Her doctoral advisor told her to amuse herself, and Fiona Watt has done just that—probing individual stem cells and determining the genes and molecules that direct them
to differentiate or cause them to contribute to cancer.
Fiona Watt finished her thesis research in record time. It was the late 1970s, and Watt had joined the lab of Henry Harris at Oxford University. Harris had perfected a method for fusing normal cells with cancer cells, an approach that allowed him to look for molecules that prevented the abnormal growth of the resulting hybrid. “When I first went to see Professor Harris, he told me, ‘There are only two intellectually important problems: cancer and differentiation,’” says Watt. “Of course, I agreed—and still do! Then he asked, ‘Which do you want to work on?’ I said, ‘Differentiation.’ So he gave me cancer.”
At the time, Harris had compiled a list of potential molecular markers for cancer cells. His students were working their way down the list—one marker apiece—to determine whether or not these molecular alterations were legitimate signs of malignancy. “Mine was the idea that cancer cells don’t have a microtubule-based cytoskeleton,” says Watt. Harris didn’t put any stock in the notion, but there had been publications in the literature suggesting it was true. “He just wanted to be able to cross it off the list,” she says.
So Watt got to work. Harris had read that Mary Osborn and Klaus Weber of the Max Planck Institute for Biophysical Chemistry were using a new technique called immunofluorescence to visualize microtubules in cells. “They didn’t want to give him their antibodies,” says Watt, “so Professor Harris said, ‘Well, you can have my PhD student,’ and I got sent to Göttingen.”
“It took me two weeks to show that cancer cells did indeed have microtubules,” says Watt. “When I got back to Oxford, Professor Harris said, ‘Well, that’s very good. Now you can amuse yourself for the next two and a half years.’ That’s what I did.”
Thirty years later, Watt is still at it—amusing herself with studies aimed at understanding the molecular basis of what she considers the most intellectually exciting games in town: cancer and differentiation. Working with mammalian epidermis, Watt has demonstrated that molecules that govern cell “stickiness” also regulate stem-cell differentiation. And she’s shown that fully differentiated, nondividing cells can fuel the development of skin cancers. Here Watt describes, among other things, her attempts to capture Scottish crocodiles, single stem cells, and the essence of what it means to be a woman in science.
Junior explorer. “When we went on family holidays, I always had my head in a pond or a rock pool,” says Watt. “I would collect and catalog seaweeds. That’s sad, but true. One time I got the fright of my life because I was peering into a pond and was convinced I had seen a crocodile. I went tearing into our caravan and said, ‘I’ve just seen a crocodile!’ And my parents said, ‘Nonsense, this is Scotland.’ I was so annoyed that I spent two or three days searching for this crocodile. When I finally found it, it turned out to be a newt. It did look like a crocodile, but a bit smaller: it fit in a jam jar.”
If I knew then…After a two-year postdoc at MIT, Watt joined the faculty at the Kennedy Institute of Rheumatology in London. “I would never have hired the young me,” she laughs. “I had very minimal lab experience. I must’ve been 25. I don’t think many of my PhD students finish much before that age.”
Second time’s the charm. In 1988, Watt and her colleagues at what was then the Imperial Cancer Research Fund published a paper showing that the cell adhesion machinery does more than keep cells where they need to be within a tissue: it regulates their differentiation. “We showed that if stem cells are prevented from spreading, they differentiate. And if they’re allowed to spread, they don’t. To me that was saying that adhesion regulates differentiation as well as anchorage,” says Watt. But the finding attracted little attention. “This was clearly a case of a concept being too far ahead of its time,” she says. “Earlier this year, we published essentially the same experiment to great acclaim.” With her collaborator, Wilhelm Huck, Watt has generated micropatterned surfaces that house individual stem cells. By trapping single stem cells, Watt and her colleagues confirmed that when stem cells lose touch with the extracellular matrix, they differentiate. And they went on to identify a transcriptional pathway that mediates the response—work published in Nature Cell Biology. “I had struggled to publish the original paper, so having the opportunity to redo the experiment with much more refined methodology, and to be able to answer some of the questions that were obvious 20 years ago, was very satisfying.”
The differentiated cell done it. In 2010 Watt and her colleagues published a paper in PNAS showing that a nondividing, differentiated cell can trigger tumor formation in skin. “In the bottom layer of the epidermis are the stem cells. The cells in the upper layers don’t divide anymore, but are undergoing a terminal differentiation process. Nevertheless, these differentiated cells can drive cancer. They do it by making the underlying stem cells divide and by attracting inflammatory cells that aid tumor development. So the initiating oncogenic event happens in a cell that never divides.”
Lab shuttle. Watt is currently deputy director of Cancer Research UK, Cambridge Research Institute and deputy director of the University of Cambridge’s Wellcome Trust Centre for Stem Cell Research. “It’s been very exciting helping to get these two new institutes off the ground,” she says. “I maintain two physically separate labs, but I do a lot of to-ing and fro-ing between them. I’m in both labs most days. It’s just 12 minutes by bike. I’m actually training for the 2012 Olympics,” she laughs. “Although I don’t know if they have the category: Cycling on a Dutch Bike Fitted with a Wicker Basket.”
Muddling through. “My PhD training made me very independent. But my skill set was pretty minimal. That made me feel that I should take more care of my own PhD students. But now, having supervised 30 or so, I do wonder whether it is best just to drop them into a project and see what they make of it. It’s a good time to find out whether or not you’ve got the aptitude for science.”
BFFs with PhDs. “For many years, I was one of the boys: pub every Friday night. And that was fine. I really like the company of men. But it’s great to have really good friends and colleagues who are women.” Recently, Watt was at a meeting in Portugal and had dinner with two of her best female science cronies. “We were sitting in this restaurant and I thought, ‘This is just like the opening scene from Macbeth.’ We three witches don’t meet together very often but it’s really good when we do.”
If at first you do succeed. “I think it’s actually a disadvantage to be too successful as a PhD student. Because it doesn’t toughen you up for what’s going to happen next.”
Publish, don’t perish. “I tell young people not to get too hung up on where their paper appears. If the work is good, it’ll get noticed. Don’t get into a mindset where unless it’s published in journal X, Y, or Z, you will never live happily ever after. When we’ve lost a particularly bloody battle to appear in a certain journal, I tell my students and postdocs, ‘Let’s just get this published elsewhere and move on. We can always write a nice, self-serving review later on.’ That cheers them up.”
Joining the circus. “In the mid to late ’80s, stem cell research was a field that was not respectable at all. Then in the early ’90s Irv Weissman organized a Keystone conference on stem cells. People from all over the place, from all different backgrounds—immunologists, developmental biologists, cell biologists, and people interested in disease—came together, and we realized that we were all interested in the same problems. It was just fantastic. Now, the field has been transformed. I always call it a circus. It has so many different acts and sideshows and it has sleazy aspects, too,” such as untested therapies for sale. “But it’s colorful, there’s a lot going on, and it’s just a really interesting, really exciting field to work in.”
Get off the bandwagon. “There’s nothing that makes me more annoyed than seeing somebody simply re-badge something they’ve been doing for decades as stem cell research. The point of stem cell research is to understand disease in new ways and to have new therapies for disease. I’m not sympathetic to using stem cells solely as a vehicle for getting grants.”
Stale data. “In the old days when I went to a meeting, my talk would be based on a story that I was thinking about publishing. I wanted to get critical questions from the audience and then go back to the lab to do more or different experiments before I wrote it up. Now, people only present work that is published or in press. At which point you can clap politely, but there’s no point giving any feedback because it’s too late. I think that’s a shame.”
Better science through childbirth. “I think my science is more playful and more creative than it would have been had I not had the kids. I had reached a point where I was working harder, longer hours than anybody in my lab and I was getting a bit sour. Having kids really brought back the joy of being a scientist. And what’s the point of going into the lab if you don’t enjoy it?”
Cross-training. “Even the most unreasonable postdoc is more reasonable than a two-year-old. And the distraction strategies you apply to a two-year-old work equally well in the lab. So being a mum has probably made me a better lab manager.”
Have child, will travel. “I remember the first meeting I took my son to. It was a Gordon conference, and normally when you go to these things everybody sits together for meals. Angus, aged 5, and our au pair and I were at one of those round tables in the dining room—and we were completely on our own. Nobody wanted to come near us. On our way back to the room Angus met a young Russian boy who was at the conference. And the au pair ended up playing netball with the graduate students. By the next night, we were all having a great time—and sitting at separate tables.”
Like attracts like? “Angus’s tolerance of my science friends is really low. He’s referred to me as a nerd magnet, which is actually a pretty good summary of the situation.”
On the nightstand. “I like to read books by women who are universally reviled. I’ve just read Sarah Palin’s autobiography. It was hard going, but I get a lot of pleasure telling male colleagues I’ve read it. Americans will say, ‘That woman is dreadful and the book is full of lies.’ I say, ‘But have you read it?’ The answer is always, ‘No.’ I also read Monica Lewinsky’s autobiography. I just think if you’re going to revile somebody or detest their stance on something, you should take the time to find out what they’ve actually said or done.”
Diving. “I took up scuba diving a few years ago. It’s heaven for me. I do it maybe once a year, but it takes me back to my childhood passion for looking at things in the sea.”
• Determined that adhesion regulates differentiation and tissue assembly in mammalian epidermis and catalogued the key pathways that govern the effect.
• Identified molecules that regulate exit from the stem cell compartment in epidermis.
• Showed that integrins on the cell surface of skin epithelia can be active or inactive, and demonstrated that antibodies against integrins could be used to obtain samples enriched in stem cells. “I fought and lost a battle to patent the method because at the time people didn’t think it was important,” says Watt. “Now if you look at the panels of antibodies that are used to enrich for stem cells, integrins are usually included.”
• Discovered that nondividing, differentiated cells can contribute to the formation of benign tumors in skin.
• Produced chemically patterned surfaces that provide “islands” on which single stem cells can live in order to identify the environmental factors that regulate their behavior.
• As editor of the Journal of Cell Science, Watt initiated a series of interviews aimed at recording the experiences of women in science. “I wanted to make sure their stories were not lost,” she says. “In the end, the exercise left me sad—sad that most women had probably had a tougher time in science simply because they are women. I hope that the same will not be true for the young women currently in my lab. I’d like to think that by sheer force of numbers they’ll elbow their way through the system and gender will cease to be an issue.”