The Power Of Genes, And The Line Between Biology And Destiny

May 12, 2017
Originally published on May 16, 2017 8:13 am
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DAVID BIANCULLI, HOST:

This is FRESH AIR. I'm David Bianculli, editor of the website TV Worth Watching, sitting in for Terry Gross. The way we understand and discuss identity, temperament, gender, sexual orientation and gender dysphoria are being profoundly changed by our new knowledge about the human genome. The study of genetics also is fundamentally changing our understanding of disease, from schizophrenia to cancer. New cancer treatments are being developed that address the genetic mutations that cause cancer.

Today's guest, Siddhartha Mukherjee, has written a best-selling book called "Gene," which is now out in paperback. It tells the history of genetics and reports on new breakthroughs and ethical questions resulting from gene manipulation. Mukherjee wrote the Pulitzer Prize-winning book "The Emperor Of All Maladies" about the history of cancer and its treatments. It was adapted into a PBS series of the same name. He's an oncologist specializing in blood cancers and is developing a therapy intended to treat certain cancers by modifying the body's immune cells.

Mukherjee is an assistant professor of medicine at Columbia University and a staff cancer physician at Columbia University Medical Center. He spoke with Terry last year when his book was first published.

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TERRY GROSS, HOST:

Siddhartha Mukherjee, welcome to FRESH AIR. So how are genetics giving us a new understanding of disease, a new model by which to understand disease and treat it?

SIDDHARTHA MUKHERJEE: Well, genetics has really overturned the classical or traditional conception of disease. We - you know, we used to think of disease as something that happened to us. Genetics allows us to really begin to think of disease as something that happens as a result of us interacting with the environment. That's not to say - let's be very clear up front - that's not to say that all diseases are genetic. And that's also not to say that all diseases are environmental.

But it is to say that many, many diseases - not all - but many, many diseases are acutely dependent on the intersection between genes and the environment. And if you leave one part of that equation out, you'll inevitably miss something important about that disease. You won't know how to treat it. You won't know how to understand it. And that's one of the ideas that's central to this book.

GROSS: So let's talk about cancer, since you're an oncologist. Cancers have always been treated based on the part of the body or the organ that they've affected. So it's like breast, liver, blood, lung cancer. What is genetics showing us about the similarities and differences within each type of tumor in each category, like, the similarities and differences of breast cancer tumors or leukemias or, you know, lung cancers?

MUKHERJEE: There's a substantial degree of reorganization in the way we fundamentally think about cancer that's going on right now. Some of it related - or a large part of it related through genetics. If you look at the mutations in individual cancers, you might find, actually, that a lung cancer carries a mutation that it shares with, let's say, a breast cancer or it shares a mutation that it shares with leukemia. The question that's being asked right now in the field, which is an important question, is is there - therefore, should we reorganize this old anatomical classification of cancer - you know, lung cancer, breast cancer - and base it a little bit more on a kind of mixed classification.

Yeah, you say breast cancer, which has these following mutations. My overall impression is that the anatomical classification isn't going to go away. I think they're very important things that the anatomy determines. There are genes that are particular to breast cancer. There are genes that are particular to lung cancer. But it's going to be vastly refined. And we're seeing this already with genetics. So we're going to say lung cancer but with genetics or genes that share some things with leukemia.

And we might, in fact, treat these two cancers similarly - this leukemia and the lung cancer similarly. But I don't think that the anatomical classification's going to go away completely. It's a very important classification that will remain.

GROSS: So I understand the concept that chemotherapy is a toxic substance that kills fast-growing cells. And therefore, it can kill fast-growing cancer cells and kill a lot of healthy cells along the way, too. So I get what works and what's bad about chemo. I don't really understand how you target a mutation, like a genetic mutation, with drugs - or with what? Like, how do you...

MUKHERJEE: Well, the classical...

GROSS: Yeah.

MUKHERJEE: ...Example is these genetic mutations make products - make proteins. Genes make proteins. They make RNA, which then is used to build a protein. And these proteins really act as kind of pathological drivers of a cancer cell. They command or commandeer a cancer cell and start making it behave abnormally. And the trick is to create a medicine, a drug, a small molecule - it could be other things - but a small molecule that goes and enlarges itself in the cleft of that protein and shuts it off like a little hand shutting off a switch. The key point here is that because the cancer cells have this mutated gene, and therefore make the abnormal protein, normal cells don't have it. And that's the ideal scenario.

And therefore, you know, your drug will have very little effect, hopefully, on normal cells and have a profound effect on cancer cells. And we have drugs like this already in the armamentarium. There's a drug called Gleevec. I've written about it. Others have written - it's obviously incredibly famous - and it does exactly that.

There's a lovely description of Gleevec that someone once described Gleevec to me. It's like an arrow that pierces the heart of this abnormal protein that's driving the cancer cell. So - and it doesn't pierce the heart of normal cells, for the most part. So that's the ideal scenario. The less ideal scenario is that, you know, the drug doesn't work with all that much specificity, it's not such an arrow that's fine-tuned to the Achilles' heel of a cancer cell. But it has some collateral damage.

But the ultimate aim is to have a drug that somewhere falls somewhere between the exquisite specificity for a cancer cell and perhaps a slightly more moderated specificity, might kill some normal cells but is nowhere near the indiscriminate killing that chemotherapy used to have.

GROSS: So in talking about how new understanding of genetics is creating new cancer therapies, I want to ask you about work that you're doing now, which is related to a certain form of blood cancer in which you're genetically modifying T cells. You're genetically modifying the immune system, basically. Would you explain what you're doing?

MUKHERJEE: We're - again, preliminary days for this work - what we're trying to do is trying to refocus the immune system on cancer.

A little bit of background here helps. The idea that your own immune system could fight your cancer has a long history. Some of it is detailed in "Emperor Of All Maladies" and led to amazing therapies for some cancers, such as bone marrow transplantation for leukemias, although it doesn't work for many other cancers.

So the idea that somehow or the other, your immune system could be refocused on your cancer is an old idea. But it's really come to life again because we now have a host of new medicines that allow us to potentially reactivate the immune system and make it recognize and kill cancer cells again. The idea grew out of something very interesting, and it was worked on in the 1990s and 2000s by a whole bunch of researchers that showed that when a cancer arises in a human being, it might do so - not true for all human beings - but it might do so by somehow escaping the immune response - that there was something about the immune response that how, fundamentally, the cancer cells had escaped.

And that led to the hypothesis that we would activate the immune system and then thereby could sort of refocus it or make it sort of wake up and recognize the cancer again. We're trying variants of that in leukemia and MDS. Other people have shown it to be very effective, for instance, in melanoma or even in lung cancers. Those are the diseases that they've been particularly effective in. And we're trying some of this in leukemia.

GROSS: So you're testing it on mice now?

MUKHERJEE: We're testing it on mice. We're testing it in test tubes. There's a whole platform that we're trying to develop to try to figure out how we could bring this to the clinic.

GROSS: So what exactly are you interfering with genetically?

MUKHERJEE: We're interfering with the way that T cells recognize cancer cells. We're interfering with the way that the cancer cells can escape from the T cells, the kind of cloaks and sheaths that they put up in order to escape from the immune system. So - and all of these ultimately are genetic. They are genes that are activated, repressed, that change their nature, that allow this kind of cloaking phenomenon to occur.

And then we're doing both. We are both activating, waking up the immune system, sort of shaking it awake and we're changing things in the cancer cells that allow it to cloak itself against the immune system and thereby escape.

GROSS: If you're just joining us, my guest is doctor and writer Siddhartha Mukherjee. And he's the author of "The Emperor Of All Maladies," the best-selling book about the history of cancer, the disease and its treatments that was adapted into a public television series. He has a new book called "The Gene: An Intimate History." Let's take a short break here, then we'll talk some more. This is FRESH AIR.

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GROSS: This is FRESH AIR, and if you're just joining us, my guest is oncologist and writer Siddhartha Mukherjee. He's the author of the new book "The Gene: An Intimate History." It's about genetics and medicine. He's also the author of "The Emperor Of All Maladies," which was a history of cancer and cancer treatments.

How do you make genetic - I know you can't explain this to me. It's probably way too complicated. But how do you make genetic changes in cancer cells?

MUKHERJEE: You know, making genetic changes in cells used to be very complicated. We used to be able to use viruses and deliver some genes into the cells. We used to make - be able to make mutations by exposing cells to, for instance, X-rays. But if you were to ask me 10 years ago, you know, can you change this one particular gene in a cell? I would say, I could do it, but it's pretty hard to do.

What's happened in the last five years - and it's really 5 years old, this technology - this technology has allowed us in an astonishing way to go into a normal cell or a cancer cell, even potentially an embryonic stem cell, and essentially directionally or intentionally make a mutation in a single gene in an intentional manner.

So I've likened this technology to saying - you know, it's like saying that if you imagine the human genome as a vast encyclopedia - in fact, if you can actually imagine the human genome as a vast encyclopedia, it would contain 66 full sets of the "Encyclopaedia Britannica," but repeating over and over again A-C-T-G-G-C-T-C-C-G-C-C, so forth.

Totally inscrutable to you and me, but of course extremely scrutable to a cell. What this technology allows us to do, essentially, is to go into that 66 entire sets of the "Encyclopaedia Britannica" and make it identify one word in that and change that word and leave most of the rest of the encyclopedia untouched. I'm saying most of the rest because there are still some collateral effects.

You sometimes get the wrong place. The technology hits the wrong place. But what it allows you to do is you can erase one word and replace it with a slightly different word. And that's how powerful the technology is.

And so, therefore, you could now ask me, which you couldn't ask me five years ago, is it easy to make a directional or intentional change in a cell? And the answer I would say - infinitely easier today, infinitely easier compared to how it was 5 or 10 years ago.

GROSS: There's a lot of ethical issues involved with this kind of technology. What are some of those ethical questions that are being raised?

MUKHERJEE: I mean, the biggest ethical questions are should we be tampering with the human genome when we don't know very much about it still? Should we be changing human genes? And that leads to the question of, you know, what is disease? What is a genetic disease? In "Gene," I offer a simple formulation that we might be able to think about. I say, you know, what we might think about - one question that you might think about is we're going to change some genetic material, are we sure that the benefits outweigh the risk?

I mean, is there truly extraordinary suffering associated with that disease? Now, the word extraordinary suffering - the phrase extraordinary suffering - you know, one person's extraordinary suffering can be not another person's extraordinary suffering, but at least we can use the word extraordinary to say that this is not a casual technology. We shouldn't be using this, obviously, to change the shape of eyes or the color of hair and so forth. So that's one.

The second idea is that we should be only using any of these technologies, any genetic technologies - and I'll broaden that idea in a second - any genetic technologies when we know that the gene really produces that disease in a relatively 1-to-1 manner. I gave you some examples before. I said, you know, some diseases, you know that when you have the genetic mutation, chances that you'll have that terrifying disease is high. Those are very penetrant. So the idea that, you know, we shouldn't be using these technologies to even do anything in diseases where we don't know how genes interact with each other, what the levels of complexity are - we should be really careful about that idea.

And the third principle or the third arena is to make sure that there's choice involved in this - that none of this is done by mandate. It's not done by - because we want people to do or behave this way but that there's a phenomenon of justifiable choice. So you can imagine this sort of as a triangle. One side of the triangle has the idea of extraordinary suffering. The other side of the triangle has the idea of complete or near complete penetrance. And the third side of the triangle has the idea of justifiable choice. As long as, I think, those - we stick within that triangle, as it were, at least we'll know that we're not just tampering with the human genome in a totally unsafe way.

But even that, it really raises a series of ethical and moral questions. How much should we change the human genome? Should we change it in a way that may lead us into areas that we are totally unsure about? Should we do it ever in an embryonic stem cell that has the capacity to become a full-fledged embryo? There are steep barricades in the United States that prevent us from being able to do much of this stuff.

GROSS: So once the genes have been altered in some kind of way, can any of those changes be passed on to the next generation?

MUKHERJEE: Again, a very important and complicated question. In simple organisms such as yeast and even worms, some simple worms, there's evidence that you can take these sort of environmental reactions and transmit them across generations. Plants seem to be able to do this as well.

The question in humans is very complicated. There's some evidence that when you have a famine, gene regulation occurs, transcription factors change, genes get turned on and off. And then they recruit other marks into the genome, which can potentially be transmitted across one generation, maybe across two generations.

Aside from that in humans, there's very little evidence of environmental information being able to transmit across multiple generations. It's just very important to be careful with this because, of course, the idea that you can transmit information across multiple generations raises the prospect of Lamarck, you know - giraffes becoming taller by stretching their necks longer or animals being able to run faster because they ran away from animals fast themselves. And somehow, this information gets passed on to their offspring and you can shortcut evolution. That's very rarely true and I would say almost never true.

The information that can be passed from the environment into the genome is very idiosyncratic. We know very little about it in humans. In simple organisms and in plants, there's evidence for it, but there's a word of caution in the book. In fact, the section begins with this idea. It says a note of caution here that these events are idiosyncratic, these are rare, and should not invite fantasies of overturning, you know, Darwinian evolution for Lamarckian evolution, which is - just really is not true.

GROSS: There's an example in your own family of inherited illness. And there's also an example in your family of identical twins. And everybody knows that identical twins raise so many questions about what is inherited and what is a function of experience and the environment that you live in. So what are we learning about identical twins and their genetic makeup and how the genes affect them and how environment affects them in spite of the genes?

MUKHERJEE: That's a fascinating area. If one twin has schizophrenia, the chance that the other twin will become schizophrenic is strikingly high - four, five - some people say a little bit less - but 3 to 5 times the risk of the general population. So we know that if you have identical genomes, the chances that you will develop certain diseases is high even though these diseases, obviously, can have multiple genes. The point is that if you and your twin have exactly the same genome - give or take some changes that occur over time and in utero. But you have essentially the same substrate.

And now more and more we're discovering that this is shared across multiple genes. Again, the important thing to realize is that for most diseases - not for all diseases - but for most chronic human diseases, that number is about 20 percent, 30 percent - that number of - the chances that you and your identical twin will have the same disease. It's not 100 percent, and therefore, yet again, we come to realize that it's not genes alone.

It's a combination of genes, plus environment, plus triggers, plus chance. As long as we remember that formula, we can generally be accurate about genetics - genes plus environments plus triggers plus form. That allows us to be careful about describing the fact that genes absolutely matter. They matter in diseases like schizophrenia, they matter in diseases like diabetes, in diseases - obviously the way your body is shaped. They matter in diseases like obesity. And yet, it's not all genes.

GROSS: So sometimes you have a genetic predisposition to something, but it doesn't guarantee you're going to get that thing.

MUKHERJEE: A classical example of that, of course, is the BRCA1 gene. Not every woman who has the BRCA1 gene will get breast cancer. And yet, the chances that a woman with a BRCA1 gene gets breast cancer are strikingly higher than the general population if you don't have BRCA1.

BIANCULLI: Author and oncologist Siddhartha Mukherjee speaking to Terry Gross last year. After a break, we'll continue their conversation. And film critic David Edelstein reviews the award-winning documentary "Last Men Of Aleppo" about emergency volunteers in Syria and I review two new TV series, the new Amazon comedy from "Transparent" creator Jill Soloway and the new Netflix adaptation of the classic children's novel "Anne Of Green Gables."

I'm David Bianculli, and this is FRESH AIR.

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BIANCULLI: This is FRESH AIR. I'm David Bianculli in for Terry Gross, back with more of Terry's interview from last year with author Siddhartha Mukherjee. His latest book, titled "Gene," is now out in paperback. He also wrote the Pulitzer Prize-winning book "The Emperor Of All Maladies," a history of cancer and cancer treatments. He's an oncologist at Columbia University Medical Center and is working on developing a therapy intended to treat certain cancer sells by modifying the body's immune system.

Genetics, he says, have helped him understand his own family. He has two uncles and a cousin who were schizophrenic, and his mother has an identical twin sister.

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GROSS: Genes are actually teaching scientists a lot about the nature of gender and of gender identity and maybe of sexual orientation. So let me start with sexual orientation. There was talk in the '90s about discovering, like, a gay gene. What do scientists think now? Is there a genetic explanation for homosexuality?

MUKHERJEE: Tremendously important question and a tremendously controversial question, but we know quite a lot of data on it. So let me just present the data, and then we'll go into this idea in a second. If you take identical twins, male twins, the chances that these male twins will share a sexual orientation is much higher than siblings, for instance.

Now, what does that tell us? That tells us that there may be genetic determinants - because identical twins have exactly the same genome, there may be genetic determinants that determine one's sexual orientation. That number that - the - how much they share is not 100 percent. So in other words, if one twin is gay, the other twin will not necessarily be gay. It's not 100 percent exactly the same.

So we know that either genes or intrauterine exposures or some other factors, environments, have a powerful effect on this society. Culture has powerful effects on this, but we know also that there must be at least some genes involved. And if you look carefully at the patterns, it's clear that not one gene is involved. There's not one single gay gene, that probably multiple genes are involved. In fact, I don't even like that term gay gene. I think it's very misleading as an idea.

It's a gene that influences a sexual preference, and, of course, most of this work has been done in males. There's very, very little evidence in females. So we know that there's some genetic determinants - plural - that are involved. But when people have gone to look for those genetic determinants, the hunt has come up quite not so clear. So the summary is basically that thus far, we have not found - as I said, I don't like the word or the phrase - we've not found a gay gene. And it's unlikely that we'll find one.

There probably will be - like many phenomena in human identity - there will be multiple genetic determinants interacting with environments. But it's very important to be clear about these ideas 'cause otherwise we fall into language that's all incorrect and wrong. And then you just foster nonsensical controversy.

GROSS: But by saying that there is likely some kind of genetic predisposition to be straight or to be gay, that makes a significant contribution to discussions about gay-related issues and marriage equality and things like that.

MUKHERJEE: You know, in some ways - and I like to think of "Gene" this way - "Gene" is a massive plea for equality and equanimity. Human variation abounds. We have a huge amount of variation, and we don't know yet the consequences of this variation. But we also have a huge amount of similarity. We are a young species. We haven't been around for very long. So in fact, there are deep similarities and a few dissimilarities, and the gene is a plea for a kind of radical conception of human equality.

GROSS: So let's talk about gender identity. What are genetic scientists learning about people who have the discrepancy between their gender anatomy and their gender identity?

MUKHERJEE: So for the large part, gender anatomy, whether you're male or female in terms of the sexual anatomy, is determined really by one master regulator gene. It's a transcription factor, as you can imagine, one of these master genes. And unsurprisingly, it sits in the Y chromosome. If you have the Y chromosome and therefore inherit the gene, then you will be born a male. You will have, for the large part, for most people, you will have the gender anatomy of a male. If you don't have the gene, you will be born female and have the gender anatomy, for the most part, of a female.

Now - but once in a while, this pattern is changed. Occasionally, there are people, rare human beings, where you inherit the Y chromosome, but you don't - you have a mutation in that SRY gene. So essentially, for the - you are born with the Y chromosome. But essentially, your anatomy, and for the most part your identity, is female. That teaches us something very important.

That means that as far as gender anatomy is concerned, as far as even gender identity is concerned, there is one master regulator. So it tells us that it's a single master regulator, and we know what that master regulator is. What it also tells us, and this is where things get most interesting, is that that master regulator, we now know, begins to recruit downstream things. It's not - it doesn't act on its own.

It's sort of like the commander in the army. But the commander in the army still has to have recruited its deployment of all the other troops, all the other - you know, the hierarchy, as it were. And there are infinite variations along that hierarchy. So you could still have, as it were, the master regulator, a commanding male gender anatomy and a different hierarchical organization flowing down from it, which would lead to slight different variations or radically different variations in gender identity. In other words, you'll have male anatomy, but you may not have all the same aspects - or people have different aspects of male identity.

So the point here being is that genes can sit at peaks or at pentacles of cascades or hierarchies and command things in an on-and-off manner - female, male. But the way that these genes - this genetic information percolates down into the individual, the way this hierarchy percolates down into an individual might be very different from one person to another and therefore create the kind of infinite ripples or variations in human identity that we experience in human life.

GROSS: If you're just joining us, my guest is oncologist and writer Siddhartha Mukherjee. His new book is called "The Gene." He's also the author of "The Emperor Of All Maladies," which was a best-selling history of cancer and cancer treatments. We have to take a short break here, but then we'll be right back. This is FRESH AIR.

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GROSS: This is FRESH AIR. And if you're just joining us, my guest is oncologist and writer Siddhartha Mukherjee. His new book is called "The Gene." It's a history of genetics and how what we're learning about genetics can be applied to the treatment of diseases. And he's also the author of "The Emperor Of All Maladies," which was a history of cancer and cancer treatments.

So I would like to think that genetics doesn't mean that biology is destiny. In other words, I would like to think that just 'cause you're born with female sex organs doesn't mean that you are genetically confined to being, you know, less strong or less capable than men, which was what, historically, was projected on women.

At the same time, I'd like to think that genetics can help us understand people who identify as trans, who were born with, say, female sex organs but identify as male or vice versa - born with male sex organs but they identify as female. Is that too much to ask? Do you think that genetics may be able to do both, to say biology isn't destiny when it comes to gender, but also help us understand why some people identify as trans?

MUKHERJEE: Absolutely. The centerpiece of this book is that biology is not destiny. But some aspects of biology and some aspects of destiny are commanded very strongly by genes. And we talked about one such aspect, at least. The anatomy of gender is strongly determined by genes. But you could - there's no reason that that cannot be reconciled with the idea that there are a thousand variations that might influence some other aspect of your destiny and biology. And that might be the nature of your identity.

So the fact that these two are held up as sort of mutually oppositional, biology isn't destiny and biology is destiny, reminds us why we need to understand the details. The truth is in the details. We need to understand genes - what they are, how they act, what they do - in order to be able to make that statement that, you know, biology isn't destiny. And biology is some parts of destiny. These are not mutually opposed. It depends on what you're talking about. It depends on what question you're asking and what answer you're seeking.

If you don't know how to ask these questions and if you don't know to use the language of genetics or genes, you'll get misled. And once you're misled, you now enter a tremendously divisive public discourse in a way that's incorrect.

GROSS: That's a very helpful answer. Thank you very much for that. I want to ask about your own genes. Have you decided whether to or not to get genetically tested yourself? And I should mention here that there is a history of schizophrenia in your family. You had two uncles and a cousin with schizophrenia. You know, what scientists are learning about schizophrenia is that there is a genetic component to it, a genetic predisposition. So do you want to get tested for that or other illnesses?

MUKHERJEE: I've chosen not to be tested. And I will probably choose not to be tested for a long time, until I start getting information back from genetic testing that's very deterministic. Again, remember that idea of penetrance that we talked about. Some genetic variations are very strongly predictive of certain forms of illness or certain forms of anatomical traits and so forth.

I think that right now, for diseases like schizophrenia, we're nowhere close to that place. The most that we know is that there are multiple genes in familial schizophrenia, the kind that our family has. Essentially, we don't know how to map, as it were. There's no one-to-one correspondence between a genome and the chances of developing schizophrenia.

And until we can create that map - and whether we can create that map ever is a question - but until I - we can create that map, I will certainly not be tested because it - that idea - I mean, that's, again, the center of the book. That confines you. It becomes predictive. You become - it's a chilling word that I use in the book - you become a previvor (ph). A previvor is someone who's survived an illness that they haven't even had yet. You live in the shadow of an illness that you haven't had yet. It's a very Orwellian idea. And I think we should resist it as much as possible.

GROSS: Would you feel that way if you were a woman and there was a history of breast cancer in your family?

MUKHERJEE: Very tough question. If I was a woman and I had a history of breast cancer in my family and if the history was striking enough - and, you know, here's a - it's a place where a genetic counselor helps. If the history was striking enough, I would probably sequence at least the genes that have been implicated in breast cancer, no doubt about it.

GROSS: OK.

MUKHERJEE: I recommend this for my patients.

GROSS: OK. Thank you for that. Siddhartha Mukherjee, it's been a pleasure to talk with you. Thank you so much.

MUKHERJEE: Thank you. It's been a pleasure being on the show.

BIANCULLI: Author and oncologist Siddhartha Mukherjee speaking to Terry Gross last year. His latest book, titled "Gene," is now out in paperback. Transcript provided by NPR, Copyright NPR.