A Trailblazing Geneticist Reflects On Her Life And Work

FLORA LICHTMAN: Hey, I’m Flora Lichtman, and you’re listening to Science Friday.

[MUSIC PLAYING]

Today on the podcast, this scientist changed how we think about hereditary cancer. Coming up, a conversation with genetics pioneer Mary-Claire King about her career and approach to science.

MARY-CLAIRE KING: It really led me to believe that once your evidence is good, you really have to be very loyal to your own evidence. You really do. You have to be very, very critical of it. But once you’re convinced you’ve got it, you can’t cave.

FLORA LICHTMAN: Today, it’s common knowledge that many diseases and conditions have some kind of genetic link. But that wasn’t always the case. Long before the Human Genome Project tied so many health issues to differences in genetics, way back in 1990, researchers identified a gene called BRCA1. This was the first gene linked to a hereditary form of any common cancer. People with a mutation of BRCA1 stood a higher risk of developing breast and ovarian cancer than those without the mutation.

Dr. Mary-Claire King is a geneticist at the University of Washington. She and her lab were the first to identify that gene back in 1990. That discovery changed the way we thought about the inheritance of certain cancers.

But that’s not her only claim to fame. She used genetics to reunite children who were born in captivity or kidnapped by the Argentinian military dictatorship with their families. Her PhD work upended conventional wisdom about our evolutionary origins. Her research has changed the game again and again.

So today, we are sitting down with Mary-Claire King to find out how she thinks about her work, what propels her, and what we can learn from her remarkable life in the lab. She joins us from KUOW in Seattle. Mary-Claire, thank you for being here, and welcome back to Science Friday.

MARY-CLAIRE KING: Thank you very much, Flora.

FLORA LICHTMAN: Thank you. Let’s go back to your salad days. I read your interest in problem solving began with Cubs games.

MARY-CLAIRE KING: Mm-hmm. When I was about six, my dad was already disabled. He was retired early with what was a very serious form of Parkinson’s, and was home. And already, even in the early ’50s, one could have on black and white TV baseball games every day. So we would watch together the Cubs games.

And my favorite player was, of course, Ernie Banks. And my dad would make up story problems about Ernie Banks. So my favorite one that I have, of course, remembered all these years goes like this. Ernie Banks is coming up to bat. He’s been batting 277. He’ll probably have three at-bats this game. What’s it going to take for his average to go up to 280? And I was six.

FLORA LICHTMAN: You’re six. Yeah.

[LAUGHTER]

Most kids at six are working on counting.

MARY-CLAIRE KING: There we go. There we go. So I looked at my dad– the first time I heard this story problem, I looked at my dad and I said, I don’t know. And he said, you’re right. You can’t know with that information. What more do you need to know? And of course, I didn’t know that either. But he helped me work out that what more you need to know is how many times Ernie’s already been up to bat. So when you add three to it, what’s it going to do?

And I was so taken with that logical way of thinking. And of course, this was one incident out of hundreds and hundreds, and it went on from the time I was six and until I was an adult, that I just never lost the flavor for it. It’s what I find most intriguing about science in general. And I hope Ernie Banks is listening from Heaven. Ernie, it’s you.

It’s the idea that you can take a very complex phenomenon, and if you think about it a while, you can state it in terms that you can then solve. And formulating that notion, stating a hypothesis is to me what’s absolutely critical about all these different types of work.

FLORA LICHTMAN: Hmm. It’s the problem solving. It’s the puzzle.

MARY-CLAIRE KING: Mm-hmm. It’s the puzzle. And of course, genetics is the absolute soul of puzzle solving. I apologize to all biochemists, but genetics is absolutely the basis of formulating hypotheses and then being able to test them both experimentally and quantitatively. So it has both of those sources of knowledge as appeals.

FLORA LICHTMAN: Hmm. OK, fast forward. You major in math in college. You go on to do applied math in graduate school. You change over to genetics. I read that during your PhD, you were on the brink of leaving.

MARY-CLAIRE KING: Oh, yeah. Well, this was the ’60s in Berkeley, and you can only imagine. There were a number of incredible forces converging. Personally, I couldn’t get any experiments to work. And I was in an experimental lab, a very fine experimental lab. But it was such a fine experimental lab, and I think they honestly didn’t realize how totally inept I was. I’d been a math major.

FLORA LICHTMAN: [LAUGHS] I mean, was that it, that you actually weren’t good at getting the experiments going? Or is it just like the normal thing for PhD students? Things fail?

MARY-CLAIRE KING: Some of both, I think. I mean, I have now, of course, had many PhD students, and the vast majority of them have far better hands than I did. But in the midst of all this, of course, we had the civil rights movement, the anti-war movement, the feminist movement, the National Guard on campus, which will resonate with a lot of people now.

Ralph Nader hired me for a number of months to work on– one of his very early projects was, who owns the land of California, and what are they doing with it? So there were countervailing trends to do something else.

And Ralph and his staff offered me to come to Washington, DC, to help form what became the Congress project. And it was very tempting to go, but I didn’t. I talked to Allan Wilson, who was at the time a political friend. He wasn’t yet my advisor, but he was mentor to many of us.

And he said something to me that I have said to many people since, and that is– a couple of things. First, if everybody whose experiments didn’t work left science, there would be no one left.

FLORA LICHTMAN: [LAUGHS]

MARY-CLAIRE KING: So it’s important to design a project that takes into account the fact that you can think of experiments well, but the techniques for you need to be relatively straightforward. And that’s honest and blunt and true.

And the other thing he said, which I think we all need to keep in mind, is that if you leave a mentee role, a trainee role early, you will certainly do righteous projects, but you will never control the agenda. You won’t be able to decide what projects are done. You’ll be always working for someone else.

FLORA LICHTMAN: If you don’t get a PhD.

MARY-CLAIRE KING: Well, in my particular case, if you don’t get a PhD. But I think it’s generally true that it’s very important to stick with it through the discouragements in order to get to the point in whatever field, whether it’s medicine or law or science, that you get to decide what the projects will be.

FLORA LICHTMAN: It can be hard to stick it out, though.

MARY-CLAIRE KING: It’s terribly hard to stick it out. And I think that one thing that I’m seeing now in students post-pandemic is that the discouragement from the period of the pandemic, the upheaval from that time, the need to be able to turn on a dime during that time in order to cope with an ever-changing larger environment have made it– have made sticking it out even more difficult.

So I think for people– for those of us of my era, it’s very important just to continually encourage people that this has always been true. Obviously, the particulars are different, but the need to stick it out is really, really important. And if you look at all the people that any of us admire historically in whatever field, they’re people who stuck it out.

FLORA LICHTMAN: You stuck it out. And during your PhD, you made this discovery that humans and chimps share 99% of our protein coding DNA. OK. When I read this, I was like, that’s a pretty big discovery for a PhD student.

MARY-CLAIRE KING: [LAUGHS] Mm-hmm. Of course, I had the world’s best mentor in Allan. And the main thing that struck me about the project was that I had indeed mastered the electrophoretic techniques that Allan recommended, because they were relatively straightforward compared to honest biochemistry that was otherwise going on in his lab.

And I had got pretty good at them, based mostly on the work of Elo Giblett, the late Elo Giblett who was up here in Seattle at the time and who set up elegant, elegant protocols for doing all of these experiments. So I just followed them as one– in the same way that when I went home, I followed Julia Child. I had Julia Child on one side, and I had [INAUDIBLE] on the other.

Anyway, so I was doing these experiments, and the experiments themselves worked, but the results were negative almost all the time. That is, the human and chimpanzee proteins for any specific assay that I would apply were the same. They had the same charge. They had the same length. There were occasional exceptions, so I knew I wasn’t completely hopeless. But mostly, they were just the same. I thought, how can this be? What is this?

FLORA LICHTMAN: Did you think you were doing the experiments wrong?

MARY-CLAIRE KING: Of course. Of course. Naturally. Right. So I took all of these gels and photographs and all that, and I said, Allan, I know you set me up with the world’s most straightforward experiments, and Elo Giblett’s book is totally terrific, but look, they’re all the same.

And he kind of looked at me, and he smiled this very Allan Wilson-like smile. And he said, has it ever occurred to you that you’ve got it right? And I said– but here am I, looking at a picture of a chimpanzee. I said, we can’t have it right. And he said, no, let’s think it through.

And that was the conversation that led to our formulating this idea that the clear differences between humans and chimpanzees in morphology– that is, in length of limbs, in body– in anatomy, in body structure, in ways of life, we’re not denying those. Obviously, they are dramatically different, and they are the reason that taxonomists working with the species at that level had put humans and chimpanzees into different families.

But that level of evolution could be completely consistent with the very, very minimal number of differences that we were seeing between humans and chimpanzees at the level of protein sequences if, in fact, those dramatic differences in anatomy and morphology and ways of life were due not to changes in sequences of proteins, but to changes in the timing of the expression of those proteins and the spatial distribution of the tissues in which those proteins were expressed.

And those differences would, of course, to use modern terminology, be regulatory, and they would be due to changes in genomic sequence in regions other than protein coding genes that led to differences in timing and spatial distribution of expression of genes. Of course, at the time, it was only a hypothesis. We didn’t have a genome. We didn’t have the word genome.

FLORA LICHTMAN: That is– can we pause for a second? We didn’t have the word genome at the time.

MARY-CLAIRE KING: [LAUGHS] You guys are wonderful. There’s a whole lot of very active scientists for whom the word genome came after we had our PhDs. Honest.

[LAUGHTER]

Including the people who made the Genome Project.

FLORA LICHTMAN: When you say “you guys,” you mean millennials, right? And below.

MARY-CLAIRE KING: I mean millennials. Millennials and thereafter, right? [LAUGHS] No, and that’s what’s so wonderful about working with millennials. You have a completely different worldview. You have a global, holistic worldview. And I hope you stick with it. [LAUGHS]

FLORA LICHTMAN: After the break, more with Dr. Mary-Claire King. Stick around.

[MUSIC PLAYING]

So Mary-Claire, we were just talking about this major finding, how much protein coding DNA we share with chimps. Did you get blowback?

MARY-CLAIRE KING: Oh, what a very good question. No, but the no has a context which is also, I think, important as a general feature. Until that paper, Allan’s work had had a terrific amount of blowback, because he and Vince Sarich had been working for– oh, gosh, years on the interpretation of data that indicated that humans and chimpanzees had diverged, evolutionarily diverged, only five to seven million years ago, whereas the standard wisdom was that the divergence had occurred, oh, 15 million years ago. And that standard wisdom was based on fossil evidence.

And Allan would say to us, all living beings have ancestors, but not all fossils have descendants. And that was at the heart of what he and Vince and the rest of the Wilson lab were working on. And you can imagine how much blowback that assertion had. It was terrific. It was very difficult for the people in the lab.

And my watching it really led me to believe that once your evidence is good, you really have to be very loyal to your own evidence. You really do. You have to be very, very critical of it. But once you’re convinced you’ve got it, you can’t cave.

In any case, what our paper did was make the point that these two ways of thinking are absolutely consistent. We can have molecular evolution that occurs in parallel with and causes anatomic and behavioral and neurological evolution, but in ways other than one can detect from the fossil record.

So the fossil record is absolutely legitimate. It tells us one kind of story of evolution. And molecules are also absolutely legitimate and tell us a parallel story. And both are true.

FLORA LICHTMAN: Hmm. So how do you make the jump from chimp genetics and evolution to cancer?

MARY-CLAIRE KING: After I finished my– well, essentially as I was writing my PhD with Allan, my then husband and I went to Chile to teach in a cooperative arrangement between the University of California and the Universidad de Chile. And we went in ’72 briefly, and then we went back in ’73. And we were there during the golpe de estado, in which the military overthrew the government of President Allende. President Allende died in the attack on the Moneda, and everything was shut down.

So you wonder, what does this have to do with my shifting to breast cancer from evolutionary biology? But it meant that our time in Chile was both fraught and very different than we had anticipated. And it was an extremely important, informative time for me in terms of all the work I did later. But it also opened to me the idea that one could apply genetics as a way of thinking to just about anything.

In practical terms, the convenio was shut down, and we left Chile on Christmas Day of 1973. So I returned to Berkeley far earlier than I had anticipated without a job. But of course, incredibly discouraged, depressed. I mean, it was very much at loose ends.

And I started looking for a job. And I heard through friends of friends that there was a position open over at UC San Francisco in the lab of a lovely, lovely oncologist named Nick Petrakis. It was there because Nixon had fairly recently declared war on cancer, and many of these sorts of entry-level or just post-PhD positions were being made available for people from other fields to study cancer biology.

So I went to see Dr. Petrakis. He knew about the work with chimpanzees. And he said, it will be quite a shift. And I said, well, if you’ll teach me about cancer, I’ll teach you about evolutionary biology.

And I worked in his lab. He was not an experimentalist. He was a pediatric oncologist. But he introduced me to all his friends. And it was very clear right away that– two things.

First, that breast cancer was causally, at the fundamental level, complex. The prevailing theory at the time is– and it was being proven for multiple cancers– was that cancers were caused by oncoviruses, but became renamed oncogenes. There was not yet known any sort of oncogenic story for breast cancer, but there was very clear familial clustering of breast cancer that had been noticed all the way back to the times of the ancient Greeks, which, of course, Dr. Petrakis, being of Greek ancestry, was quick to tell me.

FLORA LICHTMAN: [LAUGHS] I guess what I’m wondering is it was clear that breast cancer had this family component, but also, I read that people were kind of skeptical of the idea that there was inheritance or that you could find a gene. You tell me. Where was the skepticism?

MARY-CLAIRE KING: Yeah. Of all of the above. [LAUGHS] I think there was– if you cast your minds back to that period, people thinking about genetics at the level of inherited genetics– not mutations and cancers, but at the level of inherited genetics, and people thinking about the epidemiology of cancer came from two very different worlds. So you have to cast your mind even farther back to the beginning of the 20th century and the horrors of the eugenics movement. The eugenics movement, of course, grew out of early thinking about inherited genetics. Not Mendel’s thinking, but some of the other ways of thinking about inherited genetics.

Meanwhile, in parallel, progressive people who were oriented toward the public health were thinking about epidemiology. So those two strains, even after the end of the eugenics movement, those two strains were still, by the 1960s and 1970s, were still very independent.

And epidemiologists thinking about breast cancer were thinking about it extremely well. And they didn’t deny the familial clustering, but they did not think of it in terms of inherited genetic predisposition, because they simply didn’t think in those terms.

FLORA LICHTMAN: Huh.

MARY-CLAIRE KING: And geneticists who were thinking about cancer, and were thinking about it very well, were thinking about what we call somatic events. That is, events at the level of the cell that alter the gene specifically in the cell– for example, the activating mutations in oncogenes– that are, indeed, responsible for very large numbers of cancers.

And it was Mike Bishop who essentially at the same time formulated the idea of there being both activating mutations in oncogenes and the possibility of there being mutations that could be inherited in what became known as tumor suppressor genes.

FLORA LICHTMAN: Mm. You might have both.

MARY-CLAIRE KING: You could– and that both certainly existed in the world, and that both could be present as the cause of one cancer, but they could be globally both causing cancers, even if for any one cancer you might have one rather than the other. Or you could have both.

But this was all still rather ethereal at the time we’re talking about. I mean, I was accustomed to thinking across both of these ways of thinking. And I was very drawn to the work of what we now call an epidemiologist– she was called a statistician at the time– Jane Lane-Claypon who worked in the first part of the 20th century for the British home office. And she was a public health person.

And she was very interested in what we would now call familial clustering. So she asked the question, are daughters of women who die of breast cancer more likely to die of breast cancer than daughters of women who have died of something else? And the answer was emphatically yes. But almost uniquely in her work, Dr. Lane-Claypon did not posit any environmental exposure that might be responsible. Bear in mind, her brief is to sort out public health and environmental exposures.

So I looked at all this, and I thought, well, if all else fails, maybe think about genetics, and that the critical thing was to identify those families and then to try to trace, first just epidemiologically, what exactly had happened to all of the women in those families in terms of their cancer, their cancer histories?

And then to use the tools of genetics that existed at the time, which were increasingly the capacity to try to locate genes on chromosomes. A chromosome is a physical reality. A gene is a physical reality. Every gene has an address on a chromosome or in mitochondrial DNA.

And if one can find that address, even if one doesn’t know the sequence of the gene– a situation that now would not obtain, because we would know the sequence immediately, but in those days, of course, we didn’t– one will have shown that that gene has to exist. So what my contribution was in all of this was that realization, that you could use what was then called linkage analysis in families and chromosome mapping to prove– as an epistemological tool to prove the existence of the physical reality of a gene, even though the Genome Project was more than a decade away.

FLORA LICHTMAN: Mm. You know, I’ve talked to a lot of researchers about intuition and the importance of following their intuition. And hearing this story where you’re sort of breaking out from the pack here with this idea, what’s your take on that, the importance of going with your gut in science?

MARY-CLAIRE KING: I think intuition is extremely important. Extremely important. And I worry now that we aren’t encouraging intuition enough in our students and even in our postdocs. I think clearly, there are tremendous advantages to team science. But I think one of the disadvantages to team science is that everyone has a small part of a huge problem. And the opportunities to indulge your intuition are far fewer in that context.

FLORA LICHTMAN: Because you’re in charge of one specific little tiny cog in the machine rather than the big problem. And how do we address it?

MARY-CLAIRE KING: Exactly. You got it. Mm-hmm.

FLORA LICHTMAN: Did it feel risky to you to pursue this?

MARY-CLAIRE KING: Yeah. [LAUGHS] Yeah.

FLORA LICHTMAN: Tell me more.

MARY-CLAIRE KING: Well, again, you need to bear in mind the social context. [LAUGHS]

FLORA LICHTMAN: Always.

MARY-CLAIRE KING: I mean– how many– right? How many young women with PhDs in genetics were trying to solve breast cancer, or anything like it? I mean, with the exception of some really fabulous mid-level program officers at NCI, without whom I couldn’t possibly have done this, nobody was paying any attention to me at all.

FLORA LICHTMAN: [LAUGHS]

MARY-CLAIRE KING: So I wrote a grant saying all the things I’ve just said to you, and I got this $35,000 grant. And no one cared. It’s– [LAUGHS]. Who is she again? And it was a very different world.

FLORA LICHTMAN: But was that a good thing or a bad thing? I can’t quite tell.

MARY-CLAIRE KING: Well, of course, I think it’s a good– I think it was a good thing in retrospect. It didn’t feel like a good thing at the time, because you feel very, very isolated. Very isolated. But in retrospect, it buffered me, because it took 17 years to do that mapping experiment. It took 17 years to go from the idea through the necessary statistical proofs with population-based theories of families of all sorts. That is, not all severely affected families.

And then to working with very severely affected families and building the map as we went along, which many people were contributing to because many people were trying to do this for various kinds of– usually more explicitly genetic disorders like cystic fibrosis and Huntington’s disease. And so everyone who was making a map that enabled one to identify chromosomal locales was sharing data on the map– on the map bits. Where are the markers, the signposts that helped you do this analysis? And I was one of many, many people, hundreds of people contributing to that.

But I think many of these folks were working in relatively individual obscurity and isolation. I think those who were more prominent had a tougher time, because people were looking over their shoulders. But nobody looked over my shoulder on this project between 1974 and 1990.

FLORA LICHTMAN: Wow.

MARY-CLAIRE KING: Yeah. [LAUGHS] But I had friends. When you and I spoke early on about this conversation, you said that one thing you were curious about was, how does one pick a project, and how does one stick with it? And of course, I was thinking about that a lot. And I realized that one really important component is that you have friends who are engaged in it with you. You absolutely need a posse. You need friends. You need people– right? Who care about the project also.

FLORA LICHTMAN: Yes.

MARY-CLAIRE KING: Yeah.

FLORA LICHTMAN: I think friends are underrated in work.

MARY-CLAIRE KING: Yes! Yes! It’s true!

FLORA LICHTMAN: I really do.

MARY-CLAIRE KING: How could you do what you do without your friends? They’ve really got your back. And on days that are hopelessly discouraging, they’re still there.

FLORA LICHTMAN: This is Science Friday from WNYC studios. If you’re just joining us, we’re talking with geneticist Mary-Claire King about some of her discoveries, including the discovery of the BRCA1 gene. Was there a scientific or technical reason to target breast cancer? And/or, was it personal in some way to you?

MARY-CLAIRE KING: I think it’s an and. The scientific reason was the fact that of all of the different sorts of cancer that Dr. Lane-Claypon had looked at and that really fine epidemiologists had been looking at in the intervening 60 years, breast cancer was the most striking in having very strong clustering in families, but without any obvious environmental exposure that was responsible.

There was no smoking. There was no exposure to an occupational carcinogen. But the familial clustering was very strong. So that’s a technical reason. It didn’t, of course, make the actual process any easier, but it gave one a real underpinning for it being logical to think about.

And the other was not specifically personal to me. My best friend had died of what subsequently much later I understood to be a Wilms’ tumor when we were both teenagers. But I hadn’t had at that point any close friends die of breast cancer. But clearly, for women– and this was, of course, the period of the women’s movement– it was enormously important. And it was and remains a major cause of death in women.

And the physicians caring for these women, who were, as you would expect, overwhelmingly male, cared about these families enormously. And they had my back also. And so trust me. When the major breast surgeons of the entire world say, oh, yes, I have a family you need to look at. Mary-Claire, I’m going to send you this family by [INAUDIBLE], you take it seriously. The experience of these very senior colleagues so much resonated with my understanding of the problem from a quantitative point of view that it really became irresistible.

FLORA LICHTMAN: My conversation with Dr. Mary-Claire King continues after the break. Stay with us.

[MUSIC PLAYING]

You know, it’s interesting, because we know that women’s health has been neglected historically. And I think about your story and how we are where we are in part because of you and your orientation towards this specific disease, and how it’s so helpful to have different kinds of people doing science who might be interested in different kinds of problems.

MARY-CLAIRE KING: Exactly. You’re absolutely right. And to have those people be able to talk with each other easily. I think, again, for me– this is– of course, it’s easy to say this in retrospect.

But for me, it was an advantage that I was not a physician, so there was no question of my moving in on the patients of anyone as their oncologist, although the people who were helping me out were so senior that, believe me, that would not have been an issue. But they appreciated that someone– this woman the age of their daughters, coming from another field, was interested in what they were working with day in and day out in trying to save these women.

And I mean, the stories I would hear from concerned surgeons– I cared for Jane Doe. And now, god help me, I’m caring for her daughter. MC, you’ve just got to take care of this. It was that kind of conversation many times. And they would talk to me, and they would talk to me because Dr. Petrakis had facilitated introductions.

Probably the most important ones was he introduced me to Mary Lasker. And once you know Mary Lasker, you know everyone in cancer biology. [LAUGHS] And she also– the main thing she said to me was, this is an important problem. Don’t get distracted.

[LAUGHTER]

I said, yes, ma’am. [LAUGHS] And so it’s very important to take seriously the viewpoints of people from very different perspectives, and to be taken seriously by them. I think equally important to friendship is respect.

One thing about working with breast cancer is obviously every woman is vulnerable, whether she has an inherited mutation or not. And it’s enabled me to meet women from every imaginable background, and we respect each other. We understand that we all are there for the same reason.

And if we could build that respect into all the steps of scientific discovery– it’s not the same as lacking criticism. It’s understanding that criticism of an idea is the greatest form of respect, because it means you’re taking the person seriously. We just need to build that in more and more and more, and people not be sensitive to being criticized, because the criticism is meant as respect.

FLORA LICHTMAN: Mm. I want to talk about the downstream effects of your work. I mean, now there’s testing available for the BRCA1 gene for people who might have a familial risk. What are the next logical steps as we understand the inheritance of diseases better and better? Do you think, for instance, there’s a case to be made for gene therapy even in utero? Genetically modifying embryos or fetuses to prevent diseases. Or is that just beyond the pale?

MARY-CLAIRE KING: Let me not jump ahead that far.

FLORA LICHTMAN: OK. [LAUGHS]

MARY-CLAIRE KING: But take your first statement about genetic testing for BRCA1. We’re already well beyond the way you stated that. You stated it correctly. There are certainly genetic testing available now for mutations in BRCA1. There’s genetic testing now available for mutations in all of the known genes responsible for inherited predisposition. Genomic sequencing is now a product.

It’s now– in the time we’ve been having this conversation here at UW, hundreds of thousands, probably millions of base pairs have been being sequenced for various projects. I mean, it’s done very, very routinely in many labs, obviously, including mine.

And that testing is available not only to patients who have a family history, because bear in mind that since men and women have the same genes, and men can pass mutations to their daughters as easily as women can, about half of women who have inherited predisposition to breast cancer have inherited the mutation that’s responsible from their father, who’s unaffected.

So about half the women who turn out to have mutations in these genes don’t have any family history that would trigger concern. So from my point of view, every woman– every woman at about age 30, regardless of her personal history, regardless of her family history, should be offered testing for all of the known breast and ovarian cancer genes.

There are tens of thousands of different mutations, and new mutations are discovered all the time. That’s no longer an impediment. Of course, it was originally. But it’s not any longer because sequencing is so– is such high quality and so inexpensive.

So from the point of view of my personal favorite project, we should be offering every woman complete sequencing of all the known breast and ovarian cancer genes as part of normal gynecologic practice when she’s around 30. It’s a good thing to do. To identify mutations in these genes that predispose to such high risks of devastating diseases while they can still be prevented is enormously important. So from my own personal perspective, that’s what I’m advocating for most strongly now.

FLORA LICHTMAN: Do you think that’s likely in this current climate?

MARY-CLAIRE KING: Well, in the current climate, it– it’s hard to say. Most things are hard to say in the current climate, right? In principle, there’s nothing in this that runs afoul of any of the ways of thinking of MAHA, but it’s hard to say. I see no reason to stop advocating for it in the current climate.

FLORA LICHTMAN: Have you been affected by the cuts to science?

MARY-CLAIRE KING: Oh, we’re on a roller coaster at every level. I mean, in my own little lab, in the department, in the School of Medicine at the university. The very short answer is yes. At this moment– and I mean as of last night when I most recently checked– my funding was intact. I haven’t checked yet this morning, because I’m here speaking with you. It’s a roller coaster. One never knows.

Funding of friends is present, and then it’s gone, and then it’s back. And I’m not thinking about funding that has to do with DEI initiatives. I’m just talking about research projects that one is ghosted about. So yes, it certainly had an effect.

FLORA LICHTMAN: I’m going to ask you a big question now. What do you think the purpose of science is?

MARY-CLAIRE KING: Ah. It’s a wonderful question. I think there are two. On the one hand, it’s to satisfy intellectual curiosity, and that transcends all forms of science, from astronomy through molecular biology, archaeology through botany. Everything. And then in parallel with that, and obviously knit together with it, is to be useful.

FLORA LICHTMAN: To be useful.

MARY-CLAIRE KING: Mm-hmm.

FLORA LICHTMAN: I don’t think we can talk to you without talking about your human rights work. So while you were embarking on this inherited breast cancer project, you also began this project to help the abuelas in Argentina to use genetics to prove the identity of grandchildren who were kidnapped as babies during the Argentinian military dictatorship. I feel like we could do a whole hour on that–

[LAUGHTER]

–alone. I think one question I have about it, though, is just in my experience covering science, I’ve noticed that sometimes scientists are dissuaded from being too political, or activist, or having a point of view, in general. I think that may be changing now by necessity. But how do you think about that?

MARY-CLAIRE KING: It’s a very good question. I think each of us has to be our whole selves. And part of my whole self is that when I see a problem [LAUGHS] of any sort, I want to solve it. And many of those problems are not, in the narrow sense, scientific problems, although obviously in this case, it came to be. But many are political problems. I was, of course, a young adult in Berkeley in the ’60s, so–

FLORA LICHTMAN: Unavoidably political. Yeah.

MARY-CLAIRE KING: Unavoidably. And that was a very important political education. And it was a political education that we learned from each other, but we also learned from our mentors who had been variously Holocaust survivors or survivors of the American McCarthy era. None of these things happen in a vacuum.

So what I learned from them, I enacted myself, of course, in very different contexts, and I hope I have conveyed to the people of the next generation who work with me. I think it’s part of our whole selves.

And again, I think it takes a couple of forms. In one sense, as scientists, we are citizens of the world. We have the capacity to communicate with people all over the world who will take us seriously because they know us through our science. And we can communicate with them in areas that are specifically scientific or areas that are not scientific at all. And I think that we have the– indeed, the obligation to take advantage of those excellent communications networks when the situation arises.

FLORA LICHTMAN: Hmm. From that project, what did you stick in your backpack to sort of– what did you take away?

MARY-CLAIRE KING: That if concepts are explained well to people, even by people who come in from other places who don’t speak their language very well, if they’re explained well, people from very different kinds of backgrounds will understand that teaching and learning are at the core of being able to make progress on even the most difficult, horrific projects, and that everyone will understand.

So to me, it really set up the primary role of the teacher in everything. In everything. [LAUGHS] Whether it’s religion or rescuing grandchildren, teaching is still teaching. It’s our responsibility as teachers to keep working on how to explain until we get it right and we see the eyes of our students light up. So that was one thing.

The second thing was that the most important questions come from people on the front lines. The grandmothers formulated this question for me. They said, we need to know not who our child– so children were becoming– were surfacing in contexts where children hadn’t been expected. And the question that the grandmothers posed to me is, who is this child?

And they said, it is not our concern who the child is not. It is our concern who the child is. And we must assume that the parents are dead, have been murdered. So we need to be able to do that through the grandparents.

And ultimately, of course, I guess probably a year or so, we were doing this through– in a maternal relative with mitochondrial sequencing. But at the beginning, we were thinking in terms of having information on grandparents. And of course, this was all before anybody was using DNA to do this. So the most important questions come from people on the front lines.

Third thing is the most righteous projects demand the most rigorous science. It would be one thing if I would get a map location wrong for this hypothetical gene for breast cancer. It was something else if I got a child misidentified. And the fourth thing, [LAUGHS] it’s a little arrogant, but no question’s too big to ask.

FLORA LICHTMAN: No question’s too big to ask. This is Science Friday from WNYC studios. I’m Flora Lichtman, talking with geneticist Mary-Claire King about her life in science and her advice for the next generation. If you were a PhD student today, what project would you work on? What do you think is the most exciting frontier in science?

MARY-CLAIRE KING: If I were a better experimentalist, I would be working on gene therapy. You have to have fabulous hands to do that. But if I had the hands of a surgeon, I would– I would work on that area. I’m not sure which condition I would choose to work on. Certainly, ophthalmology and otolaryngology are now the fields where gene therapy has been the most effective. But it’s going to increase quickly. And this is all somatic gene therapy, of course.

Given my own skill set, I think I would work on understanding the genetic bases of severe mental disorders. And I would try to do that by working both with families, to the extent that that’s possible, but it’s often not, and to working then with our capacity to take blood cells from patients, and in vitro, convert those blood cells into iPSCs, and then to differentiate them down lines of various sorts of neuronal capacity so that one can see the consequences of individual damaging mutations.

Both of these– both of these ways of approaching science have the good feature that one can do them either in a large group or as a small project oneself. And I think having the capacity to carry out a project where you decide what you want to do remains enormously important.

FLORA LICHTMAN: You know, these feel like weighty– weighty challenges. Breast cancer, human rights. Are you hard on yourself or on your work?

MARY-CLAIRE KING: Yeah.

FLORA LICHTMAN: [LAUGHS]

MARY-CLAIRE KING: Yeah. But they’re not as– they’re not weighty once you break them down into the component story problems. So I think I’m both kind of denying your premise, but acknowledging the reality–

FLORA LICHTMAN: Go for it, please.

MARY-CLAIRE KING: Yeah. [LAUGHS] I and the people that I work with, my posse now, we’re all very hard on our evidence. We have to be. And the people that we ask to review our evidence are hard on it. We don’t ask– we don’t ask people who are going to say, oh, yes, yes, dear, and pat us on the head. No abuela has ever patted me on the head. Trust me. You need people around you who have your back vis-a-vis the outside world, but who will challenge you on your thinking as you develop the evidence.

FLORA LICHTMAN: Mary-Claire, this was an absolute pleasure. Thank you for taking the time to talk to me today.

[MUSIC PLAYING]

MARY-CLAIRE KING: Thank you so much, Flora.

FLORA LICHTMAN: Our thanks to audio engineer Brad Loving at KUOW for his help with this interview. Thanks for listening. Don’t forget to rate and review us wherever you listen. It really does help us get the word out and get the show in front of new listeners. Today’s episode was produced by Charles Bergquist. I’m Flora Lichtman. Thanks for listening.

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