Chief Scientist in A*STAR Singapore
APBN was very honoured that it had the opportunity to speak to one of the most influential speakers at EmTech Asia 2017, Professor Sir David Lane, a scientist credited with the landmark discovery of cancer gene p53. The p53 gene is considered the most significant of all genes altered in cancerous cells because its mutations cause almost 50% of all human cancers.
Sir David is the Director of the p53 Laboratory, which primarily focuses on research on p53 using both mammalian and zebrafish systems. He is currently the Chief Scientist of A*STAR, supervising and engaging in scientific development across the Biomedical Research Council (BMRC) and the Scientific Engineering Research Council (SERC) at the strategic level.
In view of your huge contributions to cancer research, especially in relation to the discovery of p53 in 1979, could you comment on the mutation in gene p53 being the leading cause of human cancer?
Sure! What had been found over many years now is, about half of all human cancers have mutation in the p53 gene. Mutation in p53 plays a critical role in the steps turning a normal cell into a cancer cell but we know there are other steps as well. Having a mutation in p53 is not enough to give you ‘cancer’, it is just an important part of the journey from turning a normal cell into a cancer cell.
Are there other gene mutations that may directly lead to cancer?
Yes, we studied the genome of cancer cells and found that they might contain hundreds of mutations, maybe 5 or 6 of these are what we call drivers of mutations, and these cell mutations are very critical for the altered behaviours of cancer cells. That’s why cancer is sort of a rare disease because there are many changes and unknowns.
Is the type of cancer determined by the type of gene mutations in different body parts?
One of the important factors in causing cancer is the environmental or external factors, and smoking is the most straightforward. We could say that smoking is something that damages genes so it could cause particular types of mutation. Obviously, it seems that different cells in our body have some types of genes that are more frequently the driver gene of cancer than others. In pancreatic cancer for example, RAS mutation always occurs whereas in breast cancer it is much rarer. We did a fascinating study on the cancer cell evolution and closely observed the changes that took place when an individual tumour evolved from one that is not malignant into a serious stage. So we are getting more and more understanding of the cancerous stepwise process and p53 has an important part in the process.
However, there is an issue in cancer diagnosis now – the phenomenon of being over-diagnosed. We have sensitive tests for cancer but many of us have some cells with p53 mutation as we get older. That doesn’t mean it is a cancer cell; it just means that cell is on a long journey, though it could possibly not giving rise to cancer. So we have to think more carefully about what kind of tests we would use because we don’t want to give faulty diagnosis and cause unnecessary worry to the people.
Your discovery of p53 led to possibilities in anti-cancer drug development. What are some of the current developments in cancer drugs/therapies?
Several pharmaceutical companies are developing cancer drugs directed at the p53 pathway such as Roche Pharmaceuticals. There are currently two drugs directly related to p53 in the late stage of clinical development. One is the drug targeting the broken signalling pathway and in this case the p53 mutation is not required. Another amazing drug is manufactured by a Swedish company. It takes mutant p53 proteins and seems to make them fold correctly until it sorts of restore its function. The drug is also in clinical trials. It’s exciting times, if we are lucky to have p53-based therapy in the next few years, I will be very happy.
What is the efficiency of existing cancer drugs/therapies? What should we do to reduce the risk of getting cancer?
The idea of one drug eliminating the cancer does happen, but it is unusual. Typically, we need about two to three drug combination. So my feeling with p53 would be like that. They will contribute to, be part of the armoury. But this approach is working very well now. We are beginning to see very good responses as we get the right combination of drugs for particular type of tumour.
There is huge area that we call chemoprevention. We try to come out with drugs that will block the metastasis process or reduce the frequency of which cancer arises.
Lifestyle choices are very important. Not smoking is a fantastic way to prevent some cancers. Clearly if we catch this disease early and they haven’t spread, surgery would be extremely effective. One trend that is happening is improving the imaging of cancer.
There is an inherited cancer called Li–Fraumeni syndrome which is caused by inheriting the mutant p53. The children inherit a mutant p53 from their parents and have a high frequency in cancer. They have a program now called the Toronto Protocol where they make measurements of the children and do image analysis every year. The result is successful in that the children involved are living much longer and doing much better. This implies if we could have early detection, reduce the false positives of screening, and monitor people very well and at a lower cost, we could actually do more for the patients with the standard treatments.
Overall, it is a very sensible thing to do, but for individuals, you could see where it is sometimes inappropriate. So getting this balance right is very important. The other big area is trying to understand that we can identify people who are particularly high risk so in the classic case, if you have inherited one of these mutations like in the case of breast cancer mutation, such as in the case of Angelina Jolie, you could say that you are in very high risk and take appropriate action.
In the wider population, different approaches may apply. If most of the risks are present in say 10% of people, it is more effective to do screening in that small population. People are beginning to do that what we call genome-wide association. Start to look at huge number of people and say that with this combination of variables you need more screening than the other people. That is another trend that is coming.
How has your research experience influenced the work that you are doing for Chugai Pharmaceuticals in Singapore?
In Singapore, I have been working with Chugai Pharmaceuticals, their antibody technologies are combined with sophisticated protein engineering to produce cancer treatments that are very successful. So you are suddenly seeing what you thought of as a well-developed technology having additional great capability so I think some of this are quite spectacular to me. I especially feel the bispecific antibody technology developed by Chugai, that can get two cells to come together is truly interesting. One of the antibody arms binds to T-cell, and another arm binds to tumour cell, and pulls them to come together to give an exciting elimination result. There is a lot still in the pipeline at Chugai.
I am involved in their R&D and I enjoy that. There are a lot of possible targets (for the antibody technology) that you can choose when you have a program like that. My own experience in research helps to contribute to those choices and those ideas. That is a big risk to take up a new target, which requires a lot of discussions but is also very inspiring.
Are there other developmental trends or directions that you foresee for research and potential therapy pathways?
There is something that we need to know. The tumour of one person is different from another person’s tumour even if they are called breast cancer, for example. In the past, you might suffer from the fact that they are all categorised under one roof but in fact they are rather different. We see personalized medicine becoming very important in cancer treatment in the bid to find the right drug. I think in the future, we are going to have many medicines and also good genome sequencing, and that would be demanding.
Is genome editing technology the current hot topic because of its application in the biomedical field?
Yes, I think the CRISPR-Cas9 genome editing method is incredibly powerful, at this moment it allows us to do our experiments much better. Listening to the impressive talk at EmTech Asia today, I feel that it is not far to see a shift happening with the method going from a laboratory tool to being directly used as part of a treatment. We begin to realise something that the immune system is very effective in fighting cancer and if we can give it a boost, that helps in many applications.
What do you think are the essential qualities that innovators and entrepreneurs should have?
They have to be willing to take risks. Essentially if you want to make a breakthrough, you have to disbelieve what others tell you. If you want to change something, you have to be a bit radical in that things might not be the same as what was told in the textbook. It is important for the person to be willing to challenge the system, be a bit stubborn, persistent and have personal courage.