Understanding how cells divide – the story of a Nobel prize

The announcement of this year’s crop of Nobel Prizes is a time to celebrate great achievements. Today we heard that John O’Keefe from UCL and Norwegian couple May-Britt and Edvard Moser have won the 2014 prize in physiology or medicine for their discovery of the ‘inner GPS’ system in the brain.

But back in 2001, Cancer Research UK scientists Paul Nurse and Tim Hunt were celebrating their own Nobel prizes – and the centenary of the awards – along with US researcher Leland Hartwell.

So, as part of our Milestones series, we thought we’d take a timely look back at their award-winning findings, how they changed our understanding of cancer, and what they mean for future treatments.

Basic building blocks

Our story starts with cells – the ‘bricks’ from which every living thing is built. Simple organisms like yeast or amoebas exist as just a solitary cell, while humans are made up of billions.

We all begin life as a single cell – an egg fertilised by a sperm – which divides in two. Each of these ‘daughters’ then divides, creating four cells. This process of cell division continues thousands upon thousands of times, ultimately producing a baby.

Cell division continues throughout our lifetime as we grow to adulthood. New cells are also produced to heal wounds, and to replace the millions of cells that die every day in our gut, bone marrow and skin. This production line is tightly controlled, ensuring that new cells are made only when and where they’re needed.

But if this control is lost, the results can be disastrous. Uncontrolled cell division – cells multiplying when they shouldn’t – leads to cancer.

Although scientists have known since the mid-19th century that new cells can only come from existing ones, more than 100 years later it still wasn’t clear exactly how this process worked.

The answer, as Nurse, Hunt and Hartwell were to discover, was not only a shining example of biological elegance, but also proved that virtually all living things – from yeast to humans, plants to pandas – produce new cells in the same way.

Making cells

The process of making two cells from one is a complex biological ballet, involving a multitude of different genes and proteins. For a start, a cell has to know that it’s the right time to divide. Then it has to copy all its DNA – around two metres of microscopic tangled strands in each cell – once (and only once) and separate the two copies.

Finally the cell has to split in two, leaving an entire copy of the ‘parent’ DNA in each ‘daughter’ cell. Any mistakes in the process – such as copying the DNA more than once, or failing to divide it equally – can be catastrophic.

As far back as the 1880s, scientists were carefully documenting the different stages of cell division by studying cells down a microscope. But although this kind of work revealed a lot about what was physically happening when a cell divided, it didn’t explain what was controlling it or how the process worked.

Beginning with Start

Leland Hartwell (Lee to his friends) was the first person to begin to unpick the answers to these questions in the early 1970s, when he discovered a series of genes responsible for controlling cell division in bakers’ yeast (Saccharomyces cerevisiae to its friends).

Through careful experiments he found more than 100 genes, and also showed that many of them were interdependent – events controlled by one gene would have to be completed before the next gene could be switched on.

This work led to the concept of the ‘cell cycle’ – a biological clock irreversibly ticking onwards and driving a cell to divide. Once the cell has split in two, the clock is reset, and the process starts again.

Out of the myriad genes Hartwell and his team tracked down, perhaps the most important was one they named Start (later known by the less catchy name CDC28, short for Cell Division Cycle gene 28) which seemed to be essential for kicking off the entire process.

He also discovered that cells have to go through a number of ‘checkpoints’ on the road to division – where the DNA and other biological machinery is inspected to make sure everything is in order before proceeding to the next step.

Hartwell’s discoveries were a key part of the puzzle, helping to explain how cell division gets started and why everything runs in the right direction. But there were still several gaps needing to be filled.

From beer to eternity

Paul Nurse

The year is 1976. It’s a time of glam rock, long hair and flared trousers. Up in Edinburgh, a curious young scientist called Paul Nurse is looking at a different type of yeast – Schizosaccharomyces pombe, used for brewing beer. His choice may have been influenced by a previous work placement at a Guinness brewery.

As a child, he’d been fascinated by the wildlife around his childhood home. As a teenager this interest extended to experimenting on fruit flies and collecting beetles. But as an adult, he turned his attention to studying yeast cells that have been treated in certain ways to encourage faults in random genes.

Paul figured that if the genes controlling cell division were faulty, then some yeast cells might divide more slowly, growing unusually large. But others might divide faster, forming smaller-than-average cells.

Sure enough, he soon noticed some unusually big cells that seemed to be unable to start the division process. These turned out to have a fault in a gene called cdc2, which is essential for getting the DNA copying process started and then later on splitting it into two daughter cells.

Another piece of the puzzle slotted into place in 1982, when Paul showed that cdc2 gene in his yeast was the same as Lee Hartwell’s CDC28.  Perhaps, he thought, this gene might also be the same in other types of cells?

The big breakthrough came once Paul moved to the Imperial Cancer Research Fund (ICRF) labs in 1984, today part of the Cancer Research UK London Research Institute, to escape the long Scottish winter nights.  It wasn’t an entirely smooth move, as he faced scepticism from other scientists in the Institute who couldn’t see how yeast was relevant to cancer. But their views were about to change.

Paul, along with a member of his research team, Melanie Lee, embarked on a bold experiment to find the human version of cdc2. They took a whole bunch of human genes and added them, one at a time, to yeast lacking the cdc2 gene that were unable to divide. It was a long shot but, to their surprise, one of them worked: thanks to the extra human gene, the yeast could happily divide as if nothing was wrong.

The implications of their results, published in the journal Nature in 1987, were profound. Despite being separated by 1.5 billion years of evolution, Melanie and Paul’s work suggested that the fundamental ‘engine’ driving the cell cycle is the same in all species. Subsequent work by our researchers and others around the world has proved this to be true across many of the engine’s molecular parts.

More findings came to light. Paul and another ICRF researcher, Viesturs Simanis, showed that the cdc2 gene makes a type of protein molecule known as a kinase.  These are the cell’s messengers, passing signals around by sticking chemical ‘flags’ on other proteins.

This discovery gave a strong hint that the processes governing the cell cycle might be controlled by these messenger molecules. In fact, cdc2 later became known as CDK-1, or cyclin-dependent kinase 1 – the first in a family of half a dozen similar genes that are all involved in cell division.

And it’s here in our story that we meet the other missing part of the puzzle – cyclin – and our other Nobel laureate, Tim Hunt.

Going on a cyclin’ trip

Tim Hunt

While Paul Nurse was looking at yeast cells to work out how they divided, Cambridge University biochemist Tim Hunt was tackling a more prickly customer: the sea urchin.

Fascinated by science from a young age – he even dissected his brother’s pet rabbit when it died – Tim had become intrigued by the unusual ability of unfertilised sea urchin eggs to spontaneously start dividing and developing when dunked in soapy water. Scientists refer to this phenomenon as parthenogenesis, roughly translated from the Greek words for “virgin birth”.

To understand what was going on required a steady supply of sea urchin eggs – something that was sorely lacking in land-locked Cambridge – so Tim headed across the pond to Woods Hole Marine Biological Laboratory for the 1982 summer urchin season. Perched on a harbour on the Massachusetts coast, it’s a perfect place for studying sea life.

Late one night, while his lab mates were out dancing at a local pub, he noticed something strange. He’d been looking at the molecules produced by parthenogenetic sea urchin eggs as they started dividing. But while most of the molecules stayed the same, one behaved very differently – just as the cells divided for the first time, it vanished.

Nobody had ever seen this kind of thing before, so Tim started to look more closely. He discovered that the levels of the mysterious protein peaked just as the cells got ready to divide, then it completely disappeared as they split. Fond of cycling, Hunt named this protein cyclin as a play on the fact that its levels cycled around.

Returning to Cambridge after the summer, Tim continued to explore this vanishing act. Together with graduate student Jon Pines – now a long-standing Cancer Research UK scientist in his own right and professor at Cambridge – he identified the gene encoding cyclin in sea urchins and clams.

In an echo of Paul and Melanie’s yeast experiments, Tim and Jon showed that the sea urchin cyclin gene could kick-start cell division in frog eggs, proving that it worked across species.  Since then, cyclins have been found in all cells, with an impressive assortment of different cyclins in humans.

In 1990, Tim moved to the ICRF’s Clare Hall laboratories in Hertfordshire – part of the Cancer Research UK London Research Institute today – and has made many more significant contributions to our understanding of how cells divide.

Putting the engine together

Between them, Lee Hartwell, Paul Nurse and Tim Hunt identified the crucial components of the engine that drives the cell cycle. And they, along with many other researchers across the globe, have spent the last 35 years figuring out how it works.

It turns out that cyclin is a bit like the engine itself, spinning through cycles of creation and destruction. The CDKs are the gears, pairing up with their appropriate cyclin at the right time. When a CDK gets together with cyclin it becomes active, sending messages inside the cell. And by having cyclins and CDKs produced and activated at the right time and in the right place, the cell is driven forward through all the parts of the division process in the right order.

Thanks to Paul and Tim’s work, we know that the cyclin/CDK engine is a fundamental component of all living things from yeast upwards, although bacteria do things a bit differently. Knowing this is vital for our understanding of cancer – a disease characterised by cells multiplying out of control – and shows that studying how cells divide in simpler organisms, such as yeast, fruit flies or worms, can shed light on tumours in humans.

Although their discoveries were hugely important, it’s taken a few more decades to turn this fundamental biological understanding into potential treatments for cancer. Our scientists and others have been busy developing drugs that block CDKs and stop them working, effectively throwing a spanner in a runaway cancer cell’s engine. These are now being tested in clinical trials in patients, with some promising results. Based on the successful results of a large clinical trial published in March 2016, one of these – palbociclib (Ibrance) – could be a “game-changing” treatment for women with a particular type of breast cancer, in combination with a hormone drug called fulvestrant.

More research, tests and trials are needed, but CDK inhibitors (as they’re known) could prove to be a useful tool to tackle cancer in the future.

A Nobel legacy

When the phone call came from Stockholm in October 2001 to tell Paul and Tim they had won a share of the Nobel prize, they found it hard to believe. In fact, they were only convinced it wasn’t a prank when the announcement appeared on the primitive Nobel website. And as well as the respect of the international scientific community, Tim and Paul were honoured with knighthoods by the Queen for their discoveries.

But it’s their differing attitudes to the prize money that highlights the separate paths they’ve taken in their subsequent careers. Tim, the quieter of the pair and self-confessed ‘tinkerer’ in the lab, used his to pay off the mortgage.

Until his retirement a few years ago, he continued to run his lab at our London Research Institute and published many important papers, deepening our understanding of how the cell cycle works. He also sits on various committees, including the Royal Society’s Vision for maths and science education programme.

In contrast, Paul bought a powerful motorbike, and has driven his rise to the top of the scientific establishment in a similarly high-octane fashion. As director general of the ICRF, he oversaw its merger in 2002 with The Cancer Research Campaign to create Cancer Research UK.

Following a stint in the US as president of Rockefeller University in New York, he returned to become president of the Royal Society and director of the new Francis Crick Institute in London – which will be the largest biomedical research institute in Europe under one roof, and the new home of our London Research Institute. And he continues to run a research lab at our London Research Institute with Jacqueline Hayles.

As the champagne corks are undoubtedly popping in London and Trondheim as this year’s winners celebrate, we also want to commemorate the achievements of our own Nobel laureates and their pioneering work helping us to beat cancer sooner.

Kat

Read more:

• Paul Nurse on the genetic mystery in his family
• An interview with Tim Hunt
• Great experiments: more about the discovery of CDKs 
• Cells, clams and cancer: The cyclin story 

References:

• Pines J. & Hunt T. Molecular cloning and characterization of the mRNA for cyclin from sea urchin eggs., The EMBO journal, PMID: http://www.ncbi.nlm.nih.gov/pubmed/2826125
• Evans T., Rosenthal E.T., Youngblom J., Distel D. & Hunt T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division., Cell, PMID: http://www.ncbi.nlm.nih.gov/pubmed/6134587
• Lee M.G. & Nurse P. Complementation used to clone a human homologue of the fission yeast cell cycle control gene cdc2., Nature, PMID: http://www.ncbi.nlm.nih.gov/pubmed/3553962
• Beach D., Durkacz B. & Nurse P. Functionally homologous cell cycle control genes in budding and fission yeast., Nature, PMID: http://www.ncbi.nlm.nih.gov/pubmed/6757758
• Nurse P., Thuriaux P. & Nasmyth K. Genetic control of the cell division cycle in the fission yeast Schizosaccharomyces pombe., Molecular & general genetics : MGG, PMID: http://www.ncbi.nlm.nih.gov/pubmed/958201
• Simanis V. & Nurse P. The cell cycle control gene cdc2+ of fission yeast encodes a protein kinase potentially regulated by phosphorylation., Cell, PMID: http://www.ncbi.nlm.nih.gov/pubmed/3516412

• Image of Paul Nurse via Wikimedia Commons – [CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0)],
• Image of yeast cells by By Masur (Own work) [Public domain], via Wikimedia Commons