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Cycle of life

Paul Nurse’s failed experiment inspired a career that would uncover key mechanisms of cell division

Photo: Jason Brooks, courtesy of the National Portrait Gallery, London

When Paul Nurse was a student in the 1960s, scientists knew that cells divided and make copies of themselves. Yet key questions remained a mystery: What controls these divisions? How is the copying of DNA initiated? What drives cells to divide? Gripped by these puzzles, Nurse, Chair of EMBL’s Scientific Advisory Committee and Secretary-General of EMBO, would go on to win a Nobel Prize for identifying crucial mechanisms underlying the cell division process. Yet things could have turned out very differently.

“I had very good grades in school and was offered a place at every university I applied for,” says Nurse, who now heads the Francis Crick Institute in London. “However, the offers were conditional on me passing a very elementary French exam, and I failed it six times – it’s not like I wasn’t trying, but I am completely incompetent at languages.”

Against the odds

Struggling with his French re-sits, Nurse left school and spent time working as a technician in a laboratory run by a local Guinness brewery. Each week he quickly completed his work, leaving plenty of time for research projects, which he loved. But he just could not pass French and it took a chance encounter with Birmingham University Professor of Genetics John Jinks to ignite his scientific career. Jinks recognised Nurse’s potential and arranged for him to enrol as an undergraduate biology student. “There was a sting in the tail because the University Senate insisted I study French in my first year!” Nurse recalls.

The cell is the simplest thing that demonstrates life

But there were more hurdles to come. “I was initially interested in ecology, but a field trip collecting specimens in freezing waters taught me I was better suited to the warmer environment of the lab,” Nurse says. It was here, under the guidance of an eccentric zoology lecturer Jack Cohen, that he undertook a project measuring the respiration rate of dividing fish eggs.

“Cell division is the basis of all growth and development – I was immediately fascinated by it,” he recalls. Over the course of the following months, Nurse carefully collected eggs from the University aquarium, placing samples in a sealed chamber. He then measured ambient oxygen levels, painstakingly observing the effects of different inhibitors. “I soon saw that the respiration rate oscillated every fifteen minutes or so, which is also roughly the time needed for the fish eggs to divide,” he says. “Strangely this pattern persisted no matter what I did to the system – it seemed incredibly robust.”

Do controls early on in your study, as soon as it becomes interesting!

Yet a week before Nurse was due to hand in the work, a seemingly routine control test left him stunned. “I ran the experiment with no eggs in the chamber and I measured the same, perfect, oscillation,” he says. “I repeated the experiment again and again, convinced there must be a mistake. But I eventually realised that rather than measuring the respiration rate of the eggs, all the time I had been monitoring the effects of a thermostat in my apparatus. It was a complete failure from beginning to end.”

With his grades at stake and just one week to go before presenting the study, Nurse faced a big problem. “The only thing that I could think of to salvage my degree was a piece of theatre,” he recalls. “In my presentation I re-lived the whole study, from its exciting beginnings to its disastrous ending – and somehow the audience was impressed. One key message was: do controls early on in your study, as soon as it becomes interesting!”

Keep going

“At my low points, I contemplated alternative careers,” he says. “But I am very much an experimentalist at heart and I have been lucky over the course of my career to have had very supportive colleagues.” Ultimately undeterred, Nurse successfully completed his degree and PhD. As a postdoc, he saw the cell cycle as a way to learn more about what fascinated him most: the nature of life. “The cell is the simplest thing that demonstrates life,” he says. “Key to understanding that is knowing how information is managed in the cell to generate order in space and time.”

Inspired by studies showing how genetics could be used to study the budding yeast cycle, Nurse returned to a research subject that he first encountered working in the Guinness laboratory: brewer’s yeast. “I wanted a model organism that would be simple and effective,” he recalls. He led work that treated yeast in a way that induced mutations randomly in genes throughout the yeast genome.

Sometimes nature provides the best leads

Nurse figured that the key to identifying genes controlling cell division in the yeast would come from studying cells that divide particularly slowly (creating bigger cells) or particularly quickly (creating smaller cells). The second category he discovered by chance. He observed some unusually small cells that divided more rapidly before they could grow and identified a mutation in a gene called cdc2 that appeared to play a role in initiating key stages of the cell division cycle. “Sometimes nature provides the best leads,” he says.

After discovering that a cdc2-like gene was also in another type of yeast, Nurse wondered if the gene might exist in all organisms – a question he began to tackle at the Imperial Cancer Research Fund labs in 1984. “There were a few eyebrows raised as to what exactly a yeast researcher was doing at a cancer research centre,” he says. His team took a human gene library and added it to yeast lacking the cdc2 gene. Incredibly, after one of the human genes was added to the yeast, it resulted in the cells dividing as normal. It enabled Nurse to go on to draw the astounding conclusion that a fundamental engine driving the cell cycle was the same in all species, a mechanism that had traversed 1 to 1.5 billion years of evolution.

It is important to know the real stories behind science to inspire the next generation of scientists

The work led to the discovery (together with friend Tim Hunt) of cellular messenger molecules called cyclin dependent protein kinases – cellular messengers that pass signals and other insights into the nature of the cell cycle, all crucial for understanding health and disease.

“It is important to know the real stories behind science and the failures and successes that are part and parcel of our work to inspire the next generation of scientists,” Nurse adds. “There is still a lot we don’t know about how cells organise in space and time, but I think we will make real progress in the coming half century because of the methodologies that we have developed in the past five decades. And of course, as I learned from my fruitless experiments on fish egg respiration, from the countless failures we have made along the way.”

Tags: Cell biology, Cell division, Genetics

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