It's not unusual for a man of a certain age to find himself pondering the mystery of life. What makes Jack Szostak different is that he may have a better chance than anyone of solving it.
A Nobel prize-winning biochemist at Harvard University and Massachusetts General Hospital, Prof. Szostak is preoccupied with uncovering the obscure sequence of events that got life started some four billion years ago – and with rekindling that ancient spark in his own laboratory.
"We want to understand how a bunch of chemicals get together and start acting like cells," the 61-year-old biologist said.
The magnitude of the question is a worthy match for Prof. Szostak's insatiable curiosity – a trait that first emerged when he was growing up in Montreal and Ottawa. His father, an aeronautical engineer for the RCAF, built a basement lab where the younger Szostak was able to experiment with "remarkably dangerous chemicals," supplied by his mother, who worked for a chemical firm at the time. Later, a high-school biology teacher cemented his fascination with the life sciences. After completing a degree at McGill, he headed to Cornell University for his graduate work and has remained in the U.S. since.
Prof. Szostak's current quest emerged after years of groundbreaking work in genetics, including a key role in the discovery of telomerase, an enzyme that protects DNA molecules from degradation and which has become associated with longevity. That work, done in the 1980s, earned Prof. Szostak a share of the 2009 Nobel Prize in Physiology or Medicine.
By then, he had come to realize that the powerful new tools associated with manipulating genetic material could be applied to the origin of life itself. That conundrum – once considered unexplainable without invoking divine intervention – has tantalized and frustrated thinkers for centuries.
In the mid-19th century, Charles Darwin famously showed that, given vast stretches of time, lifeforms could evolve, diversify and become astonishingly well adapted to virtually every corner of the planet. When the structure of DNA was deduced, scientists knew they had at last found the molecular machine that drives evolution forward by copying itself, sometimes imperfectly, for succeeding generations. Once the first self-replicating cells appeared, natural selection took over, generating ever more complex and specialized forms, including entire communities of cells working together in a single organism, such as a human being.
But that still left unanswered the thorny question of what started life in the first place.
In 1953, Stanley Miller and Harold Urey, two University of Chicago researchers, tried a now-famous experiment in which they placed in a closed flask some of the basic chemicals thought to have been present on the nascent Earth, including water, methane and ammonia. After heating them and applying a sparking electrode to simulate lightning, they found that their simple chemicals soon produced more complex ones, including amino acids, which living cells use to build proteins.
Yet the leap to life itself has not proved so straightforward. Initially, the obstacle was the classic chicken-and-egg problem: Every cell contains DNA, which transmits instructions via another molecule, RNA, to the parts of the cell that make proteins. The proteins, in turn, are essential to all living processes including the function and replication of DNA.
"Everything in the process depends on everything else," Prof. Szostak said.
To get around the problem of which part came first, researchers in the 1970's began to explore an alternative idea that life as we know it was preceded by a simpler set up that depended on RNA alone. In theory, RNA can generate copies of itself while at the same time acting as a chemical catalyst, triggering other essential reactions needed to keep primitive cells going. And those cells could simply consist of some RNA trapped inside little bubbles of fatty acids, which can form on their own and play the role of primitive cell membranes.
But getting such an RNA world to work has proved extraordinarily difficult. Prof. Szostak's lab has tackled one of the hardest part of the problem: recreating how the first RNA molecules copied themselves. One stumbling block is that the chemicals that can help RNA do this also tend to destroy the surrounding fatty acid bubbles, immediately bringing the process crashing to a halt.
Last November, Prof. Szostak and his colleagues reported that citrate, a molecule related to citric acid, can play a key role in protecting the fatty acid membrane, allowing the RNA copying to proceed without complete destruction of the primitive cell. "That really shows that if we could do the replication of the RNA, we'd be there," he said just before giving a public lecture in Toronto this month, organized by the Royal Canadian Institute.
The result has fuelled optimism that a much clearer picture of how life bootstrapped itself into being is now emerging – a development that could also shed light on where else in the universe life may exist.
John Dirks, president and scientific director of the Gairdner Foundation, which co-sponsored the talk, said that Prof. Szostak's track record in science means he's well equipped to push ahead with such a far reaching work. "He's unafraid – not only of asking big questions, but the biggest question," Dr. Dirks said.
Prof. Szostak said that while there remains much work to be done, he thinks the chances are excellent that the mystery of how life began will be answered during the course of his remaining scientific career. "I would never have gotten into this if I didn't think it was doable," he said.