Dr. Jack W. Szostak
For decades, biologists contemplated a confounding riddle: How do cells protect the ends of their chromosomes (and the DNA within) from fraying during cell division and replication? It’s a significant question, as cell division and replication enable the human body to grow and repair itself.
Jack W. Szostak, PhD, of Massachusetts General Hospital’s Department of Molecular Biology, and former colleagues Elizabeth H. Blackburn, PhD, University of California at San Francisco, and Carol W. Greider, PhD, Johns Hopkins School of Medicine, found the answer.
The trio’s breakthrough discovery—that chromosomes are protected by structures called telomeres and the enzyme telomerase—earned them the 2009 Nobel Prize in Physiology or Medicine. This basic biological mechanism is having intriguing implications for aging and cancer research today.
The Telomere Mystery
Scientists hypothesized the existence of telomeres, special caps found at a chromosome’s ends, in the 1930s. These caps—like those at the end of shoelaces—were thought to safeguard chromosomes during cell division. Once Watson and Crick described the structure of DNA in 1953, biologists began to ask how telomeres functioned on a molecular level.
In 1980, Szostak and Blackburn began exploring how chromosomes behave when cells divide. Together, they demonstrated that telomeres of a single-celled organism known as Tetrahymena (which commonly grows in shallow ponds) also could protect chromosomes in yeast. This suggested a fundamental biological mechanism was at work.
“Initially, we were interested in answering basic scientific questions about copying DNA and how chromosomes behave,” says Szostak. “It's critical to get a more fundamental understanding of how things work if you want practical applications to emerge. In fact, it wasn’t until years later that the full implications of our work started to become more apparent.”
Understanding the Role of Telomerase
View a graphic explaining the science behind Dr. Szostak's Nobel Prize-winning discovery
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In 1984, Szostak, Blackburn and Janis Shampay, then a PhD student at the University of California, Berkeley, speculated on the existence of a new enzyme (later known as telomerase) that added new DNA to chromosome ends.
Greider and Blackburn isolated the enzyme a year later. Together with Szostak, they found that telomerase replenishes telomeres to preserve chromosomes and DNA—along with the health of the new cell—during cell division. Conversely, decreased telomerase activity shortens telomeres, sapping their protective power and causing the cell to age.
“In most cells in our body, telomerase is shut off very early on,” explains Szostak. “This early activity ensures that our cells start out with nice, long telomeres. However, in tissues where a lot of cell division occurs—such as the skin, intestinal lining and bone marrow—telomeres can eventually get too short due to the lack of telomerase. This is thought to lead to certain aging problems.”
Researchers now are investigating whether increased telomerase production can combat aging-related diseases such as heart failure, skin deterioration and immune-system collapse. In addition, Szostak’s work is having possible ramifications for treating cancer.
“As with normal cells, the absence of telomerase limits the number of times that potential cancer cells can divide,” says Szostak. “Only those few cells that manage to turn telomerase back on can continue dividing, which is what has happened in most cancers that we actually see.”
As a result, researchers are experimenting with vaccines directed against telomerase production to try to fight cancer. And therein lies a potential catch-22. “Turning on this enzyme can allow cancer cells to continue to divide and spread disease,” notes Szostak. “On the other hand, shutting it off can cause telomere shortening, the death of certain body cells and even worse aging problems because the needed cell renewal and replacement cannot occur.”
Outside of aging and cancer, telomerase defects now are known to cause some inherited diseases, such as congenital aplastic anemia and several diseases of the skin and the lungs.
Exploring the Origins of Life
Over the past three decades, Szostak, 57, also has made pioneering contributions to the field of genetics, constructed the world’s first artificial yeast chromosome and developed in vitro evolutionary technology.
His current research focus is the molecular origins of life. The question here is how complex chemicals evolved into simple organisms on early earth.
“I try to find questions that are important because answering them will open up new doors,” says Szostak. “But they also need to be questions that you can approach scientifically and where you can actually make progress. That’s where I’ve been lucky—identifying a few of the right questions.”
At his Mass General lab, Szostak’s team has been attempting to create “protocells.” These primitive cells, which contain nucleic acid strands encased within a membrane, ideally will replicate themselves and evolve in response to environmental factors.
Studying this synthetic model should lead to discoveries about the universal properties of modern cells as well as chemical and physical phenomena that have practical applications for biomedical research. According to The New York Times, Szostak “has already made advances in this long intractable field” and future successes in this field would make him “a candidate for a second Nobel Prize.”
Many of Szostak’s recent successes have been the indirect result of Mass General’s encouragement of basic science. Hospitals typically favor translational research, which places greater emphasis on developing clinical applications, at the expense of basic research.
“One of the great things about Mass General is that it supports a large basic research program, but in a context where we can see implications developing because there’s so much translational research going on,” says Szostak. “Although most of my research is basic, I have led a number of applied research projects. It’s nice to be in an environment where you can see both sides of the research coin.”