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Today, Jack Szostak is focused on creating a cell from scratch. His lab team is working to build a self-replicating nucleic acid genome and put it into a fatty acid vesicle, something he calls a “protocell.”
“We thought it was a long shot because yeast and Tetrahymena are so distantly related,” recalls Szostak, now an HHMI investigator at Massachusetts General Hospital, whose early work on telomeres won him a share, with Elizabeth Blackburn and Carol Greider, of the 2009 Nobel Prize in Physiology or Medicine. “Yet it was a very easy experiment to do. If it worked it would tell us a lot, and it would open up the field.”
It was the autumn of 1980 and Szostak, then 27 and a new faculty member at Harvard Medical School, had been excited about trying the experiment ever since he'd returned from a Gordon Research Conference on nucleic acids a few months earlier. At Harvard, he had focused the efforts of his small team on understanding the molecular nature of recombination—the process by which higher organisms shuffle the genetic deck, exchanging pieces of DNA between chromosomes before reproducing.
Szostak was particularly interested in what happens to the ends of DNA molecules. DNA exists as a double helix that can be extended like a long piece of rope. Just as the ends of a rope tend to fray, the ends of a DNA molecule are less stable than the rest of the molecule: enzymes inside the cell can chew them back, attach them to other DNA ends, or recombine them with other DNA molecules.
But the DNA at the tips of chromosomes is not degraded, and biologists had long wondered why.
At the Gordon Conference, Elizabeth Blackburn, of the University of California, Berkeley, presented her results on Tetrahymena's curious chromosomes. The unicellular freshwater organism contains thousands of very short chromosomes that are linear yet remain stable inside the cell. Blackburn had used these minichromosomes to get a large enough quantity of chromosome tips to study, and at the conference she described how the unusual, repetitive DNA sequence of those tips seemed to confer stability.
“It was a surprise, a shock almost,” Szostak recalls. “Here I was working on all these reactions that DNA ends engage in. Then here's Liz talking about some little piece of DNA that just makes a stable end. It was completely the opposite behavior.” He button-holed her, and the two had an intense conversation about chromosome tips. Szostak floated his wild idea about a telomere transplant experiment, and the two agreed to try it.
Blackburn sent Szostak some DNA from Tetrahymena's chromosome tips. Szostak attached it to a piece of linear yeast DNA and then introduced the hybrid into yeast cells. Once the yeast had multiplied in culture, he ran their DNA on a gel, transferred it to a special paper, treated the paper with a radioactive probe that would bind to Tetrahymena DNA, and exposed it to a sheet of x-ray film. If the yeast maintained the hybrid DNA as a linear chromosome, Szostak would see a single band on the film.
Photo: Leah Fasten