Jack Szostak: the Nobel of Niche

Volume 5, Number 2

By Valerie Henderson

In the world of science, where carving out a specialty is often the key to success, Jack Szostak is a master of the nook and cranny. The soft-spoken Nobel laureate and McGill alumnus built his career on conducting research few others dare attempt, steering clear of popular and better-funded fields. As he sees it, why take on work others will end up doing the next month or year?

Nobel laureate, and McGill alumnus, Jack Szostak

“I’d rather try to think about things that are a little more out there… things that you can approach experimentally and make some progress,” Szostak said in an interview during a recent visit to McGill University, where he began his undergraduate degree in the Faculty of Science at age 15.

Szostak’s attitude seems counterintuitive in the fierce competition for research dollars. But then again, Szostak’s originality led to his winning the 2009 Nobel Prize for Medicine, for discovering how cells protect their DNA from damage, which has helped us understand both the aging process and cancer biology.

The discovery by Szostak and his colleagues turned the world of cell biology on its head. They found that chromosomes—essentially chapters of genetic information, 46 of which make up our full genome—are protected by buffer zones which are created and maintained by an enzyme called telomerase. These buffers zones on the tips of each chromosome are called telomeres. Without them, our genome would be vulnerable to attack by other enzymes in the cell that are designed to clean up broken, unwanted DNA. As we age, the buffer zones on the tips of our chromosomes shorten, leaving them less protected from attack by other enzymes, which eventually wreaks havoc within the cell.

“I have generally sought to work on questions that I thought were interesting and approachable, yet not too widely appreciated,” Szostak said in his Nobel Lecture, delivered a year ago in Stockholm. “To struggle to make discoveries that would be made by others a short time later seems futile to me. This, coupled with a distaste for direct competition, attracts me to areas of science that are less densely populated.”

His Nobel is a case in point. In typical fashion, he dropped the work that would later win him the world’s most coveted scientific prize to pursue other research avenues. This move eventually led to his current research on the origins of life—a multidisciplinary field with comparatively few researchers and a paucity of public research dollars.

Basement Chemistry Lab

Szostak’s interest in biology and chemistry began early in childhood, when his father built him a chemistry lab in the basement of the family home in Pierrefonds, a Montreal suburb. His mother, who worked for a Montreal chemical company, fed his passion and supplied some of the chemicals he needed to experiment with, often with explosive results.

His fascination with controlled experimentation continued through his adolescence at Riverdale High School in Pierrefonds, where he spent nearly every day after school in the chemistry lab. During his undergraduate years at McGill, he made it a priority to volunteer in many laboratories. In his senior year, he helped discover that a simple species of algae releases peptide hormones that trigger sexual development.

After finishing his studies at McGill at age 19 with a BSc in cell biology in 1972, he headed to Cornell University for graduate studies in the Department of Plant Physiology. Here, he hoped to show that his beloved algae would make a wonderful model organism to study developmental genetics.

“It was a complete disaster,” Szostak said of his Cornell research. “The experiments didn’t work. I didn’t know anything about genetics. There was no one else to talk to, no one knew about genetics. I eventually had to give it up.”

Silver Lining

This hard lesson was not without a silver lining. While “waiting for his experiments not to work,” Szostak hatched an ambitious plan for a series of experiments with a fellow graduate student, John Stiles. These experiments, now routine in molecular biology, had never been attempted before. The idea was to synthesize chemically a short sequence of DNA that would be identical to a certain gene. This piece of DNA could then be used as a dangling worm, or probe, to fish out the gene and its products from the complex pool of such molecules in yeast.

To accomplish this would have huge ramifications for a field which could at the time only detect large-scale changes in the expression of all genes at once.

The demanding synthetic chemistry necessitated Szostak’s shift to the lab of Ray Wu in the Department of Biochemistry at Cornell. Wu is known as a founding father of plant genetic engineering whose work included creating strains of crops, such as rice, resistant to environmental stresses. Despite the injection of Wu’s expertise, the synthesis research proved to be exceedingly tricky and Szostak toiled without success for more than a year to create the tiny probe. Recognizing that this was a struggle for the young researcher, Wu seconded Szostak to the lab of Saran Narang at the National Research Council in Ottawa, where he could learn cutting-edge techniques in DNA synthesis.

Szostak returned to Cornell invigorated and was able to synthesize the probe and speed through the remainder of the project. He used the probe to detect the sought-after gene, and his PhD work on this project earned him a coveted publication in Nature.

Szostak stayed in Wu’s lab as a post-doctoral fellow—a career move Szostak said he normally wouldn’t recommend. Postdocs, he explained, should gain experience in different labs. For Szostak, however, it turned out to be a wise choice. He established a fruitful collaboration with an incoming postdoc, Rodney Rothstein. Szostak and Rothstein trained one another in molecular biology and yeast genetics, and this experience seeded Szostak’s enduring interest in yeast biology.

Nobel Research

Szostak’s passion for yeast biology put him on the path for the Nobel Prize. After leaving Wu’s lab, Szostak accepted a position at the Sidney Farber Cancer Institute—a teaching affiliate of Harvard Medical School—as an assistant professor. Here, he drew on talented graduate students from Harvard and continued both his collaboration with Rothstein and his work with yeast.

Szostak’s lab focused on a process called recombination, which is one of the desperate mechanisms a cell will employ to repair broken DNA. This process can be exploited by researchers to introduce foreign pieces of DNA into the genome of yeast and study its effects. Szostak’s lab focused on ways to make this process more efficient.

Musings about recombination occupied Szostak until a serendipitous collaboration set his research on a different and exciting course.

“I was at a scientific meeting, a Gordon Research conference, in the summer of 1980, and I heard a fantastic talk given by Elizabeth Blackburn. Liz was studying DNA ends, telomeres, in an obscure organism called Tetrahymena.”

However, Blackburn’s telomeric DNA ends were highly stable and did not do all the strange recombinatory things that Dr. Szostak’s broken DNA ends did in yeast. “So that really struck me very strongly and right after the session, I sought out Liz.”

Their chat resulted in a collaboration to see if her telomeric ends from Tetrahymena could maintain their stable function in the yeast system. “It was a complete long shot,” Szostak explains of their collaboration.  Indeed, both Szostak and Blackburn thought the possibility very small that the underlying biochemistry would be so conserved that these ends would work in both Tetrahymena and yeast. When a cellular process, such as telomere function, is shown to work in organisms as evolutionarily distinct as Tetrahymena and yeast, it signals that the process is fundamentally important and not just a quirky anomaly in nature.

The experiment was quite easy to perform and it worked. Szostak described it as “definitely one of the most exciting results in my career”—an assessment that would be shared years later by the Nobel selection committee.

Further seminal discoveries made it increasingly evident that telomeres probably played a key role in aging and even cancer biology. Instead of rejoicing and going with the flow—and reaping millions in new research dollars—Szostak cut himself loose from that area of research. “It was kind of obvious that lots and lots of people were going to come in and the field would explode. So, I thought that was a good time to leave.”

Origin Of Life

Transitioning fields did not happen overnight and in the mid-1980s, Szostak was back in the classroom in search of a new field of discovery. He sat in on university courses as disparate as applied math and cognitive neuroscience. But it was a course in enzymology given by Jeremy Knowles, combined with inspiration from Tom Cech’s work on catalytic RNA, that convinced him to switch his lab’s work from yeast biology to catalytic RNA.

Over the next five years, Szostak’s lab became immersed in developing new molecules called ribozymes, pieces of RNA, the more flexible genetic cousin to DNA, which are able to fold into complicated shapes and do important jobs in the cell that were previously only attributed to a type of protein called enzymes.

“Then we realized that there aren’t that many ribozymes in nature. They didn’t do what we wanted them to do so we started to learn how to evolve our own ribozymes and aptamers [short pieces of RNA which can recognize and bind tightly to a chosen target]… and that got extended into protein evolution. But all that sort of led more and more to the origin of life.”

Szostak perceived a link between his ability to evolve novel ribozymes and proteins in the lab and pressures that would have existed during the first evolution of genetic material on the pre-biotic Earth. However, for this evolution to work, the genetic material would need to be contained to a small space, such as within a simple membrane.

“Once we started thinking about the origin of life, the membrane part of the problem seemed very important and there weren’t that many people working on it. We kind of jumped into that area.”

Szostak then set out to teach himself organic chemistry, a subject that during his undergraduate years seemed somewhat purposeless but now had become intensely exciting as he set his sights on a lofty goal: the development of a protocell.

A protocell is an artificial cell, perhaps not unlike the first cells that arose on the ancient Earth. A protocell would exhibit all the hallmarks of a living cell, including growth, replication, and the ability to evolve. However, this cell could be made from entirely non-living chemical precursors, things that can be bought from scientific suppliers. A protocell has has yet to be successfully created, but Szostak is confident that it can be done.

With only a self-replicating genetic component and a rudimentary membrane to keep it all together, the first cells to arise spontaneously on early Earth would have to grow, replicate their informational content, divide themselves, and adapt to the changing and inhospitable environment. This had to be done without all of the bells and whistles enjoyed by modern cells, including structures that evolved later, such as complex protein machinery, sophisticated membranes, and all internal organelles (little organs within cells).

The identity of the self-replicating genetic component which could functionally replace all of these components has remained a hot topic for decades. Others have postulated that the ancestral DNA- or protein-like molecules could have filled this role, but the most widely-accepted hypothesis taps RNA-like molecules as the first informational polymer.

Szostak’s work operates from this camp, and his protocell design reflects this. According to Szostak, life at its most basic would include a fatty-acid membrane, and an RNA-like molecule capable of storing information and catalyzing its own replication. His lab has advanced the current knowledge of both the membrane dynamics and the synthesis of a suitable RNA-like polymer separately. However, the big test remains: to mesh the two components together to create the final protocell. “It would be really nice to watch Darwinian evolution emerge from chemistry. That’s my goal.”

Branching Out Again

For a researcher who has never stagnated in any one discipline, the origin of life community is a perfect fit for Szostak. The multidisciplinary nature of the subject and his success in securing basic research funding gives him the flexibility to be creative in a field that attracts scientists from diverse disciplines such as astronomy, planetary science, chemistry and biology. Without an exceptional track record like Szostak’s, however, few researchers could break into this elite club.

“It’s not funded in a big way. That’s part of the problem,” he explained.

NASA provides some funding for his research, as does the National Science Foundation, but the grants are not large. The majority of his funding is provided by the Howard Hughes Medical Institute.

“I’m lucky to have Howard Hughes funding that supports most of my lab, because they support people, not projects. But on the other hand, my lab’s in a hospital so we’re always interested in potential applications and some new observation that might lead to an application. We try to follow up on that,” he said.

Since winning his Nobel a year ago for his telomere work, not much has changed in his lab, except that he has become even busier than before. He continues to push ahead with his protocell investigations—research that could eclipse the groundbreaking discoveries that earned him a Nobel.

It’s no surprise that this somewhat shy and humble scientist continues to draw crowds and his lecture on designing an artificial cell for McGill’s Biochemistry Department was no exception. Remarkably, just the evening before, Szostak had also delivered a packed lecture to an entirely different breed of scientist: the physicists. Few researchers are able to enjoy such broad appeal but it underscores Szostak’s remarkably interdisciplinary approach to discovery.

Many scientists, once they discover their niche, persist in their field and develop irreplaceable expertise on their subject matter. This niche could be a newly proposed subatomic particle, a protein’s regulatory domain, or a mechanism describing how a disease spreads through a population. But when you are a big thinker like Szostak, why not try to answer the biggest question of all in biology?

And while he is not the first Nobel laureate to tackle the origins of life, what makes Jack Szostak unique is his ability to enter a new field, make a game-changing discovery, and then move on to an entirely different challenge.

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