| By Divya Gandhi
American geneticist Mary-Claire King, who discovered that breast cancer can be inherited, talks of the road ahead for India
In April 1975, a 29-year-old geneticist’s research finding made it to the cover of Science, vastly advancing our understanding of evolution: she had found that the genetic sequences of chimpanzees and humans are 99% identical.
Today, Mary-Claire King, Professor of Genome Sciences at the University of Washington, is better known for another key discovery: that breast cancer, which claims the lives of over 500,000 women around the world every year, can be inherited. She identified the gene BRCA1, which, when it mutates, leads to a lifetime risk of breast cancer of 80% and ovarian cancer of 50%.
In an interview to Divya Gandhi in Chennai, where she will deliver the first lecture in a four-city Cell Press-TNQ India Distinguished Lectureship Series, Professor King talks about the road ahead for India, where breast cancer is the leading form of cancer among women; about the promise of gene editing for tackling certain congenital disorders; the need to create an enabling environment for women scientists, and her latest work on the genetic origins of schizophrenia.
Tens of thousands of women in the U.S. screen for the ‘breast cancer gene’ BRCA1 every year. You have said that all women over 30 should test for the gene. What would you recommend to India, where breast cancer is the leading form of cancer among women, but genetic screening is hugely expensive, at Rs. 25,000 to Rs. 60,000?
That is a central question. My suggestion will be to begin by carrying out genetic testing for all women who are newly diagnosed with breast cancer or ovarian cancer. Now it is of course true that if we detect a mutation only after a person has cancer it is a missed an opportunity to have prevented that cancer. Nonetheless if we begin by testing women who have just been diagnosed, we do have the opportunity to direct their treatment. There are particular treatments for breast and ovarian cancer now that have been developed in consequence of the biological action of BRCA1 and BRCA2. In addition of course, if a woman who has just been diagnosed with breast cancer learns that she has a BRCA1 mutation, her daughters and her sisters can make use of that information because each of them has a 50-50 chance of having a mutation. If they learn that they are mutation carriers and are still cancer-free, they can have especially stringent surveillance or undertake preventative risk-reducing surgery.
Your point about genetic testing being expensive is extremely well taken. Technology is now being used in the States and in many parts of the world to carry out screening much less expensively, for about Rs 15,000 to test all genes. This is a moment in which technology development and translational research can really work together like a pas de deux in ballet. This is really an opportunity for Indian scientists to undertake collaboratively the adoption here of the new technologies. The intellectual capacity exists here. The scientific capacity exists here. But there hasn’t been adequate exposure to the new technologies.
On Tuesday, the U.S. National Academy ofSciences cautiously endorsed germline editing [that is creating changes in genes that can be inherited by the next generation] to minimise the risk of heritable disease in children. How significant is this endorsement for BRCA1 mutation and other diseases of the genome?
The National Academy statement, which is an international statement, is very balanced. What gene editing allows us to do is to bring new technology to medicine.
The contexts in which we will use gene editing are many. I think it will be first used for severe congenital disorders for children who are already born and for whom it might be possible to carry out a gene alteration in such a way that more normal development will proceed. For breast and ovarian cancer what I am hoping is that the next generation will have medically-based approaches to be able to approach this rather than needing to undertake the gene editing approach.
In the weeks after actress Angelina Jolie announced her decision to go in for prophylactic mastectomies when she found she carried a BRCA1 mutation, there was a staggering 64% spike in genetic testing among women in the U.S. But curiously that did not translate into a significant increase in surgeries. How do you explain that discrepancy?
People understood the message that Angelina Jolie was trying to convey, which is that being tested is important. In her case, she learned that she did have a devastating mutation and she did the wise thing. The vast majority of women who are tested will not have devastating mutations in BRCA1 or BRCA2 or any of their sister genes. But for those who do, it is important for them to be aware of that and to, at the very least, undertake very assiduous surveillance. Angelina Jolie of course had the history of her mother and her aunt. Because these mutations can be inherited from fathers as well as from mothers, half of the women who carry mutations in their genes have no family history that would alert them.
What happened with all this additional testing was that very few women proved to have any mutation in BRCA1 or BRCA2. That’s very good. Those that did [have a mutation] were then alerted to the possibilities, which can range from increasing surveillance, to preventive removal of the ovaries and fallopian tubes, to doing what Angelina Jolie did, which was to have a prophylactic mastectomy.
The main thing I would like to convey is that knowledge is power. And secondly, that our genes are not going to change if we ignore them.
We know today from your ground breaking research decades ago that the genetic sequences of chimpanzees and humans are 99% identical. Was it a controversial proposition when it was published in 1975?
It was certainly controversial among people who don’t believe in evolution. In the scientific world I think it was less controversial than I had anticipated, because the result was in the context of the realisation that we and chimpanzees are radically different in terms of anatomy and ways of life. At the level of sequences of proteins, we and chimpanzees are 99% the same. This is the level of identity that we would see in two species of field mice, sibling species of field mice, which are indistinguishable in any other way. But unlike closely related species of mice, we and chimpanzees are radically different at the level of length of long bones, at the level of behaviours and so on. So it led to the question: what underlies these two different sorts of evolution? How is it that the evolution of proteins has proceeded in this regular way, we have this great similarity reflecting our recent divergence from chimpanzees only 5-6 million years ago; and yet we have had such differences in other evolutionary pathways that have led to these radical differences in the ways of life. And what we proposed — because in 1975 we didn’t have the technology to do more than propose — was that the radical differences in ways of life might be underlain by differences in the regulation of genes, that is when genes are turned on and off during development, not in what the gene actually is.
It has been absolutely fabulous in recent years to see that we are completely vindicated about this level of protein sequences and also that the differences between humans and chimpanzees at the level of large genomic rearrangements are very striking.
The careers of women scientists are notoriously circumscribed, a trend that you have spoken about. An estimate says that women make up nearly 30% of science doctorates in India, but their representation in science faculty is just 12 per cent. What could some of the game changers be?
In many places — and I put my country among them and I suspect this is true in India also — there is much more encouragement of girls to enter science and math now than a couple of generations ago. But the one thing that none of us can change is biology: that just the time that one is completing advanced training and beginning to develop independence scientifically, coincides exactly with the time one is going to have children. Enabling of a woman both to have a family and to become an independent scientist is the most difficult question worldwide. We need structures that enable both these roles to happen successfully. A situation in which child care is available, that a woman can take maternity leave; but critically that when she returns she doesn’t lose her competitive position.
Tell us about your current research on the genetic origins of schizophrenia. What do you hope to find that could translate into intervention the way the BRCA1 discovery did.
I began studying schizophrenia a decade ago. Psychiatrist friends of mine told me some features about their patients’ families. We all understand that schizophrenia is familial. But the great majority of their patients with schizophrenia do not have a family history of the disease. Also, a number of mental illnesses — autism, schizophrenia — are more common among children who were born to older fathers. It is called the ‘paternal age effect’. Another historical observation is that the incidence of schizophrenia is increased as a consequence of maternal famine. There are two historical events in which this was rigorously documented. One was after the ‘Dutch hunger winter’ at the end of World War II, and the same thing happened in the consequence of the Chinese famine in the late 1950s and early 1960s.
One hypothesis for these spikes in schizophrenia incidence is that under starvation the uterus has much lower levels of micro nutrients, including folate, which is essential for the repair of DNA. If in the intra-uterine environment DNA is not being repaired, mutations survive. All of these observations led me to suggest that much of schizophrenia might be due to new mutations.
We hope that in the near future, it will be possible to use knowledge of the gene that is dysfunctional in a particular schizophrenia patient to being able to suggest which medication might be most useful for that patient — again, precision medicine. When physicians treat patients, it is very hard to know what will work. Any one medication will work for some patients and not for some for others. You can’t tell in advance from the symptoms — but maybe you can tell from the genes.