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A Lifelong Journey with the Guardian of the Genome
Professor Sir David Lane of A*STAR talks candidly to INNOVATION magazine about his scientific career, life in Singapore, and the future of Singapore's R&D landscape.
by Ng Yi Zhen

Professor Sir David Lane, the chief scientist of the Agency for Science, Technology and Research (A*STAR) Singapore, is the recipient of the 2012 Cancer Research UK (CRUK) Lifetime Achievement Award.

The prize recognizes the pioneering research of Prof Lane that led to the discovery of p53, which he famously described as the 'guardian of the genome.'

Since the 1979 discovery of the p53 protein — named for its molecular weight of 53,000 daltons, he has dedicated his career to understanding how it protects against cancer. In 1993, the protein was voted "Molecule of the Year" by Science magazine for its central role in cancer development.

In recent years, Prof Lane's work has focused on controlling p53 and this has identified several promising targets for developing new cancer drugs.

i: Congratulations on receiving the CRUK Lifetime achievement award! How do you feel about receiving this honor?

David: Yes, it's very nice for lots of reasons. First of all, it comes from your colleagues. The other thing is I have worked for CRUK for a long time. Right from when I first started my lab they've supported me all the way through my career in Scotland. I feel that I know them as an organization very well and I admire them a lot because they are entirely a charity. The CRUK is entirely funded by the public and gets no money from the government at all. It is a very unique organization and it does a lot of work, not just supporting science, but also supporting scientific careers and educating the public about cancer. They've also had a very big role in the smoking ban in the UK.

i: As you look back at more than 30 years of your research since you first published on the p53 protein in 1979, how would you describe this journey?

David: It's been fascinating the whole time, and in many ways it's been my life because my research in p53 is older than my children! One of the nice things about it has been the community of scientists. There are several people who were working on it very early on, and who continued to work on it, so we've also known each other for a very long time. People like Arnie Levine, Moshe Oren, Varda Rotter, and others.

There's always this compelling reason to work on p53 because it's basically altered in every human cancer. In fact we recently learnt that in serous ovarian cancer, every cancer has mutations in p53. So it's an interesting counterpoint to our current understanding of cancer, where every cancer seems to be different. We worry that we need a different drug for every single cancer, and yet we do understand from p53 that there are some very common molecular steps in the process. So on one level it's very straightforward; on the other level it's very difficult as we try to understand what p53 really does, how it works, and how to make drugs that take advantage of p53 mutations.

It's been very challenging and it's an exciting time now because the first p53 specific drug is in clinical trials. These drugs are designed to reactivate wild type p53 in the tumor, where the protein is still there but not working properly. We've working very closely on trying to understand how they work and which tumor they might work best in. It feels like the field has gone all the way from a very basic discovery, all the way to clinical trials. What we are all hoping for is fabulous clinical success. That would be a really good outcome from exploiting this pathway for therapy.

i: Did you have any idea when you first published on the p53 protein that your initial discovery would have such a huge impact? What was the context at that time?

David: No. The context at that time was simply a model system which was a virus, called SV40 virus, that is very good at transforming cells in culture. It's incredible to think back. In those days, we didn't have easy DNA cloning, we didn't have sequencing, so there were very few things we could do. Cloning had just started. The virus had a very small genome — it was one of the first viruses to be sequenced. It's funny to think that just sequencing 2,000 base pairs led to a Nature publication.

So we knew that the virus could transform normal cells into cancer cells and that to do so, it only needed to make one protein, which was viral SV40 tumor antigen or T antigen. We were doing what people would now call 'pull down' or immunoprecipitation, looking for other things that would bind to T antigen and that's how we discovered p53.

And it became clear that p53 was interesting. Other people found that p53 was overexpressed in some tumors and in the 80s, found other viruses that bound to p53, such as adenovirus and papillomavirus, so there was a common thread.

But things really exploded completely in 1989 and 1990 with the discovery that what people thought was just bad sequencing turned out to be mutation. I think a critical paper was Bert Vogelstein's paper in 1989, showing a mutation in colorectal cancer. Because we had all the reagents and we were working on the system, we and a couple of others were able to move very fast. Within two years it became clear that there were mutations in p53 in almost every sort of cancer. Not only did those mutations happen frequently, but they also often lead to the overexpression of the protein.

That allowed pathologists to look at very large number of samples very quickly. There is a very large literature using the antibodies that we have made, looking at conventional histology section to show p53 was overexpressed in many cancers, so that really had a big impact.

I guess the next phase is to try to understand what p53 did. That's when I christened it the "guardian of the genome," that got my Nature paper cited umpteen times, with the hypothesis that what p53 did was to respond to DNA damage and cause cell cycle arrest or apoptosis or something else that protected the animal from getting cancer. That idea got a lot of interest and helped us to understand what was going on.

i: Since p53 is so vital to cancer development and you mentioned that there is now a p53 drug in clinical trial, what do you think is the future for cancer therapy?

David: What we are seeing at the moment is big improvements in cancer therapy and lots of people surviving much longer. If you look at it carefully, it is a mixture of different things. It is clearly prevention — fewer people get cancer if you stop smoking. Against that, the increasing population and aging, which means that we're having more people with cancer. And then early detection which is extremely important.

We are beginning to see new drugs having an impact. The poster child for that is of course, chronic myeloid leukemia, where people really are surviving for a long time now as a result of the drug Gleevec. Then we have Herceptin in breast cancer which has had a huge impact on survival. So we are in a very exciting time where really new drugs for cancer are coming through.

I believe passionately that p53 is still a good target. There are two ways which we are thinking. One is to activate wild type p53, where we couldn't do that before and that's where most progress has been made. But there is also the concept of, "can we reactivate the mutant, can we make the mutant protein behave like a normal protein again, or can we find a way of selectively killing cells that don't have functional p53?"

Those are the really good ideas, that if they can be made to work, their impact would be very large because of the number of cancers which have that alteration. So although I think that the challenge of finding the drug that can kill the cells that make mutant p53 is a big one, the reward is huge because 11 million people could benefit from such a drug.

We are right at the edge, technically. Most of the things that I've done, people have told me you can't do and it's not going to work. Protein-protein interactions — people said it was not possible to make a drug against, but now we have several drugs in clinical trials that do work that way.

The next challenge for me is protein folding. Can we find drugs that can affect the way proteins fold, to make the mutant p53 fold up the correct way again? Some of the PhD students in my lab are taking on that challenge. It's very difficult, but I don't think that it's completely impossible and we have hints of success, so we have to keep trying. In science you have to try to do very difficult things. That's where real progress is made. Reach for the stars.

i: Other than being an entrepreneur, as the chief scientist of A*STAR, you have played a pivotal role in shaping Singapore's R&D landscape over the past ten years. How do you see this journey?

David: Singapore is amazing — the sort of will to do things, get things done, and to do new things. But it's also a very impatient place. It expects things to happen very quickly. It is quite hard for science, particularly biological science, to work at that pace. So I think it's challenging, because the expectations are so high.

For most people who have worked in Singapore, the level of bureaucracy can be frustrating at times and I think it's partly because it's government money and there's great anxiety to make sure that money is not wasted. But I think in general it's been wonderful, something happens nearly every day.

i: Which direction would you see the research in Singapore going in the future?

David: I always felt that Singapore has a unique advantage in terms of the very high quality of engineering. The dream of A*STAR, which was to bring engineering and biology together, is still a great dream. If we think about what really made biology move, a lot of it is technology. You think about a machine for sequencing, you think about a flow cytometer, you think about a modern microscope... These are tremendous pieces of engineering, and you know we still haven't quite got that together.

I've been working with the A*STAR Joint Council Office and everybody else to try and make that happen and I think it will happen. You can see it coming in now from many different directions because of the need to replace oil as a feedstock for chemicals. The chemical industry is getting very interested in biology. How can I take the leftovers from palm oil and turn that into something useful? Suddenly you are into engineering cells and synthetic biology. Maybe you can make a cell that will take this material and turn it into something useful. So it is happening and I would like to see more of that in Singapore.

I would also like to see people building equipment in Singapore. We should be able to do that very well actually and I don't think it's something that we have quite found yet. One of the problems I suppose is the tremendous attraction to these blockbuster drugs I've spoken of. If we can do that, all our problems will be solved. But actually, that's terribly hard.

Setting up a company that makes a machine or a company that makes a product that is sold to the research community is a lot easier. It's not without challenges — it (the product) has to be very good. But we probably should be building up the business environment here, so that the science in Singapore would have a close interaction between biology, engineering, and companies making products.

If you look historically, what has happened for a typical bench scientist in biology these days is that they use a lot of commercial kits and apparatus to do their work and that's a tremendous market. We could be tapping into that market. It would suit Singapore very well to be in that area, because it is something that we could do well.

i: As a very successful researcher, what are your pearls of wisdom for budding scientists?

David: I am an amazingly optimistic person. I just don't know where that came from. So optimism is a very good thing. I think you have to not listen to what other people say too much. People will always have opinions about what you are doing, what other people are thinking, what so and so said. I think you have to be quite self-contained and make up your own mind.

I would say it sounds so simple — making good reagents that other people want is immensely helpful. My career has a lot to do with making good antibodies and peptides that worked and were helpful, and then giving them out. I think that is a tremendous lesson. If you just think about game theory, it's just the best thing to do as a scientist. The more you give, the more you get back. So we made antibodies to p53 in zebrafish and within a year, everybody in the zebrafish community loved us to bits.

But I do think if you are starting out as a PhD student, look at your field, at what's not working, and see if you can come up with solutions. What is in this kit? How does it work? What can I do to make it better? Is there a reagent missing that would make an enormous difference? If I make a cell line that did this, would it have an enormous effect? And then give it to everybody. Simple!

Professor Lane is the Chief Scientist of the Agency for Science, Technology and Research (A*STAR) Singapore, where his main role is to advise and engage in scientific development across the Biomedical Research Council (BMRC) and the Scientific Engineering Research Council (SERC) at the strategic level. He is also the Director of the p53 Laboratory at A*STAR and Chairman of the Board of Chugai Pharmabody Research Pte. Ltd. in Singapore.

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