Photograph by Andrew Hetherington |
RNA could be the answer. Watching ribozymes at work revealed how primordial RNA could store genetic information and act like an enyzme. In theory, simple RNA-based life-forms could have spread and evolved for millions of years. Perhaps they eventually evolved the ability to assemble proteins as well as build DNA molecules. Because DNA and proteins did their jobs better than RNA, maybe they eventually took over these tasks.
Szostak saw in this theory a calling. “I thought, I can figure out something different to do, where we could contribute something,” he says. In a world before DNA, RNA molecules would have had to be a lot more accomplished than the Tetrahymena ribozyme. Most important of all, RNA would have to function as an enzyme (known as a replicase) that could replicate other RNA molecules. So Szostak began to tinker with RNA molecules from Tetrahymena and other organisms to see if he could make one.
In 1991 he and graduate students Jennifer Doudna and Rachel Green succeeded in making a crude prototype. They created a molecule that could grab shorter chunks of RNA and make copies of them. It was a remarkable achievement, but Szostak knew it was only a small step toward something that could accurately be called alive.
Enzymes in living cells can make duplicate RNA sequences one nucleotide at a time. Szostak’s ribozyme could only piece together chains of RNA, each of which was several nucleotides long. And his new molecule was grievously sloppy, making regular copying errors. In a single generation, it could turn a life-sustaining genetic code into sheer gibberish. To create a better molecule, Szostak decided to turn to the father of evolutionary theory, Charles Darwin, for inspiration: “We realized that if we were really going to have a chance to have an RNA replicase, we were going to have to evolve it.”
For many years biologists have been able to witness evolutionary change in the laboratory by studying organisms such as fruit flies or bacteria. Using that research as a guide, Szostak and his students began building a system to allow RNA molecules to evolve as well. Evolution produces new adaptations through cycles of mutation and natural selection. Szostak started an evolutionary cycle by randomly stringing together nucleotides to create trillions of RNA molecules. Then he and his students gave the molecules a very basic task to perform: latching onto another molecule. Typically, only a few of these first-generation RNAs could do the job—and needed a long time to fumble around until they could grab the molecule. Szostak’s team extracted the winners and made trillions of new copies, allowing some random mutations to creep in along the way. Then they set the new generation on the same task and picked out the ones that did the job fastest.
In each experiment, Szostak and his students repeated the process dozens of times. In the end they were left with RNAs that were exquisitely well adapted to the job at hand. Szostak named these evolved RNAs aptamers, which means “parts that fit.”And fit they did. Aptamers turned out to be capable of performing an extraordinary range of tasks. Some aptamers can bind to a specific virus, and others can grab certain kinds of cells or attach themselves to vitamins.
