Jack W Szostak was honored with the Nobel Prize in Physiology or Medicine 2009.

Jack W Szostak, Elizabeth H. Blackburn and Carol Greider received the Medicine Nobel prize 2009 for “the discovery of how chromosomes are protected by telomeres and the enzyme telomerase”. Unlike the other two laureates, Jack Szostak had at the time of the Nobel festivities in 2009 left the research field of telomeres and was instead occupied with the fascinating subject of creating artificial life.

The world’s first artificial chromosome

I met Jack Szostak a few days after the Nobel Prize ceremony 2009 in Stockholm. On that day, when the major part of the Nobel festivities and activities were over, he had the chance to enjoy the city together with his family. After that he was traveling back to the US and to Boston, where he worked at the Departments of Genetics and Molecular Biology at Massachusetts General Hospital and Harvard Medical School.

“He constructed the world’s first artificial chromosome, helping scientists to map the location of genes and develop techniques for manipulating genes. These findings have also been very important in the human genome project.”

Szostak has made several additional contributions to the fields of genetics and molecular biology. For example, he constructed the world’s first artificial chromosome, helping scientists to map the location of genes and develop techniques for manipulating genes. These findings have also been very important in the human genome project.

Crossing kingdom boundaries

Although Jack Szostak’s in 2009 research focused on something other than his Nobel Prize winning research he speaks very enthusiastically about the work he and Elizabeth Blackburn did in the early 1980s. He attended her lecture at a conference when she talked about her work on telomeres, and a joint experiment was planned between the two scientists. They were going to investigate if the biochemistry of telomeres was widely conserved.

“We were able to show that telomeres from one species could protect DNA from another species, even very distantly related species.”

“We were able to show that telomeres from one species could protect DNA from another species, even very distantly related species. This was very exciting, that the whole machinery is conserved across kingdoms,” says Jack Szostak.

Telomeres are specialized DNA sequences at the tips of the chromosomes and they are responsible for how the chromosomes can be copied in their entirety during cell division, as well as how they are protected against degradation. Elizabeth Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects the chromosomes from degradation. They published their results in Cell in 1982. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA.

Switching fields

The telomerase discovery has helped clarify the events that lead to chromosomal recombination, the reshuffling of genes that occurs during meiosis and the function of telomeres. It can be applied when designing treatments for cancer and understanding the process of aging. As the title of Jack Szostak’s Nobel lecture hinted, “DNA ends: just the beginning”, the finding has definitely stimulated the development of new therapeutic strategies. But he himself did not stay in the research field that long, although he finds it very important and interesting.

“After Vicki Lundblad’s work, the first experimental demonstration that telomere maintenance was essential for avoiding senescence, and all other things that follow from that, there were a lot of people interested in getting into this field. They would move it forward and explore the links to aging and cancer. But I was already moving on and most of my lab changed direction to working on RNA,” he said during our interview.

“He was inspired to try to think of ways to make RNAs in the lab that could catalyze their own replication.”

It had been shown that RNA, a sister molecule to DNA, can catalyze chemical reactions inside cells. This was previously believed to only be performed by proteins. It was believed that RNA only stored genetic information that the cells needed to build proteins. This new role of RNA made Jack Szostak believe that RNA may have existed long before DNA or proteins as it seemed to have the ability to catalyze its own reproduction. He was inspired to try to think of ways to make RNAs in the lab that could catalyze their own replication.

The origin of life

Jack Szostak and his colleagues were at the time of our interview, in 2009, focusing on understanding the origins of early life on the earth and constructing synthetic cellular life in the laboratory.

“I have always been attracted to problems that have not received a huge amount of attention.”

“I have always been attracted to problems that have not received a huge amount of attention,” he said. “This is a very important and fundamental research field and I wish that more scientists were addressing it in reality. It is, however, a rather tuff area for graduate students since it is hard to find funding and it is a long term endeavor. But it is extremely important.”

He and his research group were in 2009 working on recreating in the laboratory a hypothetical model of the process of how life began some 4 billion years ago, creating a cell-like structure in a test tube.

“We use artificial cells since biological cells are too complicated. They contain hundreds of enzymatic processes and complex machineries. We need them only to be complex enough to start evolution,” said Jack Szostak. “By focusing on artificial life, new chemical systems can be explored and possible pathways leading to the origin of life can be understood.”

A synthetic cell has the encapsulation of a spontaneously replicating nucleic acid, genetic material, within a spontaneously replicating membrane boundary, providing spatial localization. Nucleic acids are made which have modified nucleo-bases and sugar-phosphate backbones and the goal is to generate a nucleic acid system that can replicate without enzymatic assistance. The group has developed a membrane vesicle system that allows for the repeated growth and division of the vesicles, without any biochemical machinery involved. When combining the nucleic acid and membrane systems, limited nucleic acid replication can be seen within the membrane vesicles. When repeated cycles of replication of the combined systems are achieved, evolutionary forces should come into play. This will lead to the spontaneous emergence of nucleic acid sequences that contribute to the fitness of the artificial cell.

“A major challenge has been to coordinate the growth and the division of the membrane bound vesicles with the replication of its content,” said Jack Szostak.

Basic research and new applications

In the 1990s Jack Szostak developed a technique, in vitro selection, which would come in very handy in his studies of the evolution of biological molecules.

“The method screens molecules for predetermined function, like binding to a target molecule, for example, and those that do not fit are filtered out. The process is repeated over and over again and amplified using PCR, until the final molecule is found,” explains Jack Szostak.

“Remember that basic research can lead to important applications, although it might be a little more difficult to see exactly what they will be at the beginning.”

Using this technique, he and his colleagues evolved RNAs that bind to ATP, aptamers, from a library of 1000 trillion random RNA sequences. Aptamers have many potential applications in the diagnosis and treatment of diseases and as biosensors. The research group is also investigating in vitro selection for its ability to identify small molecules that bind specific target proteins. The technique may be useful for pinpointing potentially useful drugs.

“My advice for my graduate students is to work on a subject they find interesting and challenging. They should not be afraid to ask for help or advice,” concludes Jack Szostak. “And remember that basic research can lead to important applications, although it might be a little more difficult to see exactly what they will be at the beginning.”

Photo credit: Jussi Puikkonen

Facts – Jack Szostak

Born: 1952 in London, UK

Career:
1972 B.Sc. Cell Biology, McGill University, Montreal, Canada
1977 Ph.D. Biochemistry, Cornell University, Ithaca, New York
1977-1979 Research Associate Biochemistry, Cornell University
1979-1983 Assistant Professor, Sidney Farber Cancer Institute and Department of Biological Chemistry, Harvard Medical School
1983-1984 Associate Professor, Dana Farber Cancer Institute and Department of Biological Chemistry, Harvard Medical School
1984-1987 Associate Professor, Department of Genetics, Harvard Medical School.
1984-1987 Associate Molecular Biologist, Department of Molecular Biology, Massachusetts General Hospital
1988 Professor, Department of Genetics, Harvard Medical School
1988 Molecular Biologist, Department of Molecular Biology,
Massachusetts General Hospital
1998 Investigator, Howard Hughes Medical Institute
2000 Alex Rich Distinguished Investigator, Department of Molecular Biology, Massachusetts General Hospital

Family: Wife and two children