Cynthia Kenyon: 'The idea that ageing was subject to control was completely unexpected'
The Observer, 17 March 2013
The molecular biologist talks about the discovery that led to a revolution in our understanding of the ageing process
In the old Russian fable of "Little Red Hen", a hard-working hen asks her friends to help her make bread. None of them are interested in her endeavours, until the bread is ready. Suddenly, everybody wants a piece. As Cynthia Kenyon recalls her early enthusiasm for ageing research in the 1980s, as a young professor at the University of California, San Francisco, where she still works, I can't help but think of the little red hen. Kenyon's dogged determination was met with nothing but condescension and derision. She tells me how one contemporary, now a Harvard professor, told her: "Cynthia, I have friends who work on ageing and it is as if they fall off the edge of the Earth." Yet years later Kenyon's studies "meant that evolutionary biologists had to go back to the drawing board". Suddenly, like little red hen, everyone was interested in what she had been up to.
Kenyon was no science prodigy. She was a contemplative child who grew up in a college town in Georgia surrounded by her pets and music. Kenyon dallied in all sorts of subjects, including poetry, Russian and maths, and even dropped out of college for a while to work on a farm, before finally getting into science with the ambition of becoming a vet. As soon as Kenyon tried science, she discovered a natural ability. "It was like stepping on to an escalator; I could do anything. I was just made for science," she says, even if, at school, she had found it dull.
After finally settling on chemistry and biochemistry, at the University of Georgia, Kenyon's talent for science took her on to do a PhD at MIT, where her early experiments on bacteria gave her a taste for the unexpected. There she found out that a specific gene is needed in order for UV rays to cause DNA damage. "You would think that UV just causes mutations, but it doesn't, you need a gene to be active for it," Kenyon says. "That hit me hard. People had assumed ageing would be boring: there was nothing to study, you just wear out. But I was realising already that things that seem like they might just happen the boring, natural way might not."
Kenyon continued her postgraduate studies in the UK at Cambridge, where she began to work on the development of small organisms, includingCaenorhabditis elegans, a small roundworm with a short life cycle. It was during this time that Kenyon was also blown away by experiments showing how similar development is in different animals. For instance, her lab showed that knocking out a crucial development gene in a worm and replacing it with the same gene taken from a fruit fly doesn't affect the worm's development. "By the time we started working on ageing, I had in my mind the idea that scientists often think they know how something works when they don't, and they think it's going to be boring when it's not."
Cynthia Kenyon speaks about her research with an infectious energy, yet when she tried to recruit young scientists into her lab at the University of San Francisco in the early 1990s, her enthusiasm fell on deaf ears.
Eventually, she persuaded a student, Ramon Tabtiang, to help her look for specific genes that might control ageing in her worms. They were "incredibly lucky" and, before long, in 1993, had made their big breakthrough. Partially disabling a single gene – called daf-2 – caused the worms to live twice as long as normal. Not only that, but the worms appeared to be healthy until the end.
This finding built on her earlier research, but to the rest of the scientific community, "the idea that ageing was subject to control was completely unexpected," Kenyon says, before struggling to find the words to describe how she felt when she realised the magnitude of the discovery. "It was very profound because you look at these worms, and the normal worms are dying, and the worms in this other culture dish are young. And you think: 'Oh my God, they should be dead.' It was like finding something that shouldn't be. It makes your hair stand up." Then came a second realisation: "You just think, 'Wow. Maybe I could be that long-lived worm.'"
Indeed, Kenyon's discoveries have come to influence her own lifestyle choices. Take the bar of dark chocolate she's been sharing with me during our conversation. "We gave our worms a tiny bit of sugar and it shortened their lifespan by revving up the insulin pathway. I didn't go home," she laughs, "I went straight to the store and I bought a book on low-GI diets and found a recipe and that was it, I changed immediately." Kenyon now avoids all sugar, except dark chocolate, as well as bread, and sticks to low-GI foods.
The link between diet and ageing makes sense when you consider that the gene daf-2, which was partially disabled in Kenyon's worms, activates receptors that are sensitive to two hormones – insulin and a growth hormone called IGF-1. This receptor is normally activated by insulin, and too much sugar in the diet, which may have the opposite effect, overstimulating these receptors, says Kenyon, who warns that "sugar is the new tobacco".
Later experiments shed more light on the effect of weakening daf-2 activity, which triggers a sequence of events within the cell, including the activation of a second gene, FOXO. This, in turn switches on or off a whole host of other genes. The cascade effect is far-reaching, like a shift in state, says Kenyon. "It's like going from a solid to a liquid. Now, instead of expressing the normal repertoire of genes, it's a new one, and this new one does a better job of protecting and repairing the tissues, and makes them live longer." This is the molecular pathway to longer life that Kenyon had always been convinced must exist, controlling the ageing process like the strings of a puppet.
For those who doubt the relevance to humans, Kenyon points to studies showing that people who live to be 100 are more likely to have mutations in the daf-2 gene. There are also variants in the FOXO gene that are more frequent among people who live to be 100.
After more than three decades working with her microscopic worms, Kenyon's last big effort in her career is to "try to move this into people. That's my dream." She says results will soon be announced of a new drug that prolongs life in mice. In her own lab, she is looking to do the same for humans. "We are trying to find drugs, small molecules, that people could take to make them disease-resistant, more youthful and healthy. Eventually we will find them." Kenyon stresses that the ultimate aim is healthy ageing. "Just living longer and being sick is the worst. But the idea that you could have fewer diseases, and just have a healthy life and then turn out the lights, that's a good vision to have. And I think what we know about some of these pathways suggests that might be possible."
Ten questions Cynthia Kenyon
What is the most exciting field of science at the moment?
Ageing is very exciting. But if I didn't work on ageing I'd want to work on the brain. There are really cool techniques you can use now. And bioinformatics. The methods you can use for comparing large data sets – that's so powerful.
What book about science should everybody read?
The Double Helix by Jim Watson is awesome, even though he was so mean to Rosalyn Franklin. Another is The Eighth Day of Creation by Horace Freeland Judson. And On the Origin of Species is also great fun, and beautifully written.
Do you have a favourite gene?
Is Cern worth the money?
Yes, absolutely. We need [nuclear] fusion to work. It's completely clean, and so any kind of understanding of atomic structures is very important. It could save the world.
What advice would you give to a teenager thinking about a career in science?
Kids should figure out what they're good at, what they have a knack for. And then figure out what they really love. They should watch themselves. What gives them a kick? And then they should go for it all out. That's what I did. And don't worry about whether you can do it or not – if you think about that, it's like putting friction in the system, like putting sand in the wheels. Just go for it.
Do you have a fantasy experiment?
With ageing, of course. You want to do all these things with humans, but you can't.
What scientific advance would make the most difference to your daily life?
I am worried about climate change and that's a daily life thing. And it probably looks like it's going to have to be solved by science. I don't think behaviour is going to change enough.
Do you believe in God?
Part of my brain does.
Why do so few scientists go into politics?
Have you read Susan Cain's Quiet? It turns out I have all the qualities of an introvert. I didn't know that. I think a lot of scientists are, and it's not the same as being shy. If you take an introvert and an extrovert to a party they can seem indistinguishable, but the introvert is thinking, "When can I go home?" and the extrovert is thinking, "What's next?"
Who deserves a Nobel?
That's a great question. It would be nice to give a Nobel prize for finding that smoking causes cancer.