No Question Too Big
For decades after scientists figured out how the cell copies DNA, they puzzled over another question. The DNA ought to get a bit shorter with every replication, but it doesn’t: Why? In 2009, three scientists shared the Nobel Prize in Physiology or Medicine for discovering the answer: Chromosomes are protected by tiny caps on their ends, called telomeres.
For Jack Szostak, now an HHMI investigator at Massachusetts General Hospital and Harvard Medical School, the award for work conducted 30 years ago is also a vindication of the sometimes risky spirit of enterprise that continues to take his work in surprising new directions.
In 1980, Szostak heard Elizabeth Blackburn speak at a conference about her discovery of special repeating sequences that appear at the ends of small pieces of DNA extracted from the single-celled protozoan Tetrahymena. Somehow these special repeats seemed to allow the DNA to replicate without getting shorter.
Szostak had been experimenting with putting chopped-up pieces of DNA into yeast cells. Unlike normal chromosome ends, the ends of the chopped-up pieces of DNA were very reactive, and either rapidly degraded, joined together, or recombined with chromosomal DNA. Szostak and Blackburn chatted about their results. The chat led to a collaboration, and together they found that yeast chromosomes also have special repeating sequences at the ends that prevent the DNA from degrading.
After subsequent experiments the scientists predicted the existence of an enzyme, later named telomerase, that synthesizes these DNA sequences. The Nobel honored this work, along with research Blackburn conducted with her student Carol Greider, who first directly detected telomerase.
Back to the Beginning
Since then, other scientists have found that the telomeres of nearly all organisms are composed of similar simple repeats that are synthesized by telomerase, and this has turned out to be important to understanding cancer and other diseases. But Szostak’s own work has taken another course; in his Nobel lecture, he said he wanted to show students “that it is not only possible, but really fun to address very different questions in different fields during one’s career.”
Szostak started moving away from yeast in the mid-1980s, as the field got crowded. By the end of that decade, his lab was focused primarily on RNA, a nucleic acid whose ability to act as an enzyme was discovered by Nobel Laureate and former HHMI President Tom Cech. Cech's work revitalized the idea that RNA played a central role in the origin of life, prior to the emergence of DNA and proteins.
Since 1998, when Szostak was appointed an HHMI investigator, he has been concentrated not on how life persists through DNA replication but on how it came to be in the first place. Such a change in direction is not unusual for an HHMI investigator, and Szostak encourages his lab members to take similar liberties. His 15 graduate students and postdocs are, he says, united in the overall theme of the lab but otherwise free to pursue their own interests and follow their instincts.
These days, the team is attempting to build a protocell—a membrane that encases some kind of self-replicating nucleic acid. DNA has an impressively large machinery devoted to replication, made up of many enzymes. But, in theory, these weren’t necessary in the beginning.
“Enzymes just make replication go faster,” says Szostak. “So, we’re looking for the same kind of chemistry but without enzymes.”
It Takes a Team
Getting that chemistry to work is part of the project; getting the nucleic acids to self-replicate accurately is another. Still another is figuring out how to encase all of this in a lipid membrane similar to modern cell membranes, but able to grow and divide without complicated cellular machinery.
The work takes a multidisciplinary team; the lab includes chemists, biophysicists, molecular biologists, and others. Some have backgrounds in bioengineering, and some are strong in methods such as crystallography. When new students or postdocs join the lab, they have freedom to decide where their skills and interests would be put to the best use. The protocell project has plenty of questions to go around.
In particular, the cell membrane question is crucial to understanding how life began, says Szostak: “You can’t have a cell unless you have some kind of boundary structure.” It was an unconventional direction for him to take, being a nonchemist. He imagines the rejection letter he might have received, had he applied for a traditional grant: “You haven’t done that before. You don’t know anything about it. What makes you think that’s going to work?”
The gift of HHMI support, he says, is that his lab is encouraged to “follow our hunches and just go where we think is interesting or important.”