Over the next decade, Szostak's team worked out methods to evolve new and useful RNAs, and later DNAs, from scratch. Jon Lorsch, then a grad student in the lab and now a professor of biophysics and biophysical chemistry at the Johns Hopkins School of Medicine, recalls “an interestingly laid-back and fun place,” with Szostak “spending a lot of time sitting on the couch in his office reading papers and thinking great thoughts.”

Lorsch himself took lab-evolved RNAs that bound ATP (the cell's energy-supplying molecule) and evolved them further in test tube experiments into RNAs that actually catalyzed chemical reactions on ATP. “Even though everyone else said it was crazy, Jack knew it was going to work.” Szostak's decade of work on RNA evolution shed light on how RNA molecules might have evolved and how early cells could have evolved increasing metabolic complexity.

Shortly after being named an HHMI investigator in 1998, however, Szostak began contemplating an even more fundamental problem. How did the earth's first cells form from a brew of organic chemicals? For about a year, beginning in 2000, Szostak, David Bartel, a former student of Szostak's and an HHMI investigator at MIT, and Pier Luigi Luisi of the Swiss Federal Institute of Technology in Zurich brainstormed, discussed, and debated this question. In an important theoretical paper published in Nature in 2001, the three argued that membrane biophysics and test tube evolution of RNA and DNA had advanced enough to envision creating cells from scratch in the laboratory. The title of the paper was “Synthesizing Life.”

“Having put all those ideas down on paper, I thought that it was incumbent on us to actually explore them experimentally and see where it led,” Szostak says.

Today, Szostak's 18-member team operates from an airy, sunlit laboratory at Massachusetts General Hospital, a far cry from the cramped space of his first years at Harvard Medical School. At his lab bench, Itay Budin, an easy-going graduate student, uses a syringe to draw a volume of cloudy lime-green solution from a flask, inserts its needle into a small, stainless steel contraption containing a paper filter, and inserts a second glass syringe into its other side. Then, he pushes hard on the plunger of the full syringe with the heel of his right hand, forcing the liquid through the filter. The plunger on the other side slowly fills with liquid, which is now clear. Budin is preparing microscopic sacs of lipids called vesicles—as small as one-thousandth the width of a human hair—that can serve as membranes for the simple model cells that Szostak hopes to synthesize.

After contemplating the basic properties of life, Szostak, Bartel, and Luisi had realized that the simplest possible living cells—which they dubbed “protocells”—required just two components: a nucleic acid genome to transmit genetic information encapsulated by a lipid sac that could itself grow and divide. Szostak set out to build a protocell in the laboratory.

Budin is part of a contingent of Szostak's team that is building the protocell's lipid sac. Modern cell membranes are relatively impermeable and require an array of protein pumps and channels to transport molecules from one side to the other. But Szostak's team has developed sacs for their protocells that are composed of fatty acids—simple precursors of today's membrane components that are far more permeable and would have allowed primitive cells to “feed” on simple molecules.

Fatty acid vesicles can also divide into daughter cells, as any cell must. In March 2009, Szostak and graduate student Ting Zhu reported in the Journal of the American Chemical Society that adding fatty acids to vesicles caused them to morph into long filaments. But, remarkably, gentle shaking severs these filaments, and the pieces become daughter vesicles. Szostak calls the work a “breakthrough” because it provides a plausible mechanism by which a small force—say, the force of wind moving water in a pond—would cause the membranes of primitive cells to reproduce.

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