AsianScientist (Jan. 15, 2013) – In a two-part series, we talk to Professor Sir David Lane, chief scientist of the Agency for Science, Technology and Research (A*STAR), to discuss his recent win of the 2012 Cancer Research UK 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” in Science magazine for its central role in cancer development.
In the first of a two-part series, Prof. Lane describes his lifelong journey with p53, from its initial discovery until today.
Congratulations on receiving the CRUK Lifetime Achievement Award. How do you feel about receiving this honor?
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.
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?
It’s been fascinating the whole time, and in many ways it’s been my life because my research into 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’re 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.
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?
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 sections 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.
The term which you coined in 1992, “guardian of the genome,” is very apt and has really caught on since then. Is there anything that you would like to add to this?
First of all, I can’t believe it’s been 21 years. It feels like yesterday. I remember when I wrote that article, it was just the News and Views (section) of Mike Kastan’s paper. I had written something like “A new partner for p53,” a very boring title. And the journal said, “Come on David, can’t you think of anything else better?” I had just read a book called the Knowledge of Angels, and somehow that was in my mind when I came up with this idea, “guardian of the genome.” Immediately, I just thought, “This is just brilliant, this will catch on!”
In a way it’s still a good concept. One property of p53, which seems to always remain, is genetic stability. As soon as you take p53 away, and you have a stress, the cells become aneuploid – the chromosomes get very messed up – very quickly. I think that is a very important function of p53 which we don’t yet fully understand. I think we used to interpret that as being absolutely linked to growth arrest, but it may not be the case. So I still think it’s still the “guardian of the genome.” I just don’t know how it’s doing it. More research needs to be done. I think sometimes as scientists we get a little arrogant. Why would we expect to understand this evolutionary ancient, vitally important mechanism completely in a few years? Of course it’s going to take time to sort it out, but we are making progress.
Since p53 is so vital to cancer development and you mentioned that there is now a p53 drug in clinical trials, what do you think is the future for cancer therapy?
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; 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, and 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 p53 mutant cells 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 Ph.D. 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.
Part II of the interview will be published on Tuesday, January 22. An abbreviated version of the interview will be published in the upcoming issue of INNOVATION Magazine.
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Copyright: Asian Scientist Magazine; Photo: Ng Yi Zhen.
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