection of the Primordial Genetic Alphabet

  Journal of the American Chemical Society · 2026-03-30

  articleOpen accessSenior authorCorresponding

  RNA copying under mild conditions compatible with protocell integrity requires the input of chemical energy to drive the synthesis of activated nucleotides such as phosphorimidazolides. Recently, two potentially prebiotic classes of phosphate-activating agents have been explored, one based on isonitrile–aldehyde chemistry, the other on imine diimidazole (IDI)-N-cyanoimidazole (NCI) chemistry. Because such highly electrophilic activating agents may lead to undesirable nucleotide modifications, we have examined the reaction of both types of activating agents with the canonical ribonucleotides A, U, C, and G, and the potentially primordial nucleotides 2-thio-C (s2C), 2-thio-U (s2U), and inosine (I). We find that the isonitrile–aldehyde system shows minimal hydroxyl modification but does modify the nucleobases of U, G, s2U, and I. Except for guanosine, these modifications are readily reversible. In contrast, IDI-NCI systems acylate ribonucleotide hydroxyls while modifying nucleobases only transiently; mildly acidic pH suppresses undesired modifications. Both classes of activating agents modify 2-thiopyrimidines on the sulfur, with the isonitrile–aldehyde reaction promoting desulfurization and thus conversion to the canonical pyrimidines. To evaluate compatibility with model protocells, we tested the effects of activation chemistry on fatty acid vesicles and found that protocell integrity was preserved at moderate reagent concentrations. Our findings show that the potentially primordial s2U, s2C, and I nucleotides are more sensitive to modification than the canonical U, C, and G nucleotides, potentially contributing to the chemical selection of the early genetic alphabet.

  PublisherDOI

• Ultraviolet-Driven Self-Repair in Chimeric d(GAUU) Outcompetes Damage Formation

  Chemical Communications · 2026-01-01

  article

  The stability of nucleic acids under intense ultraviolet (UV) irradiation was key to the persistence of life on Earth. Among the canonical nucleobases, pyrimidines are most susceptible to UV photodamage,...

  PublisherDOI

• Mg2+ Catalyzes Nonenzymatic RNA Primer Extension through a Concerted Outer-Sphere Mechanism

  ChemRxiv · 2026-03-31

  articleOpen accessSenior author

  The nonenzymatic replication of the primordial genetic material was an essential stage in the origin of life. One intensively studied model for this process is the template-directed extension of an RNA primer with imidazolium-bridged dinucleotide substrates. This reaction is catalyzed by divalent metal ions such as Mg 2+ , but the mechanism of catalysis remains poorly understood. We have utilized classical molecular dynamics (MD) together with hybrid quantum mechanics/molecular mechanics (QM/MM) to investigate the catalytic role of Mg 2+ . We used these approaches to compute the free energy landscape along key reaction coordinates, and to quantify the impact of Mg 2+ coordination at each step of the primer extension reaction. The presence of Mg 2+ in the reaction center significantly lowers the pKa of the nucleophilic 3′-OH group and reduces the probability of O2′ attack. Based on the energetics of potential reaction pathways, our results suggest a preferred mechanism in which Mg 2+ becomes outer sphere coordinated to the oxygen of the 3′-hydroxyl group of the extending primer, followed by concerted proton transfer and nucleophilic attack on the phosphate of the incoming nucleotide. Our results demonstrate the dual structural and electronic roles of Mg 2+ in catalysis and provide insights that may inform the search for metal ion chelators that further enhance nonenzymatic primer extension.

  PublisherDOI

• Conditioning as a route to stereotyped behavior in growing populations

  arXiv (Cornell University) · 2026-05-13

  preprintOpen access

  Biological systems perform complex multi-step processes in a reproducible way despite underlying stochasticity. The standard explanation is micromanagement by molecular machinery that recognizes and corrects specific errors. Here we study conditioning, a qualitatively different strategy in which attempts failing a coarse criterion are destroyed and do not leave a physical record. The surviving, i.e., conditioned, ensemble is narrower and therefore more ordered. We model conditioning through stochastic resets in a ''socks-before-shoes'' model of a growing population, where $n$ actions must be completed in any order to replicate and any replication attempt not finished by a threshold time is discarded. We find that resets impose hierarchical temporal ordering of the $n$ actions without microscopic control over which action happens when. When disorder carries a sufficient time penalty, this ordering is free: the fastest-growing population is automatically the most ordered, with no direct selection for order required. Save points, at which verified progress is preserved across resets, allow conditioning to scale to complex multi-step processes. Conditioning provides a minimal route to reliable behavior, requiring only a clock rather than molecular machinery that recognizes specific errors. For the right class of processes, it pays for itself.

  PublisherDOI

• Autocatalytic assembly of a chimeric aminoacyl-RNA synthetase ribozyme

  Science Advances · 2025-04-02 · 1 citations

  articleOpen accessSenior authorCorresponding

  Autocatalytic reactions driving the self-assembly of biological polymers are important for the origin of life, yet few experimental examples of such reactions exist. Here we report an autocatalytic assembly pathway that generates a chimeric, amino acid-bridged aminoacyl-RNA synthetase ribozyme. The noncovalent complex of ribozyme fragments initiates low-level aminoacylation of one of the fragments, which, after loop-closing ligation, generates a highly active covalently linked chimeric ribozyme. The generation of this ribozyme is increasingly efficient over time due to the autocatalytic assembly cycle that sustains the ribozyme over indefinite cycles of serial dilution. Because of its trans activity, this ribozyme also assembles ribozymes distinct from itself, such as the hammerhead, suggesting that RNA aminoacylation, coupled with nonenzymatic ligation, could have facilitated the emergence and propagation of ribozymes.

  PublisherDOI

• Suppression of errors in collectively coded information.

  PubMed · 2025-09-24

  articleOpen access

  Modern life largely transmits genetic information from mother to daughter through the duplication of single physically intact molecules that encode information. However, copying an extended molecule requires complex copying machinery and high fidelity that scales with the genome size to avoid the error catastrophe. Here, we explore these fidelity requirements in an alternative architecture, the virtual circular genome, in which no one physical molecule encodes the full genetic information. Instead, information is encoded and transmitted in a collective of overlapping and interacting segments. Using a model experimental system of a complex mixture of DNA oligomers that can partly anneal and extend off each other, we find that mutant oligomers are suppressed relative to a model without collective encoding. Through simulations and theory, we show that this suppression of mutants can be explained by competition for productive binding partners. As a consequence, information can be propagated robustly in a virtual circular genome even at mutation rates expected under prebiotic conditions.

  PublisherOA PDF

• Nanopore-based profiling of PEGylation in nucleic acid therapeutics

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-17

  articleOpen access

  ABSTRACT Nucleic acid therapeutics, including aptamers, offer effective strategies for programmable and targeted disease treatment. To improve their stability and circulation time, oligonucleotides are often conjugated to hydrophilic polymers such as polyethylene glycol (PEG). However, current bulk techniques fail to resolve PEG heterogeneity, especially in complex biological environments. Here, we use nanopore sensing to quantify PEG conjugation efficiency of the FDA-approved RNA aptamer pegaptanib. We assembled DNA nanostructures that bind pegaptanib and then we used solid-state nanopores to quantify pegaptanib PEGylation. We further assess pegaptanib PEGylation in a serum background and demonstrate that nanopore sensing resolves PEG moieties of distinct molecular weights within oligonucleotide conjugates. Single-molecule profiling of polymer-RNA conjugates enables iterative improvements in oligonucleotide design and provides a direct means to assess their stability in complex biological environments, thereby advancing the development of more effective nucleic acid therapeutics.

  PublisherDOI

• Nanopore sequencing of intact aminoacylated tRNAs

  Nature Communications · 2025-08-20 · 11 citations

  articleOpen access

  The intricate landscape of tRNA modification presents persistent analytical challenges, which have impeded efforts to simultaneously resolve sequence, modification, and aminoacylation state at the level of individual tRNAs. To address these challenges, we introduce "aa-tRNA-seq", an integrated method that uses chemical ligation to sandwich the amino acid of a charged tRNA in between the body of the tRNA and an adaptor oligonucleotide, followed by high throughput nanopore sequencing. Our approach reveals the identity of the amino acids attached to all tRNAs in a cellular sample, at the single molecule level. We describe machine learning models that enable the accurate identification of amino acid identities based on the unique signal distortions generated by the interactions between the amino acid in the RNA backbone and the nanopore motor protein and reader head. We apply aa-tRNA-seq to characterize the impact of the loss of specific tRNA modification enzymes, confirming the hypomodification-associated instability of specific tRNAs, and identifying additional candidate targets of modification. Our studies lay the groundwork for understanding the efficiency and fidelity of tRNA aminoacylation as a function of tRNA sequence, modification, and environmental conditions.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM053936

  NIH · $2.0M · 2005

• Darwinian Chemical Systems

  NSF · $1.5M · 2004–2007

• Nonenzymatic RNA Replication

  NSF · $1.0M · 2021–2023

• Non-Enzymatic RNA Replication

  NSF · $1.0M · 2016–2021

• Self-Replicating Nucleic Acids

  NSF · $540k · 2008–2012

Frequent coauthors

• Lijun Zhou

  University of Pennsylvania

  206 shared

• Albert C. Fahrenbach

  UNSW Sydney

  170 shared

• Chun Pong Tam

  Howard Hughes Medical Institute

  143 shared

• Dian Ding

  Massachusetts General Hospital

  142 shared

• Derek K. O’Flaherty

  University of Guelph

  138 shared

• Wen Zhang

  Xi’an University

  106 shared

• Victor S. Lelyveld

  Massachusetts General Hospital

  95 shared

• Stephanie J. Zhang

  94 shared

Awards & honors

• Imbach-Townsend Award, IS3NA 2020
• Dewey-Kelley Award, Dept. of Chemistry, University of Nebras…
• Fellow of the Royal Society 2019
• Walker Prize, Museum of Science, Boston MA 2019
• Westheimer Prize, Dept. of Chemistry and Chemical Biology, H…