Lessons From the History of the Gene

IRA FLATOW: This is Science Friday.. I’m Ira Flatow. The idea that we might one day synthesize a human genome, maybe sooner rather than later, forces us to think about the future. Will we ever develop the technology to build a human being from scratch? Is it just a matter of time? And under what circumstances would we do it? Who will decide? We all start thinking a little like science fiction writers, don’t we?

But maybe we should also be thinking like historians. Last week, I read a book called The Gene, a sweeping history of human genetics. From Mendel’s pea plants to the gene-editing technique CRISPR, it turns out the history of genetics is a history of ethical conundrums. And it’s a history we can all learn from.

Siddhartha Mukherjee is the author of The Gene, an Intimate History. He’s also the Pulitzer Prize winning author of The Emperor of all Maladies, a Biography of Cancer, and an assistant professor of medicine at Columbia University. Welcome to Science Friday, Dr. Mukherjee.

SIDDHARTHA MUKHERJEE: Well, thank you for having me.

IRA FLATOW: What did you think when you heard the news that geneticists were discussing synthesizing the human genome?

SIDDHARTHA MUKHERJEE: To me, of course, it’s astonishing news still. But it seems to be a natural progression. We’ve been synthesizing longer and longer pieces of DNA. It used to be very expensive to make. The costs have come down. And we’re stringing them longer and longer pieces together.

In our laboratory, for instance, when we do our own work, we used to have to do very complicated steps to create mutations or make changes in genes. Now, we just order them out. And they send them. And they can be 2,000 ATG CC’s, et cetera, long. So I think it’s an enormous technological challenge that remains. But on the other hand, I also see it lying within the reach of future technology.

IRA FLATOW: Does this frighten you that we’re able to do this?

SIDDHARTHA MUKHERJEE: Yes, I’m apprehensive about how we want to use this information. I’m apprehensive about what people will think about doing with it in the future. I mean, is it going to be a proof of principle and we’re going to stop there? Or are we going to go a little bit beyond that and try to make artificial genomes more to specifications?

I suspect it’s going to stop by itself. I suspect there’ll be strong barricades around it. Scientists have put up barricades around these kinds of ideas before. And it’s important to prove the principles. But I do think that we will manage to put up barricades. I’m optimistic about that.

IRA FLATOW: So let’s talk about those barricades because in particular, you write about another sensitive scientific meeting in your book where scientists discussed what they could do and what they should do. And I’m talking about the Asilomar Conference in 1975.

SIDDHARTHA MUKHERJEE: Right. An incredibly important conference. And that meeting, the Asilomar meeting, was held in California. Soon after, a group of scientists, including Paul Berg and Stan Cohen and Herb Boyer, began to figure out that you could take genes from different species. You could take a gene from a bacterium and you could stitch it together with a gene from a virus, or a human gene, and you could put it into a frog cell. And because the genetic code is universal, the frog cell would think that it was a frog gene. There’s no way that it would know it any differently. And you could now make human proteins in a frog cell, or a bacterial gene, et cetera. So there’s a quote in the book. I say, “Species are specious.”

And so in the wake of those stunning discoveries, later called– or actually already then called recombinant DNA, that you could recombine, combine any two pieces of DNA, scientists and legal scholars and some bioethicists and journalists had actually an open meeting. They were invited. But you could write about it. And that meeting was Asilomar. And they decided to temporarily self-impose– or impose a self-moratorium on the use of these high gene hybrids so that you wouldn’t all of a sudden unleash biological catastrophe in the world. And that moratorium was very effective.

IRA FLATOW: You noted that that was an open meeting to the press, compared to the meeting last week, which was closed.

SIDDHARTHA MUKHERJEE: That’s right. So, I mean, my impression is that the meeting was closed because the technologies are too premature, I don’t think that the meeting– I wasn’t at the recent meeting. I don’t think the meeting discussed, oh, you know, here’s what we’re going to do. And here’s how we’re going to string together several billion little bits of chemicals to make the human genome, an artificial human genome. I think the meeting was, should we embark on it as a proof of principle. How much money would it entail? I obviously would have preferred it if it was open because we know these questions right now.

IRA FLATOW: In your new book, you really invited readers into these ethical debates. Was that part of the motivation for writing the book, to get everybody involved in talking about it?

SIDDHARTHA MUKHERJEE: Absolutely. I mean, I think everyone should be talking about it. And here we are, raising questions about who are we. Who gets to decide how to synthesize something that has so much to do with yourself, your identity? We want to eliminate diseases. We want to eliminate suffering. How do we use genes to do that in a way that’s safe and does not compromise the future?

So that debate cannot be had in an isolated place. It has to be had in the most public forum possible because it concerns you. It concerns me. It concerns my children. It concerns my future.

IRA FLATOW: Because are we at a turning point in history right now with the gene, do you think?

SIDDHARTHA MUKHERJEE: We are. I mean, we’ve progressively inched towards that turning point. And you can watch the steps happen, particularly the last 20 years. I try to walk us through that moment. How do we get here, today, when we’re sitting in a studio and asking questions like, should we be making artificial human genomes? Should we be manipulating or changing the human genome intentionally? Well, how did we get here?

Well, we need to know– in order to have this discussion in an ethical forum, and say, this is the next things that would be permissible, this would not be permissable– we need to be able to have the vocabulary and understand how the technology brought us here.

IRA FLATOW: Because you saying in your book that not only is the gene one of the most powerful, but it is one of the most dangerous ideas in science.

SIDDHARTHA MUKHERJEE: And then, the word “dangerous” is very key. I mean, we all know we want to use genetics and genes for human emancipation. We want to eliminate terrifying diseases or cure or at least treat them using genetic technologies.

But it’s dangerous, because more than once in our history, recent history, we’ve watched the idea of heredity being perverted.

IRA FLATOW: Eugenics.

SIDDHARTHA MUKHERJEE: Eugenics. And what’s amazing about eugenics, Ira, is that if you were a progressive kind of fellow in the 1910’s in England, you would very much want to believe that one way to emancipate human beings, one way to make better human beings, would be through selected breeding. And yet, that same idea, 30 to 40 years later in Nazi Germany, switches from selective breeding to selective elimination of the weak, extermination. And so, the road to that eugenics hell is paved through progressive beliefs at first, which slowly morph into the macabre Nazi eugenics that we know about.

IRA FLATOW: That’s very surprising.

SIDDHARTHA MUKHERJEE: Yeah, to me. And there’s an American interlude to this, too. It’s an important American interlude, which you couldn’t forget, which is that after the idea was born and bred in England, often among progressives, although not all progressives believed it, it actually metastisized first to America. It was America that brought up– if eugenics was born, it’s early adolescence was spent in America, where again, that idea– how do we change the human race? How do we make it better?

Remember the better babies contests and Carrie Buck?

IRA FLATOW: Carrie Buck, you write about. Tell us about who Carrie Buck was.

SIDDHARTHA MUKHERJEE: Well, Carrie Buck is an important character. I actually dedicate the book partly to her. She was a woman who was sterilized on the pretext that she carried a gene, maybe more than one gene, for imbecility, which was never proven. In fact, if you look back at her records– and more than one book has been written about her. If we look back at her records, you find out, in fact, that the evidence that she was carrying a genetic form of imbecility was very, very poor. And yet, she was forcibly sterilized. The Supreme Court basically ordered that she could be sterilized for the betterment of society because no one wanted– the famous opinion was three generations of imbeciles is enough. That was the–

IRA FLATOW: You couldn’t do that today. Well, what has changed over that period?

SIDDHARTHA MUKHERJEE: Well, we’ve learned, I think, how to stop ourselves from going over that abyss. We’ve learned that genes or genetics is more complex. We’ve learned how dangerous the seduction is of trying to use heredity in this manner. We’ve learned hard lessons through the Nazi experience as we watched in horror. We’ve learn many of these things.

The question is, have we learned enough? And will we be able to use these lessons in the near future.?

IRA FLATOW: Speaking of learning, let’s talk about another very famous case that taught us something. And I’m speaking about Jesse Gelsinger. Tell us what happened there.

SIDDHARTHA MUKHERJEE: So Jesse Gelsinger was a young boy who had a very mild form of genetic disease. It had affected his liver, among other things. And he decided to enroll in a trial of gene therapy, one of the first trials. And the night before he was going to be injected with a virus containing the corrected gene, there were some abnormalities noticed in his body, some physiologic abnormalities.

But he decided– actually, no, he didn’t decide. The team decided to go ahead. He had a terrible immune reaction to the virus. We think immune reaction, a terrible reaction to the virus. And he died as a consequence of that.

IRA FLATOW: And he was not really informed. His father– you write about his father, who is still alive– did not feel that he was adequately informed about what the hazards were.

SIDDHARTHA MUKHERJEE: That’s right. And there’s a regret there, that the father was not fully informed about what the potential risks were of the procedure that was clearly risky.

IRA FLATOW: And what’s the lesson? What do we take away from that?

SIDDHARTHA MUKHERJEE: Well, we learned a lot of lessons from that experience too. We learned about how to control. We learned about what the scientific problems were with using– the irony is that they had decided to use a common cold virus, basically, to deliver the genes, hoping that it very bland. It was not something very weird and outside the box. The irony is that that’s probably the reason, one of the reasons, that he had an immune reaction. He probably had seen or been exposed to that same virus before or to some cousin of it. And sometimes, again, it’s only in retrospect that we figure out what the scientific challenges might have been.

IRA FLATOW: I want to read another quote from your book. You write, “Our capacity to understand and manipulate human genomes alters our conception of what it means to be human.” What did you mean by that?

SIDDHARTHA MUKHERJEE: Well, the idea here is that once we start saying to ourselves that the human genome is not something that you inherit by virtue of who, by chance, you happen to have as your parents, but it’s something that we can change, that we can call it two phases, reading and writing.

By reading, I mean you can use the genome. You can look at a gene sequence, and in a probabilistic way, say that the probability of you becoming this or developing that disease in the future maybe 10%, 20%. Even that, even though it’s not certainty, that idea begins to change who we are as human beings. All a sudden, you say, well, OK, now I live in the shadow of a future illness that I may or may not have.

Or take the case of writing, in which you say, I can change something in the human genome. Then you say, well, OK, what does it mean to change pieces of oneself, particularly an embryo, embryonic cells? I mean, what does it mean to push into that arena? So I think that idea begins to change how we think of ourselves.

IRA FLATOW: Are we very close to genetically modifying humans with the CRISPR technique and the tools.

SIDDHARTHA MUKHERJEE: Again, I think there will be strong barricades against this. At least in the United States, there will be strong barricades. I think there’s a precedent for this. We’ve talked about Asilomar before. I think that trials of gene therapy and other biological, ethical situations have taught us how to stop when we need to stop.

So that doesn’t worry me so much at present. But what worries me, of course, is that internationally, people have different standards. So the first experiment, attempted experiment to modify a human embryo, was performed in China. Now, they were nonviable embryos, so the experiment wasn’t a free-for-all. But nonetheless, the first experiment was performed in China.

And so we have to ask ourselves, well, is this is going to become a kind of arms race? Other people are going to enter it? What will we do? And as I said, there are important stakes here. These important stakes might be you could potentially cure terrible diseases or treat terrible diseases with these technologies.

IRA FLATOW: In case you just joined us, we’re talking with Siddhartha Mukherjeem who is a cancer physician and author of the new book, The Gene, an Intimate History on Science Friday from PRI, Public Radio International.

Is it inevitable that once the technology exists– you talked about the Chinese starting down that road– that somebody is going to try to make a human, a synthetic human?

SIDDHARTHA MUKHERJEE: I don’t think it’s inevitable, partly because I think the synthetic human question is yet another technological leap, a wrinkle, as it were. I mean, I think that we are far away from being able to make these giant collections of strings of letters. I think it would take quite a lot of technology to get there. It has become cheaper. It has become somewhat possible. It still remains a pipe dream.

And I think that by that time– I hope that by that time– we will have figured out where to stop. I mean, do we stop at a proof of principle, and then say, OK, we know how to do this, now we’re going to stop?

IRA FLATOW: You have your own manifesto about it.

SIDDHARTHA MUKHERJEE: I have some recommendations about it. Yes.

IRA FLATOW: Three main ones, I understand.

SIDDHARTHA MUKHERJEE: Well, the three, I like to think about it as a triangle. And just to inform us about this triangle, I mean, one edge of the triangle– so the question is, under what circumstances should we be using genetic manipulations? Should it be permissible? Where should we be applying this technology?

So one the edge of the triangle, at least for me as a physician, is that there has to be extraordinary suffering involved. I mean, we cannot possibly want to use these technologies lightly. It can’t be to change the color of your hair, or to change other things that may or may not be related to genes anyway. So it has to be some extraordinary suffering.

The second is that there has to be– the relationship between the gene and the expected effect has to be very tight. There’s a word in biology called penetrance. And that is to say that if you have a gene that only has a 10% chance of producing an expected effect, it’s unlikely we should want to tamper with those because the chance is so minimal.

And the third, probably the most important is, that all of this should be done without state mandate. It should be done without someone forcing you to test the genetics of your child. It should be done without someone telling you, this is the way we would like you to manipulate the genome.

So historically, we’ve stuck within the boundaries of this triangle. It seems to be now, the question that’s arising more and more is, should we step out of one of these boundaries. And that, to me, is the crucial question.

IRA FLATOW: It’s something we need all to discuss transparently–

SIDDHARTHA MUKHERJEE: Transparently, Exactly.

IRA FLATOW: –together, and out in the open.

SIDDHARTHA MUKHERJEE: Absolutely.

IRA FLATOW: Thank you very much. We’ve run out of time. Very interesting book. I’m talking about The Gene, an Intimate History, talking with Siddhartha Mukherjee, who is a cancer physician and author of The Gene, an Intimate History. He’s also assistant professor of medicine at Columbia University. Thanks again.

SIDDHARTHA MUKHERJEE: My pleasure. Thank you so much.

IRA FLATOW: And you can read an excerpt from The Gene at our website. Go to sciencefriday.com/gene.

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