Biological mazes hide cure for cancer

June 6, 2003

The man who found the key to the cell cycle that drives life now wonders what directs it. Tim Hunt recounts his achievements and looks ahead to the future

In biology, the questions look hard, but deep questions often have surprisingly simple answers.

I thought it was too good to be true when I discovered a protein that appeared to trigger the cell cycle - the fundamental biological process whereby a cell replicates its chromosomes and then splits into two daughter cells. People looked at me askance. Surely something as complex as mitosis, the division of the cell nucleus, could not have such an absurdly simple mechanism.

Indeed, when I sent off our first paper about this work to the journal Cell , the editor wrote back to me: "Dear Tim, In time we will publish your paper. But in nothing like its current form." One reviewer said it was "wild speculation based on faulty logic". Fortunately, the logic proved to be impeccable.

The early students of mitosis, working in the 1870s, could see how complicated the process was, but had no real concept of the cell cycle.

Researchers at Hammersmith Hospital in London made a breakthrough in the early 1950s. They labelled broad beans with radioactive phosphate to tag DNA, and found that chromosome replication was exactly out of phase with mitosis. And there were gaps in between. Hence the four-stage cell cycle we know today: gap 1, S-phase (DNA replication), gap 2, M-phase (mitosis).

These findings invited questions - what triggered the transitions between each phase of the process? And how did cells know when to proceed?

In 1979, I was teaching a course at the Marine Biological Laboratory in Woods Hole, Massachusetts, studying synthesis in fertilised sea urchin eggs. Among the many excellent seminars, I heard John Gerhart lecture about an enzyme called maturation promoting factor or MPF. He explained that a group at Yale University had discovered that when progesterone activated frog oocytes - the immediate precursors of frog eggs - it turned on MPF. He was now working on the enzyme.

Gerhart's work implied that MPF was the enzyme that catalysed cell division. It was an idea that needed some getting used to, not least because I couldn't imagine what it might entail as mitosis is so complex.

MPF was found in dividing cells throughout the animal kingdom. It was clearly key to cell division. But what was it; how did it turn on and off; how did it work? Gerhart's seminar tempted me to work on the problem.

By 1982, my research on protein synthesis in sea urchin eggs was stalled, so I changed tack and asked a slightly different question. Did artificially activated sea urchin eggs make the same proteins as fertilised eggs? I took fertilised eggs, labelled them with a radioactive amino acid, extracted samples every ten minutes and analysed the newly made proteins.

To my astonishment, I saw that one protein faded away just before the cells divided. The protein came back in time for the next division, and then disappeared again. Its concentration described a sawtooth oscillation in time with mitosis, suggesting a close connection with the cell cycle and MPF.

I happened to run into Gerhart the very evening I first saw this behaviour.

He told me about his latest experiments on MPF. He found that the enzyme went up and down with each cell cycle, and had to be resynthesised each time. If my protein was something to do with MPF, its cyclical disappearance would explain why you needed new protein synthesis for cell-cycle progression.

This was amazing. The protein synthesised and catalysed cell division, and then it was degraded. So that was how the cell cycle worked. It was natural to name the protein "cyclin" as I was very fond of cycling.

Meanwhile, geneticists Paul Nurse and Lee Hartwell had isolated a gene called CDC2 that controlled the yeast cell cycle. It took us six years to realise that cyclin was an essential companion for the CDC2 gene product.

We were slow and perhaps stupid not to see this sooner, but people forget how foggy it can be at the frontiers of science.

Understanding the cell cycle needed a combination of logical genetics and messy molecular biology. When biochemists, geneticists and cell biologists came together, they became humbler and wiser as they appreciated the strengths and weaknesses of each others' approaches. A golden age of cell biology dawned, and people could see a path through the fog.

By 1995, the field began to normalise, and the usual hard puzzles of science began to pile up once more. The next challenge is to find out what drives the cell cycle. Using the analogy of a car, we now know how the engine works, with CDC2 activated by cyclins; but it still needs a driver to decide where to go. What makes cells grow in a particular direction at a particular time? What determines how fast the cycles run?

Consider your nose. Molecularly speaking, you have a new nose every five or so years, but somehow it stays looking the same. A well-formed nose looks like a nose, even though it's different from everyone else's nose. If cancer developed, however, the nose would disintegrate into a higgledy-piggledy mass.

When my mother was dying from cancer, part of me watched as a biologist. I saw how the cancer swelled her belly, while her arms and legs withered. Her muscles were feeding the cancer. But how did the cancer cells arrogate these resources to themselves? The underlying process is a fascinating mystery.

I think a lot of people thought that understanding the control of the cell cycle would help to cure cancer. But it turns out to be a red herring.

Although chemicals that stop the cell cycle also stop cancer, these compounds work by killing cells rather than simply arresting cell-cycle progression. Indeed, most of the effective chamotherapeutic agents we have today were found empirically, long before the cell cycle was understood.

The trouble is, cancer cells have all too normal cell cycles. They have no trouble growing and dividing. What we need to understand are the signals and chemicals that keep cancer cells growing when normal cells would stop.

Blocking those signals would be the way to cure cancer.

Tim Hunt is a principal scientist at Cancer Research UK. He was awarded the Nobel Prize for Medicine in 2001 with Paul Nurse and Lee Hartwell. He talked with Caroline Davis before delivering the Croonian lecture at the Royal Society last week.

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