One day a few months ago, a student walked into Mary-Claire King’s office at the University of Washington, and told the professor a movie was being made about her. In Hollywood. Starring Helen Hunt. King gave her a bemused look, thinking it was just silliness. Sure, she’d been told before that she bore a certain likeness to the blonde actress, but to make a whole practical joke out of it? She chuckled and went back to her paperwork.
Later on, Prof. King did a quick Internet search (the student had said Helen Hunt, after all) and found the following: The movie “Decoding Annie Parker” tells the story of two women − Annie Parker, who is diagnosed with breast cancer after her mother and sister have both died of the disease, and Mary-Claire King, a brilliant geneticist from the University of California at Berkeley, who made one of the most important discoveries of the 20th century: the gene responsible for breast cancer. The women’s lives gradually intertwine over 15 years, culminating in a fateful, life-changing encounter.
King furrowed her brow in consternation. As ever, she approached the matter analytically and as she saw it, had two options. One: make a big fuss over it, as she hadn’t been contacted by anyone regarding the film; no one had requested her consent and there was no telling what the movie would show. Or two: let it go and continue focusing on her own work. She thought about it and reached a decision, which we shall get to later.
In any event, Mary-Claire King is certainly prime movie material. The major breakthroughs and discoveries she has made could easily fill four movies, each one more exciting than the last. Indeed, each discovery has touched people at the deepest level. It started with the doctorate she did at Berkeley in 1975, when she stunned the world by being the first to show that humans and chimpanzees are, genetically, 99 percent identical.
I meet with King, 66, at Tel Aviv University’s medical school, which she had been invited to for a two-week visit. The following is just a short list of her titles and appointments: president of the American Society of Human Genetics; member of the National Academy of Sciences; foreign member of the French Academy of Sciences; member of the American Philosophical Society; and holder of a dozen honorary doctorates from different universities around the world. Permit me to add a few titles of my own: incredibly hardworking, most charming and completely unpretentious.
“At first I thought I must be mistaken,” she says, referring to the discovery of the genetic similarity between humans and chimpanzees. “I expected some similarity, of course. After all, Darwin claimed we shared a common ancestor that lived not so long ago, and people had already compared human and chimpanzee proteins and shown that they were similar. But 99 percent? That’s like the closeness between two species of hamsters or fruit flies!
“Since I’d done my bachelor’s degree in mathematics and not in biology, and because I’m not very good at the manual part of lab work, I thought I must have done something wrong. So I repeated the tests. I analyzed the results again, extra carefully, and again I came out with 99 percent. I went over the data with my adviser and suddenly he said: ‘Maybe it really is the truth!’”
The discovery shook the scientific world and beyond. Here was real, physical, quantitative proof of the first-degree familial relation between man and ape. Now let’s see anyone try to deny the existence of evolution.
“But anyone with eyes in his head can see there’s a paradox here,” King adds. “Because despite the striking similarity, obviously there are vast differences between us and chimpanzees: size of brain, length of limbs, posture, communication, and so on. Therefore, we proposed that the big differences in appearance and behavior derive not from changes in the genes themselves, but in their regulation.”
In other words, evolution did not cause major changes in the proteins that make up the bodies of humans and chimpanzees, but rather affected some regulatory regions that determine how many of these proteins will be expressed, and when and where. Think about an enzyme that affects bone growth – a difference in the length of time this protein is active during arm development in the fetus is enough to result in the chimpanzee having much longer arms than humans do. Variations on the same theme − this is what makes the difference.
Years later, with advances in DNA technology, molecular biologists were able to prove King’s theory correct: The differences between humans and chimpanzees derive primarily from the regulatory mechanisms of the genes.
After you made this tremendous breakthrough in evolutionary biology, you put the subject aside and began studying breast cancer instead. Why the switch?
“It was quite by coincidence. After my doctorate I got married and traveled to Chile with my new husband. He went as an ecologist and I taught science to local students. After the military coup there, in which President Salvador Allende was killed, we were forced to leave and returned to Berkeley. I was depressed because I didn’t know what became of my students who were left behind there.”
Applying math to biology
“We were distraught over that good world that had been shattered. And then I saw an advertisement for a research assistant in the genetics of breast cancer. I knew nothing about cancer, but I figured that cancer is essentially a kind of small-scale evolution, and so the work may actually suit me. After all, what is a cancer cell? A cell that has undergone a random mutation that causes it to divide, and produce more and more offspring that compete with healthy cells for the body’s resources. Cancer cells undergo a gradual evolution the more mutations they amass − the ones that survive and thrive are those that are able to increase their vitality: cells that acquire the ability to grow in new tissues that are not the original tumor, those that are able to evade the immune system, to recruit blood vessels that nourish them, etc. So I thought that my background in mathematics and all the techniques I acquired in order to study inter-species evolution could help me study how cancer evolves as it passes from one generation to another in a single family.”
How did you find the gene that’s involved in breast cancer? What did you do that others before you hadn’t done?
“We looked at families in which there were many instances of breast cancer. Such family statistics always raise the question of whether genetic factors are involved, because they could also derive from environmental factors.
“Take a lung disease like asbestosis, for instance. Many people in one family may be sick with it just because they live in the same environment, in which asbestos is present. With breast cancer and other types of cancer, the prevailing hypothesis then was that it was a viral disease. Two scientists, who received the Nobel Prize for their work, showed that cancer arises when mutations occur in oncogenes, which are certain viruses that entered the human genome early in evolution.
“Since at that time we didn’t have the direct access to DNA that we have today, all I could do at first was apply mathematical reasoning. As I said, my undergraduate degree was in mathematics, and although I wasn’t a great mathematician, it was natural for me to think that way.
I showed that, for the families I worked with, the best explanation for their high frequency of cancer was genetics. To prove this, I had to show that this genetic component could be physically mapped on a specific chromosome, and it took me 17 years to do so. I called this gene BRCA1, using the initials for breast cancer that are also the initials for Berkeley, California, where the work was done. When the discovery was published, it aroused many objections because the manner of proof was so different than what was the norm: applying mathematics to biology.”
But it was also mathematics that led Gregor Mendel to discover the very existence of genes. He did experiments and crossbred pea plants, but derived his insights by analyzing the results mathematically.
“Mathematics and genetics have a lot in common: the search for patterns, finding similarities and differences. I remember when I was doing my undergraduate degree in mathematics, I took a course in genetics, just for the fun of it, and thought: Good God! People solve riddles like this and get paid for it? I was enchanted by the possibility of taking a complex system and analyzing it intellectually. Now the technology of molecular biology is very advanced and you can easily examine DNA directly. At the time, understanding the consequences of changes in DNA was more indirect, and for me mathematics is what made it possible to crack the riddles.”
As soon as the gene was mapped, a mad race to isolate it from the genome began, and in the process another gene involved with breast cancer was found. It turns out that 85 percent of women who have mutations in one of these two genes are expected to get breast or ovarian cancer, and so they are consistently monitored and can also opt to undergo preventive treatment (by removal of the breasts or ovaries). Scientists also discovered other genes, but at present these two main genes are now routinely examined in women who have a family history of breast cancer.
“Naturally, this gives me a great deal of satisfaction,” King says. “Before I start in on a project, I give it a lot of thought. People laugh at me for being indecisive, but I consider every subject for a long time because there are two things that are very important to me: first, that it will satisfy my curiosity; and second, that it will be meaningful for someone.”
King’s “meaningful projects” include being highly active in promoting human rights around the world. The first of these endeavors, starting in 1983, was the effort to recover the “lost children” of Argentina. This was after the fall of the military junta which had ruled the country from 1976 with the aim of cleansing society of socialists, communists, intellectuals, priests, teachers − anyone with the potential to become a subversive. People began to disappear. Students suddenly stopped showing up at their universities, people never made it to work, whole families vanished. People were grabbed off the street, from work, from home. Every Thursday, women whose children had disappeared without a trace gathered in front of the presidential palace in the Plaza de Mayo. In defiance of a police order banning more than three people from assembling, these women marched and carried signs and pictures of their loved ones, demanding information on their fate.
“One day my phone rang and a woman from Buenos Aires who’d heard about my work asked me to come over to meet a group of grandmothers who were looking for their lost grandchildren. I flew there to meet with the grandmothers. There was all kinds of evidence indicating that these very young children had been given to the families of military and police personnel, who had ties to the military dictatorship. In addition, about 120 women had been kidnapped while pregnant. There was evidence they’d given birth in detention centers. Some of this testimony came from midwives who were brought to the centers to assist with the births, and from priests who collaborated with the military and police to transport the children. The grandmothers wanted me to help them find their grandchildren.
Finding the lost children
“I flew to Buenos Aires. The grandmothers told me their stories, and I explained to them what could be done with the genetic tools we had then. I think they turned to me because I spoke Spanish from the time I spent in Chile, and also because I was the same age as their daughters, and my daughter was the same age as their grandchildren. I could easily identify with them. The stories were horrible. One woman told me about her daughter’s family that had been kidnapped and murdered: a couple and their three children. After the fall of the regime [in 1983], when they went to open up the five graves, she saw bones in all of them except for the last one, the grave of Matilda, who was just 8-months-old at the time of the kidnapping.
“Instead of bones there was a tiny pajama outfit placed in the grave, and the grandmother wanted to know where the bones were. She was told that a baby’s bones dissolve, and she asked me if this was true. Since bones do not dissolve, we understood that apparently the baby did not die and could still be alive somewhere.
“Another grandmother told me her 3-year-old granddaughter went to sleep over at a friend’s house, and when the mother came to pick her up the next day, she discovered that the whole family had vanished, along with her daughter. The panicked father went to the police to find out what happened to his daughter, and he disappeared too. Terrified, the mother took her other child, a 4-month-old baby, and left home to find shelter with friends. On the way, she saw a military car approaching. She quickly glanced around, spotted a 12-year-old girl standing there and shoved the baby into her arms. The military car stopped and took the mother away. I heard a lot of stories like that.”
In order to find these lost children, who by this time would have been school age, those searching made use of the fact that their birth certificates had to be presented in order for the youngsters to be enrolled in school. When they surveyed these documents, they found some that appeared to have been forged, others that said the child had been born at home − which was far from the norm then − and some that were signed by physicians who were known collaborators with the military. As a result, some suspected “lost” children were found, but how could their true identity be proven?
King: “We had to show that the child’s DNA was consistent with that of the grandmother who reported the lost grandchild, and sometimes that was all we had because the child’s parents and siblings had also disappeared. What we did was focus on segments of DNA that are very distinct among different people, so that a similarity between two people in such a segment is a definite indication of genetic closeness between them. Tracing one of these segments, mitochondrial DNA, which is only passed down hereditarily through the mother, enabled my doctoral adviser, Allan Wilson, to find a genetic relationship between people who belong to different ethnic groups, and to identify ‘Mitochondrial Eve’ − the ancestral mother of all humans whose origins could be traced to Africa.
“I thought we could develop this approach to prove a genetic relationship among people from the same family. In this way we found the lost baby girl whose grandmother found her pajamas in the grave, and we also found the girl who was kidnapped when she was sleeping over at her friend’s house. It became a standard and powerful tool in the field of ‘forensic genetics.’
“There were cases when even after we proved that it was a ‘disappeared child,’ the people holding the child insisted on keeping him or her, and then I went with the grandmothers to the family court. On the basis of the evidence, we asked for rulings that the children must be returned to their biological families. But in some cases, the people holding the child fought at multiple levels of the Argentinean court system. Every case was a challenge.”
How many children did you return to their families this way?
“The grandmothers have found and returned 108 children. It wasn’t always a struggle. In the case of the mother who gave her baby son to the 12-year-old girl who happened to be passing by, the girl gave the baby to the local nurse. This young nurse said later that she felt like Pharaoh’s daughter who rescued Moses. The nurse placed the baby in the care of a lawyer, who promised to look after him until his parents came looking for him. Nine years later, that’s just what happened.”
Your research on the relationship between humans and chimpanzees was intellectually challenging; the discovery of the breast cancer gene was a conceptual breakthrough but also practical because it saves lives; and the lost children project was about saving lost souls. What now?
“These days I’m very interested in the genetics of mental illness. It was almost an unknown area until very recently. I was drawn to it, because if I’d learned anything from the study of breast cancer, it’s that even when dealing with a complex disease it may be possible to find individual genes that have a particularly big impact. I wondered whether the same held true for schizophrenia. If you take a close look at the epidemiology of the illness, you can find several things that indicate a unique genetic component at work.
“First, schizophrenia is clearly familial but, nonetheless, the illness most often erupts in people who come from completely healthy families. Second, schizophrenia has been around since the dawn of humanity and is quite common (estimations are 0.7 percent - 1 percent of the general population). This is strange, because there is selection against it. Persons with schizophrenia are much less likely than healthy people to marry and have children. So how is it possible that the frequency of the disease has not decreased? Third, there is a higher rate of schizophrenia among children born to older fathers than among children born to young fathers. And last, schizophrenia is about twice as common among people who were fetuses during times of famine.
“All of these observations suggest that schizophrenia is a disease that arises many times anew. It’s often a genetic disease, in the sense that it’s caused by mutations in genes. But often, the mutations are not passed down hereditarily from parents to offspring, but rather formed de novo in the parent’s germ cells or in the fetus in utero.”
Have you found these genes that impart the potential to get schizophrenia?
“We’re searching for new mutations that persons with schizophrenia have, but which their non-schizophrenic relatives do not have. We’ve found that if you compare schizophrenics to their healthy siblings, they all have the same frequency of mutations, but in the schizophrenics these are concentrated in specific genes. When we used mathematical models and bioinformatics tools, we built a network among all of these genes, and we found that many are connected in some way to brain development. There are genes that are involved in the development of nerve cells, others that are important in the transmission of signals, etc. There are probably at least 1,000 genes involved in brain development, and so there are plenty of chances for disruptions. This explains why schizophrenia has so many different faces.”
How do you manage to be the first in everything: our similarity to chimpanzees, the breast cancer gene, the gene responsible for a tendency to schizophrenia?
“No one’s ever asked me that, and I have to say I’ve never thought about it. Let me think. First, I’m certainly not the first one to have thought about all these topics. But maybe what I did have was the freedom to try. I come from a conservative middle class family that had no connection to science, so I was foreign to this culture. I’m a woman and came to biology from mathematics, so I was an outsider from several perspectives.”
In other words, in your case you could say that a one is not born a scientist, but becomes one.
“Definitely. As a woman in the world of science, I had the chance to bloom from nothing. There were no expectations placed on me, and so I could grow as a scientist slowly and independently. I could do only what I believe in and examine things objectively and cautiously without bringing any prejudice to it. When you’re a young woman working on the side, in relative isolation, people leave you be. They don’t take much interest in you because you’re simply not worth their time. So I carefully went about my own work, I obtained modest research grants and kept working under the radar.
“Of course, after I stood up and came out with my discoveries, detractors tried to tear me down. I was no longer under the radar. But as long as scientists are not armed, one can present controversial findings. The risk level is moderate. If the grandmothers and I could overcome the military in Argentina, I could overcome some unarmed opposition in my own country. I always said to myself: ‘What have I got to lose?’ You have to take responsibility, be methodical and work very carefully, and then stand behind your results. In Israel there are many people with this attitude, so I love coming here to work with my friends.”
Speaking of coming here, you are active in fostering connections between Israeli and Palestinian scientists.
“First of all, I like working with my friends, and I have both Israeli and Palestinian friends. But, clearly, if it weren’t for my emotional and ideological involvement, I wouldn’t be so committed to these efforts. My role is basically to raise funds for the benefit of productive scientific partnerships − not to make political pronouncements. I believe in the idea of ‘the scientist as citizen of the world.’
People sometimes get angry when successful women, but not successful men, are asked how they combine work and family. But I’ve read that you were once asked how you’d like to be remembered and you replied that, above all, you’d wish to be remembered as a good mother.
“Women become pregnant and give birth, and men don’t. These are biological facts. In most cases, the mother is also the main parent responsible for raising the children, even today. The period in professional life when people have to work the hardest to establish themselves is also the period when a woman can have children. It’s a profound problem. It’s important to choose the right mate, to be highly organized and have a good social infrastructure (preschools, day care and so on). In Israel I see that often there is assistance from the grandparents, too. In the United States this is often not possible because families are more spread out. I myself was a single parent for my daughter, but tried to be organized and very diligent.”
When we first spoke, you were in Stockholm during Nobel Prize week. What did you do there?
“This year, for the first time at the Nobel ‘festival’ – which lasts a week – there was a special symposium with selected scientists from around the world. It was held in honor of the 50th anniversary of the Nobel Prize that was awarded to Watson and Crick for the discovery of DNA, and it dealt with the genetic revolution and its impact on society.”
Will you be there one day for another purpose?
“I doubt it.”
And that Helen Hunt movie. What did you decide to do about it?
“When it comes out I’ll go see it in the theater with my students. We’re already planning on it. I have no idea what it will be like, but one thing’s for sure: The woman scientist will have a really great hairdo.”