Biophysics, Chemical Biology
Massachusetts General Hospital
Dr. Szostak is also a professor of genetics at Harvard Medical School, professor of chemistry and chemical biology at Harvard University, and Alexander Rich Distinguished Investigator at Massachusetts General Hospital, Boston.
The Origins of Cellular Life
How did life begin? Scientists may never know exactly how a swirl of chemicals came together to form the first living organisms some 4 billion years ago, but Jack Szostak is working to recreate a hypothetical model of this process in the laboratory. By building simple cell-like structures in a test tube, he and his colleagues are attempting to establish a plausible path that led primitive cells to emerge from simple chemicals. Ultimately, Szostak hopes to answer fundamental questions about evolution's earliest steps.
At the outset of his career, Szostak made pioneering contributions to the field of genetics. His discoveries helped clarify the events that lead to chromosomal recombination—the reshuffling of genes that occurs during meiosis—and the function of telomeres, the specialized DNA sequences at the tips of chromosomes. He is also credited with the construction of the world's first yeast artificial chromosome. That feat helped scientists to map the location of genes in mammals and to develop techniques for manipulating genes.
But a Nobel Prize–winning discovery in the 1980s by former HHMI President Tom Cech and Sidney Altman propelled Szostak down a new research path. The pair independently demonstrated that RNA, the sister molecule of DNA, can catalyze certain chemical reactions inside cells, a job previously thought to be the exclusive domain of proteins. Until then, RNA was thought to have just one function: storing the genetic information cells need to build proteins. This new revelation about RNA's dual role suggested to some scientists, including Szostak, that RNA likely existed long before DNA or proteins because it might be able to catalyze its own reproduction. Their discovery made it easier to think about the origin of life, Szostak says. "They inspired me to try to think of ways to make RNAs in the lab that could catalyze their own replication."
By 1991, Szostak had shifted the entire focus of his lab to evolving new functional RNAs and other molecules in a test tube. As the basis for his work, Szostak developed a technique called in vitro selection to study the evolution of biological molecules. This method screens vast numbers of molecules for a predetermined function, such as the ability to catalyze a specific chemical reaction or bind a target molecule. Those that don't fit the desired profile are filtered out and the process is repeated over and over again until researchers find the molecule that does a particular job.
Using in vitro selection as a way to apply the forces of natural selection in a laboratory setting, Szostak and his colleagues evolved RNAs that bind to ATP, a common biological substrate, from a massive library of 1,000 trillion random RNA sequences. Such artificially evolved RNAs that bind to target molecules are now known as aptamers, and they have many potential applications in the diagnosis and treatment of diseases and as biosensors. Szostak's team has also used in vitro selection to evolve catalytic RNAs, called ribozymes, from trillions of random-sequence RNA molecules. "Many new ribozymes have now been evolved by in vitro selection," Szostak says. "The range of chemistries these artificially produced ribozymes can catalyze is much greater than that carried out by ribozymes found in living cells. It raises the interesting possibility that in an earlier era, ribozymes might have played a wider role than they do today." Szostak is also investigating in vitro selection for its ability to identify small molecules that bind specific target proteins. If successful, the technique may provide a streamlined way to pinpoint potentially useful drugs to fight disease.
Today, Szostak's main focus is the construction of a simple, artificial cell that can grow and divide as well as evolve in a Darwinian sense to adapt to its changing environment. To do this, he is attempting to make and then combine two self-replicating systems: a nucleic acid (such as RNA or DNA) that can transmit genetic information and a simple membrane-bound vesicle that keeps the nucleic acid chains from drifting apart. A major challenge is coordinating the growth and division of the membrane-bound vesicle with the replication of its contents. Szostak has found that the nucleic acids themselves can drive the growth of the fatty acid membrane; as they replicate, the internal osmotic pressure increases, swelling the vesicle and stretching the membrane so that it absorbs fatty acids from other vesicles that are under less internal pressure. Cells with faster nucleic acid replication should therefore grow faster than cells with slower nucleic acid replication. In this way, simple physical principles coordinate the replication of the nucleic acid genome and the replication of the rest of the cell structure, leading to the emergence of natural selection and Darwinian evolution based on competition between cells.