Jack Szostak’s Lab

In the early 1970s, Jack Szostak began his graduate studies at Cornell. There, he worked with the DNA of yeast. Over the next decade and a half, that work deepened and spread, culminating in Szostak’s discovery of how the vulnerable ends of yeast chromosomes, and indeed all chromosomes, are protected by molecules called “telomeres”—work for which he won the Nobel Prize (shared with Elizabeth Blackburn and Carol Greider).

In the late 1980s, Szostak began shifting his focus to RNA (ribonucleic acid), a molecule very similar to DNA and thought to be its ancestor in the evolution of life. Since then, Szostak and the researchers in his lab have been at the forefront of the creation of life from nonlife. Some of their significant achievements include the creation of cell membranes from simple chemicals and demonstrating how these membranes could grow and divide under simple chemical and physical processes, and understanding how RNA can be replicated within a primitive surrounding membrane.

Szostak and many other biologists who study the origin of life subscribe to a view called the “RNA World.” This concept, first proposed by biologist and biophysicist Alexander Rich in 1962, holds that the first replicating molecule in Earth’s early history was not DNA but RNA. The two molecules are chemical cousins. They differ in a few ways. In modern cells, most DNA is a double-stranded helix, while most RNA is single-stranded; one of the four letters of the genetic alphabet used by the two molecules is different, and the backbones of the two molecules incorporate slightly different sugar molecules. (The sugar molecule found in DNA derives from the simpler sugar molecule in RNA, another reason why many biologists believe that RNA came first.) Both RNA and DNA store information for the reproduction of the organism. Unlike DNA, RNA has other duties in the cell. It reads the information on the DNA molecule and then carries that information to another part of the cell where proteins are made. Thus, RNA can be both an architect and a builder.

Says Szostak, “We are interested in the chemical and physical processes that facilitated the transition from chemical evolution to biological evolution on the early Earth. To explore these processes, our laboratory is trying to build a synthetic cellular system that undergoes Darwinian evolution. Our view of what such a chemical system would look like centers on a model of a primitive cell, or protocell, that consists of two main components: a self-replicating genetic polymer and a self-replicating membrane boundary.”

Biologists do not entirely agree about when to declare a particular smidgeon of matter “alive.” In general, the requirements include some kind of surrounding membrane (what Szostak calls a “compartment” or “vesicle”) to separate the organism from the outside world and to confine the most critical molecules in close proximity, the ability to utilize energy sources, the ability to grow, the ability to reproduce, and the ability to evolve. In a 2001 paper in the prominent journal Nature, Szostak and colleagues identified four vital ingredients of a minimal living cell: a compartment, an embedded molecule like RNA or DNA that can replicate, a means for that replication, and some interaction between the compartment wall and the replicating molecule so that they can help each other in response to the forces of Darwinian evolution. What distinguishes Szostak’s work in this field from the work of many other synthetic biologists is that he wants to create a living cell from scratch, using only the simple molecules present in the primordial Earth, which he calls “prebiotic” molecules. By contrast, most other labs start with complex molecules snatched from existing life forms, and have already benefited from natural selection and evolution over hundreds of millions of years.

In 2003, Szostak and his colleagues demonstrated that a common mineral clay called montmorillonite, formed from volcanic ash and used in cat litter today, could accelerate the assembly of cell “compartments” needed for life using only the simple molecules available in the primordial Earth. Montmorillonite seems to be an extraordinary catalyst. It was already known that it could help assemble RNA molecules from their basic building blocks. Now, Szostak and his colleagues found that when placed in contact with the clay, simple molecules called fatty acids bond together to form membranes. The membranes then automatically close up and assemble tiny fluid-filled sacs, or compartments, which could contain replicating molecules like RNA or DNA. Furthermore, these microscopic sacs grow all by themselves in the presence of clay by incorporating other fatty acids. Evidently, the surface of the clay has unique geometrical and chemical properties that catalyze these reactions. Szostak and his colleagues also showed that passing the tiny sacs through a material with small pores would cause them to divide, in a sense, “reproducing.” Thus, he demonstrated a cell compartment’s creation, growth, and reproduction.

Szostak believes that a primitive cell might not need much more in its innards than a strand of RNA and some simple chemicals to serve as raw construction materials. How that construction occurs is not yet understood—a significant obstacle to understanding how to create life from nonlife. “In my view, the critical problem right now is understanding the chemistry that enabled the first mode of RNA replication,” says Szostak. In other words, exactly how does the replication molecule, carrying all the blueprints for the cell, replicate itself? Szostak says it is easy to replicate RNA using protein enzymes (catalysts) and other complex molecules developed over millions of years of evolution. But he wants to know how life began. He is trying to show how RNA replication could have happened on primitive Earth, with only the simple molecules then in existence. “Our approach has a way to go: so far, we can copy short stretches of an RNA template to generate a complementary strand in the form of an RNA double helix.  However, our ability to copy RNA is limited to very short lengths, and we cannot yet do multiple cycles of copying; in other words, copy the copies.  Indefinite replication within protocells is our goal because we think that with replicating RNA inside replicating vesicles [membrane compartments], we would have a system capable of evolving in a Darwinian sense.”

SOURCES: University of Chicago Profile; Harvard Profile; The Origin of Life on Earth, Explained; “Modern Prometheus” in Probable Impossibilities (Pantheon Books, 2021) by Alan Lightman

Additional reference: 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.