基因编辑：罗伯特-克里兹曼（Robert Klitzman）：概述、伦理与不远的将来

ALEX WOODSON: Welcome to Global Ethics Weekly. I'm Alex Woodson from Carnegie Council in New York City.

This week, I'm speaking with Dr. Robert Klitzman. Robert is a professor of psychiatry at the College of Physicians and Surgeons and the Joseph Mailman School of Public Health, and the director of the Master of Science in Bioethics program at Columbia University.

He is the author of several books, including the recently published Designing Babies: How Technology is Changing the Ways We Create Children and The Ethics Police?: The Struggle to Make Human Research Safe.

This is the first of several podcasts we'll be doing on gene editing or genetic engineering. As Robert is a medical doctor and a professor with a deep interest in ethics, he’s the perfect person to get us started.

In this talk, Robert gives us an overview of gene editing, the ethical and governance issues, and the future of this technology. We also spoke about the birth of genetically edited twins in China last year and why that was a "seismic" event, in Robert’s words.

For more from Robert, including a 2015 interview with Joanne Myers, former director of the Public Affairs program, go to carnegiecouncil.org. He also conducted two interviews himself, on medical tourism and health care in times of crisis, that are definitely worth checking out.

For now, calling in from a different part of New York City, here's my talk with Robert Klitzman.

Thank you so much for doing this call. I appreciate it.

ROBERT KLITZMAN: Sure. My pleasure.

ALEX WOODSON: This is the first in a few podcasts we're going to be doing on gene editing, ethics, and governance. To get started, I was hoping you could give us a brief overview of gene editing, some definitions, and what its applications are.

ROBERT KLITZMAN: Yes. And I think it's great that you're addressing these issues.

Just as background, our genes are our DNA. DNA consists of a sequence of four different molecules that we abbreviate ACTG for adenine, cytosine, thymine, and guanine. Three billion of these letters in a unique combination is what makes each of us; it's the blueprint for each of us. My 3 billion letters may be ACCGG, yours may be ACCT, etc. Humans are 99.9 percent the same in terms of these 3 billion letters, so we differ by just several thousand letters, but those thousand letters that we differ by are important, that 0.1 percent, because those are the genes that give each of us our hair color, our eye color, and our predisposition to certain diseases. I may have certain genes that make me predisposed to certain diseases.

We also know, for instance, that 50 percent of intelligence is genetic and 50 percent is environmental. There are probably many, many genes involved with that. Genes are involved with height. The fact that we tend to look like our parents and not like the people who live a few blocks away is because of our genes.

What we're now able to do is go in and alter those genes. Gene editing is also called "genetic scissors" or use of genetic scissors. Let's say there's a gene that may give me an increased risk for a certain kind of cancer, we can go in and cut it out or disable that gene, so presumably I then won't get the cancer. We could also, however, say, "I want some genes for height added to my future child," and it looks like we'll probably in the near future be able to do things like that.

There have been several different ways that scientists have attempted to edit genes. Recently, in the past few years, one has gained a lot of attention and is known as Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR). CRISPR was found partly in yogurt; it was found that yogurt bacteria could clip out the genes of viruses, and people figured out, Gee, if bacteria have this mechanism, maybe we can have plants and animals do it. We use this to make different kinds of plants resistant to viruses, for instance, or make them last longer on the shelf and not get as bruised, and various things.

With humans we now can also alter genes, and we can do this either when someone's already up and living. Let's say I have cancer; we can put a gene into my body that may alter what goes on in my body as treatment. There's gene therapy, for instance.

Where there has been a lot of controversy recently is gene editing of embryos, "germline editing," and "germline" because when we edit the gene in an embryo it then germinates or creates a whole person and will affect their future children as well. For instance, CRISPR has been used in animals, bacteria, and plants, and then about three years ago a scientist in China began to use CRISPR to alter a human embryo.

Of course, when a human egg meets a human sperm and the sperm fertilizes the egg it forms an embryo of one cell that then splits to become two cells, then four, then eight cells, then 16 and 32, and eventually becomes a human being. When it's at the one-cell stage—what he did is he went in and began to alter the genes in the embryo.

This created a big international furor. People were afraid: "Are you going to create Frankensteins? Are you playing God here?" I'll talk about some of the risks and concerns ethically in a moment.

There were international summits held at that point where the Chinese Academy of Science, the U.S. National Academy of Science, the Royal Society, and other equivalent bodies and scientists around the world got together and said, "Okay, let's have an agreement that it's okay for scientists to alter the genes in a human embryo as long as they don't implant the embryo into a woman's womb to create a child."

This was the agreement that went on for two or three years, I think from 2015-18. I think it was in November 2018 that Dr. He Jiankui—who was a scientist who worked in China near Hong Kong in a city called Shenzhen—went ahead and actually took the altered embryo and put it into a woman and created children. So we now have children who were designed. That is to say we've altered the genes in a very direct way. This has been controversial for several reasons.

First of all, we have these, as I say, genetic scissors, but it's new technology, and we're not very precise yet about it. We haven't got it as exact and precise as we need to. He went in and said he was cutting out a certain bit of DNA, but he cut out more DNA than he thought. So we now have children who have more of their DNA cut out than anyone thought, and we don't know what the risks are of that. In other words, presumably if you're missing part of your DNA, it may affect your brain development, it may affect your muscle development, it may affect your immune system. We don't know.

ALEX WOODSON: These are the twins who were genetically engineered to be HIV-resistant.

ROBERT KLITZMAN: Yes. Exactly.

ALEX WOODSON: They were born I guess about a year ago. We don't know exactly what the status of these twins is at the moment?

ROBERT KLITZMAN: There are rumors, but we don't know. This gets into an issue of governance, global governance, and who knows what about what. He created Lulu and Nana, I think were the names. There has been a suggestion that there may be other children he created as well.

There was a public outcry about this, and there is some evidence that the Chinese government at first thought this was great, and then when the public outcry occurred Dr. He Jiankui was put under house arrest, and it was a source of embarrassment. Very little information has been made public about this experiment since the initial announcement last year, which is a problem.

One reason it's controversial, as I said, is that because you're creating a human being—who had no choice in the matter—you may be creating kids who are deformed, who are disabled because you didn't quite edit the right genes. If I go into a computer and rip out a bunch of wires or open your phone and take part of it out, maybe your phone won't work. Maybe it will work, but maybe I'm trying to fix one app, and I may accidentally mess it up in other ways. You have problems like that.

The other issues is that if you take out one gene—remember it's only around 60 years ago that Watson and Crick discovered how information was encoded genetically with DNA, and it's only about 17 years ago that the first human genome was sequenced, so we still don't know a lot about human genes. We're constantly finding new things.

To give you an example, when genes were first sequenced 17 years ago scientists thought we would find "the cancer gene" or "the depression gene" or "the alcoholism gene," and we know now that there are hundreds of genes involved in different cancers or in mental health problems such as alcoholism or depression. We're finding out how much we don't know. We're finding several things that we do know, we're finding several things out, but also how much more complicated genetics is. If you're going to knock out a gene, it may be that that gene is involved not just with letting HIV come into a cell, but it may be involved in brain development, muscle development, or heart function. So there are other risks which are involved ethically, which is problematic.

Another problem with what Dr. He Jiankui did is he worked with HIV-infected fathers, and he sought to disable a gene called CCR5, which lets HIV virus get into cells. The problem is that if you disable that gene, as a result it will be more likely that other viruses will get into the cells, so it increases the likelihood of influenza getting in the cell or West Nile Virus.

In addition, if a father is HIV positive, there are other ways of preventing the transmission of HIV to his children. In the United States, we do sperm washing, where if a man has HIV, they wash the sperm and separate out the virus, and they have the sperm without the virus, and that's what they use. He could have just done that and avoided all the problems.

He thought he would win a Nobel Prize for this. He thought that this was going to make him rich and famous. He was going to make a clinic for wealthy Westerners to come and design their babies, and he would win the Nobel Prize. Again, there are several kinds of risks.

What has happened since then is complicated. As a result of that, there have been a series of discussions at the World Health Organization (WHO) and elsewhere about what do we as a world do? The danger is, I could try to make a superhuman, or I could end up making a lot of diseased people.

Again, if I affect the genes of a child, I'm affecting the genes of that child's child and grandchildren and great-grandchildren, etc. This is very powerful technology. It may be in the future that people want to put genes in that they are think are associated with intelligence; do I want to put in genes associated with blond hair and blue eyes or with musical ability or other things? Again, there is controversy around each of these.

In some ways we have been able to find genes that are involved with some of these traits. It has been more complicated than people thought, but there are concerns that this is where we're heading. It's one thing to say we're going to prevent diseases, but it's another thing to say if you're wealthy you can afford to have a tall kid who has maybe some genes associated with intelligence.

ALEX WOODSON: Let me just stop you there. What would be the ethical problems with parents deciding that they want their children to have blue eyes or they want them to be tall or they want them to be intelligent?

ROBERT KLITZMAN: Right. A few things. There was a movie called Gattaca a few years ago, and in the movie—I think it had Ethan Hawke in it—there was a future society. At birth, a little blood stick would be taken from each child that would determine how healthy the child would be. Infants were separated to be genetic inferiors or genetic superiors, and if you were a genetic superior, you got sent to college and got a lot of attention and could choose a career. If you were dubbed to be a genetic inferior, you were slated to work as a janitor somewhere and were considered second-class.

The last time there was an effort to improve the genes of a society was during the Nazi era. It was called eugenics, and the Nazis thought they would improve the genes of the German population. They therefore decided they would kill all the gypsies, all the disabled people, anyone with intellectual disabilities, all the homosexuals, and all the Jews. So this easily can get into racism. There have been debates already; people have written books saying that blacks are "genetically inferior." There is a lot of evidence to show that is not the case.

But, given racism, there is a concern that if wealthy people can afford to alter their genes, there may be discrimination and there may be a stigma that's involved. Certainly groups may not be able to afford to do this. Let's say there's a gene—or a few genes—that can increase intelligence or height or something else or that may increase certain kinds of athletic ability. Some people can afford to do that and others won't in our society, so it creates injustice.

A lot of this may be foolhardy. In other words, do we want to be creating people who are deformed, for instance? Who should be making these decisions?

I would say the answer is not that you should never use germline editing but that there needs to be a discussion about it so the society as whole can decide, "Is this something that's okay? If so, when, for whom, and for what?"

Jeffrey Epstein, for instance, who committed suicide it seems in jail and who was involved in all kinds of unfortunate doings, apparently wanted to create clones of himself. He was invested in trying to create a genetically superior group of people who would be his descendants.

It could be unfair to the children if we create people and we want them to be a certain way and they don't. It raises questions about should we be playing God, and what does that mean, and should there be limits, and who should decide? These are important questions.

First of all, there are risks involved when you start doing this. Second, as I said, it leads to advantages for some. Some people may not be able to afford it, certainly they can't now. So many of us feel that the divide between the haves and have-nots both in our country and globally is increasing and that that's not a good thing. That's unfair. It could lead to revolution, it could lead to exploitation, and we think that's not a good thing to encourage.

These are the kinds of concerns that many people have, and I think what's key is that people understand: What are these technologies, what is gene editing, what can it do, can it do things that are good, what might the risks be, and how should we decide, and who should decide?

ALEX WOODSON: How close are we to the point where parents can decide to have a baby with a different hair color, eye color, or height? I understand that there could be unintended consequences, but how close are we to making that a reality, or are we there today?

ROBERT KLITZMAN: A few things. One is that we now have a technology called pre-implantation genetic diagnosis (PGD), where we screen embryos for many conditions. I wrote about this quite a bit in a book, Designing Babies: How Technology is Changing the Ways We Create Children. For instance, there are couples that now say, "I just want a boy. Give me a boy."

As I said, when a man and a woman want to have a child, sperm meets egg, and it makes an embryo. They'll make, say, 10 embryos, and the doctor will say, "These five will be boys; these five will be girls," and many people just want a boy.

Many people feel that that's discriminatory. There are feminists and others who point out the fact that in countries like India and China there are around 20 percent more boys than girls for various reasons. This could cause sexism or other problems. But we're now already using this technology every day all over the country to just choose boys, for instance.

Also, people are screening embryos for diseases. I'll actually clarify that there are different kinds of uses. On the one hand, you can get rid of certain diseases through this, for instance, breast cancer. There are genes associated with breast cancer, and many people—let's say if they've had their mother die of breast cancer or their sister, or they may have had breast cancer, and they have the genes—are telling the doctor: "Let's test the embryos for which ones have genes associated with breast cancer, and we won't use those. We'll use only the embryos that don't have genes associated with breast cancer."

What that means is that in the future if you're wealthy you can afford to screen out breast cancer genes. Diseases like breast cancer that now affect both wealthy and poor people, in the future will increasingly become diseases of poor people because wealthy people will be able to screen the genes out. Again, not all breast cancer is genetic, but a significant percentage is, so there may be less research in breast cancer treatments in the future, etc.

The question is, how do we use these technologies now, and who should decide? I should say there are other diseases like Down syndrome which cause mental disability, often severely, and many parents are using PGD for that. Some of these conditions I think are ethically justifiable in terms of screening embryos; others I think are more problematic.

The American Society of Reproductive Medicine, which is the group of in vitro fertilization (IVF) doctors who do this work, has an Ethics Committee that has come up with various statements of when these technologies should be used. They say, for instance, that it's okay to choose the sex of a child if it's for "family balancing," but they don't define that. The problem is that some people say, "Well, I have one girl, and now I want one boy." It's different if I say, "I have six girls, and I want a boy." Those morally raise different kinds of issues.

That technology is already here. It is being used every day. The gene editing is now, as I said—Dr. He Jiankui has created children. There is a Russian scientist who is planning to go ahead and do more of this, and I would guess in a few years more and more of it will be done. In other words, it has been done with the people in China.

There are questions, too, because it's not clear that there are any medical benefits of this. In other words, when there are diseases involved, we already have PGD, the screening of embryos, so we can already screen embryos and make sure that if you have a terrible mutation it doesn't get passed on to your kids. We don't need to be going in and actually clipping out the bad gene, given that doing so may cause other kinds of problems, so-called "off-target" effects, as I said.

There's a debate: Is it ever needed? Some people say, "Well, you can't produce many embryos." You probably need a lot of embryos with gene editing also. What if both people in the family have the same terrible disease? Again, PGD might be able to use or—there's a question, which again is an ethical issue: Should everyone be entitled to a child? If both people have mutations they're going to pass on to their kids, and they both have diseases, there's a question: Should we spend $100,000 to help them have a kid? Should everyone get $100,000 to have a kid? Some people say, "Look, we have people dying of starvation in the world. We have people in the United States who can't afford health care."

Infertility, some people say, is not really a disease. You can live a perfectly healthy life. As I understand, many people say it's not as fulfilling, not having a child. Some people would say you can adopt a child, but it has gotten more difficult.

In other words, it's a complex issue, but again there are questions: Should we use this technology? If so, where? Should the government be spending money on this? In other words, if it's not clear that there are going to be benefits to people, if it's going to be for in some way wealthy people adding genes associated with height or IQ or something, a socially desirable trait, should government say, "Well, we're not going to spend money on that; that's not a priority"? Again, these are ethical questions.

A problem with global governance with this is that there are many countries in the world that can do this right now. This CRISPR technology is advertised online. You can buy a CRISPR set, and you too in your garage can do it. There are people doing it in their garages. Obviously, you need an IVF clinic to get to that point, but people are doing stuff.

Even if the United States, China, and the United Kingdom say we're not going to allow it, people may go to Mexico, Ukraine, Peru, India, or Malaysia. It's hard to control it. As I said, a lot of people will pay a lot of money for their vision of a perfect child.

I should say the genetics is complicated. As I mentioned, we know that IQ, intelligence, is 50 percent genetic. We don't know which genes. People have looked at a lot of genes. The gene so far that gives you the biggest increase of IQ gives you a one-point increase in your IQ if you have this one gene. But there may be many genes in combinations. Maybe if you use three of them it would increase significantly.

Again, there is research going on, but this is a very active area in which I would predict in 5-10 years this conversation will be very different because people will be doing things, we'll know more, there will be more genes associated with socially desirable traits that people may try to manipulate, etc.

ALEX WOODSON: Speaking about global governance, this is something we're very interested in. As you said, the United States, China, and the United Kingdom, it seems like most established doctors and scientists were pretty strongly against what happened in China with Dr. He Jiankui, but as you said that doesn't stop people in Country X or Country Y from doing it.

What's the status right now of governing this type of technology to make sure that there is one standard for the world, and you don't have people traveling to far-flung places to get what sound like very risky procedures and applications done?

ROBERT KLITZMAN: Right. There's not much global governance. As I said, the leaders—really China, Russia, and the United Kingdom—have been convening meetings. Many scientists have recommended a moratorium, that we should not be implanting embryos that have been gene-edited into wombs.

The problem is, it has been controversial because they say, "We should wait until there's societal consensus." What is societal consensus on this? In this country there still are debates about abortion. Do we have consensus in the United States about abortion?

ALEX WOODSON: No.

ROBERT KLITZMAN: I think the majority of people support Roe v. Wade. Whether the Supreme Court continues it is up for grabs, and the president is much against it. This is an area where there's going to be divisiveness.

At what point do we say, "Okay, we have 51 percent of the world's support; let's go ahead and design babies"? There are questions about what means.

The other question is, if you put a moratorium, let's say because it's risky, at what point is it safe enough? In other words, we won't know what the effect is on children until we start doing it on children.

Humans are different than even dogs and chimps and baboons—and again there's hesitancy to work on primates like that—but let's say we find that it works on a chimpanzee. That doesn't mean it's going to work on a human. There already have been the first humans, but it will be very important given their risk to follow that child, and you may want to follow that child through his or her whole lifetime and look at his or her kids to see what the risks are. That's going to take a long time.

Some people say that's too long to wait, so again there's a question: If we do have a moratorium, when do we end the moratorium? When is it safe enough to start in some way on a limited scale? That's one.

The second is, there are rogue scientists and rogue countries, and you could have rogue scientists in a non-rogue country. You can have garage scientists. There's a process called mitochondrial replacement therapy, which the media has dubbed "three-parent babies." It's illegal to do in the United States, but there was a physician in the United States who was involved, and as I understand it he sent the couple to Mexico.

You have a lot of reproductive travel already. For instance, there are only three countries in the world where you can buy and sell human eggs, Russia, India, and the United States. It's illegal in all of Western Europe. But you have people from all over the world who come to the United States to buy human eggs. You can go to drop-down menus online and scroll down and choose the hair color, the eye color, the ethnicity, the religion of the egg donor, their SAT scores. The prices go up with SAT scores.

Already you have people traveling all over the world because there are different kinds of regulations on these procedures. If you're a gay couple, you can go some places and get treatment; other places you can't. There are women who "rent their wombs"—so-called "gestational surrogates"—who will carry a fetus for someone else. It's legal in California, it's illegal in New York, it's illegal in all of Western Europe to pay someone to do that.

Again, even for 10-20 years with assistive reproductive technologies, there has been huge variation between countries and people traveling. In Germany for a while it was illegal to screen embryos, so women would go abroad and have their embryos screened and come back pregnant to Germany. So even if you have a law saying you can't do this in Germany, people go across the border to whatever country and do it.

I think this suggests in many areas of ethics, in bioethics—I run the Bioethics Program at Columbia—we have had immense advances in technology in the past few years, in the Internet, in cellphones and smartphones, and in assisted reproductive technology and genetics. Our ability to think through issues of the ethical, legal, social, and regulatory implications has been lacking. We have not been ahead of the game; we've been behind the curve. We are still struggling to catch up and figure out what should the regulatory framework be; what can it be?

The United Nations is not as strong as many of us think it should be. We can't prevent wars; we're certainly not going to be able to prevent people from going across borders to have things done that are in their own body, I think. But again, I think the concern is: are people going to create super-races?

The other concern, by the way, is rogue scientists who say, "I'm going to make a super-bacteria or a super-malaria or super-mosquito." It's a new kind of germ warfare: "I'm going to send mosquitos with terrible malaria into your country if we're in a war," and will have gene edited the mosquitos or gene edited the malaria or gene edited to bring back smallpox. CRISPR and gene editing also have issues internationally in ethics, in terms of it potentially being a weapon of mass destruction.

ALEX WOODSON: The WHO set up a committee to look at some of these issues in early 2019. Do you think something like that is a step in the right direction?

ROBERT KLITZMAN: Yes, absolutely. WHO getting involved is important. WHO unfortunately has not been a very powerful voice. If WHO comes out with something, and the United States doesn't like it or China doesn't like it, I don't know the value.

The bottom line is there needs to be more discussion and assessment of these issues, and I think WHO putting together a group is critical. But as I said WHO recommended the moratorium, and there has been pushback from some scientists, saying, "What does this mean?" When do you think you'll really get "societal consensus?"

I think absolutely WHO plays an important role here. I think the national science associations in various countries play important roles. The more discussion and efforts to figure out when is it safe enough, when is it still too risky, how long should we follow people, what should we use this for? Again, the case of He Jiankui using it to prevent HIV transmission from a father with HIV did not make sense because there are other ways of preventing such transmissions. The question is, When should it be used?, and there is a debate about that.

I think it's terrific that WHO is addressing the issue. There are lots of scientific complexities and ethical complexities that remain to be tackled. Hopefully, they'll begin to address those.

ALEX WOODSON: Last question. This is something that you've been interested in for a while. You were at Carnegie Council four or five years ago talking about a lot of these same issues. You did a couple of other interviews as well for us, which were great and which we'll link to in the transcript.

I guess we have your answer already, but I just want to push a little bit further. Since this incident in China last year has happened and a few other things that you've been talking about, have you seen the conversation around this pick up around scientists or around doctors, maybe around the general public? Is there starting to be momentum to have these kinds of conversations that you hadn't seen maybe 5–10 years ago?

ROBERT KLITZMAN: Absolutely. He Jiankui's announcement in November last year, almost a year ago, was seismic. It really shifted the ground because it made all of this very real. The fact that you could do it, people could do it, makes it very immediate. So there's much more attention to it as an issue.

Some of it is, let's begin to think, What do we need to do to set up the first human experiment? Another issue is, of course, that in the United States there maybe pushback given views of conservatives and pro-life people, but China may go ahead, Great Britain may go ahead.

So there's a complicated political discourse that may happen, even in this country, of do we want to cede the ground? People, who may say—there's a "yuck" factor. People say, "You're designing babies? Yuck!" But then they'll have to face the question, "Well, do you want China to get ahead on this or some other country?"

But to answer your question, yes, there's much more attention to it and WHO getting involved. I think it's still largely uncharged territory, and I think we need more research in certainly plants and animals and even in human embryos without implanting them into the womb to characterize the risks and to understand those risks, to understand more about genetics, etc.

At the same time, I should say that another concern I have—I wrote about it in Designing Babies—even with pre-implantation genetic diagnosis and as I mentioned buying and selling human eggs, in the United States the IVF industry is called the "Wild West." It's relatively unregulated compared to Europe, and I think this bodes poorly for our ability to control or oversee what happens in the future.

So if there are doctors who do it in this country, maybe they'll just send their patients to Mexico or something. There have been a lot of experimental procedures that have been widely used by IVF doctors that turn out to not be effective and too often be harmful. For instance, there's a process called intracytoplasmic sperm injection (ICSI), in which if a man has a low sperm count, you can take sperm and inject it right into an egg. This is made for men who don't produce many sperm.

Well, it's now used in two-thirds of all IVF cases, and it turns out it doubles the risk of the kid having intellectual disability and severe intellectual disability, but it's still used on two-thirds of all patients in the United States who undergo IVF, and most patients don't know that and don't understand the risks.

Probably because IVF is generally not covered by insurance, there's not much oversight. The Centers for Disease Control (CDC) tries to collect data, but IVF clinics are not required to provide data to the CDC. It's voluntary. Clinics that don't provide data have been increasing their business.

I think we need to have more data, find out what's going on, have data reporting be required by CDC, and have more data that's reported, etc. Again, I think this should also shed light on the broader set of issues around assistive reproductive technologies that again cost a lot of money and help the rich more than the poor.

I think the fact that if we don't regulate the IVF industry now in which use of germ editing will occur, if and when it does bodes poorly for our future ability to govern it and oversee it, and I think this also needs attention.

ALEX WOODSON: These are issues that we'll be following very closely over the next few years.

Thank you very much for speaking with us today.

ROBERT KLITZMAN: Yes. Thank you.