基因编辑管理与贺建奎博士，与杰弗里-卡恩合作

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

This week's podcast is with Dr. Jeffrey Kahn. Jeffrey is the Andreas C. Dracopoulos Director and Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy at the Johns Hopkins Berman Institute of Bioethics.

This is the second in our series of gene editing podcasts. A couple weeks ago, I spoke with Columbia University's Dr. Robert Klitzman. He gave us an overview of the technology and some ethical and governance issues. This week, Jeffrey and I spoke mostly about governance.

Before we get to the talk, I just want to share some background. Jeffrey and I speak about Dr. He Jiankui and his extremely controversial work last year in China. Using CRIPSR-Cas9 technology, Dr. He modified human embryos to be HIV-resistant. Then, using in-vitro fertilization, he implanted these embryos into a woman. In October 2018, that woman gave birth to twins, the world’s first germline genetically edited babies.

As you'll hear, about one year ago this research was formally presented at a conference in Hong Kong that Jeffrey was attending and speaking at. We talk about why this was so historic and troubling, what the atmosphere was like at the conference, and how this has changed the research and conversations around gene editing in the past year.

I also spoke about Dr. He in detail with Robert Klitzman, so I urge you to check out that podcast.

For now, here's my talk with Jeffrey Kahn.

Thank you so much for coming by and speaking today. I'm looking forward to this.

JEFFREY KAHN: My pleasure. Thanks for having me.

ALEX WOODSON: Of course. Just to get us started, I talked last week with Dr. Robert Klitzman from Columbia University. He gave us some definitions and talked about some ethical concerns. I'd like to focus more on governance today, though, with you.

What is the current status of the governance of genetic engineering? I know that's a big question, but we can do an overview and then get a little bit more specific.

JEFFREY KAHN: Sure. There has been a long history of trying to do genetic modification of humans using different tools over the course of close to 40 years now, and that process—so long as it's limited to somatic cell alteration; that is, the cells in your body that are not your germ cells, not your sperm or eggs—has been attempted and now finally seen success for, as I said, about four decades. There's a very well built-up process of oversight and control, including the Food and Drug Administration (FDA) in this country and the equivalent regulatory agencies around the rest of the world where that work is being attempted, human subject protection.

There are also special oversight bodies. In the United States it's called the Recombinant DNA Advisory Committee of the National Institutes of Health (NIH), which actually just was sunsetted because the techniques it had used for "human gene transfer"—as it's called—have been in use for so long and are so well understood that everybody thought, We don't need to have this special oversight anymore.

Then, genome-editing tools like Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) came along, and everybody's scrambling to think, Well, maybe that was a little premature and not clear.

So long as it is in the somatic domain, there's a very well built-up governance structure. The thing that is very difficult and is causing us all a lot of consternation and has a lot of work being devoted to it is the attempt to do the same thing in germ cells in a way that would create a change that would not only affect the person but the person's offspring and the offspring's offspring and into future generations. That's called a "germline modification."

If that's attempted—which we think may have actually happened in China—then we need a different governance structure for that. The answer to that question is, it's all over the place, so there is not this well built-up approach that we've had a lot of experience with, with somatic gene transfer.

The answer in the United States is it's currently illegal. It's prohibited because the FDA is not allowed to receive a license application to even start a clinical trial. In the United Kingdom it's not permitted, but they have a mechanism by which it could be overseen if they decided it could go forward. In many other parts of the world there just aren't any rules. So it's a little bit of the Wild West at the moment, which I think is the very short answer—which is probably what I should have said first, rather than at the end of your question.

ALEX WOODSON: You mentioned China, and we'll get into what Dr. He Jiankui did about a year ago. Are there no rules for gene editing in China? That's a very big market. There are a lot of scientists working on this issue.

JEFFREY KAHN: It's a little unclear is the answer to that question. When Dr. He, as you rightly pointed out, announced—it was almost exactly a year ago; it was right after Thanksgiving in 2018, and we're taping this right before Thanksgiving 2019—we were all dumbfounded that this had happened, for a lot of reasons which we can talk about if you like. The first thought was, Well, how could this happen anywhere, including in China? There was a lot of waiting to see what the Chinese authorities would say.

Subsequent to the announcement, and when the world reaction was distress and 100 percent condemnation, the Chinese government said that he broke numerous laws but haven't articulated what those laws were, but it seems clear that they don't want it to happen again. I think there's an expectation that there will be much more strict and clear governance coming out of China, but it hasn't happened yet.

ALEX WOODSON: I want to talk a little bit more about Dr. He. You were there actually at the Second International Summit on Human Genome Editing at the University of Hong Kong. There is a YouTube video before that announcement, there are some news articles about it as well. So you knew this had happened already when you were sitting there at the conference.

JEFFREY KAHN: Yes. That's right.

ALEX WOODSON: But it still must have just been an interesting atmosphere, to say the least. If you could take us there, it's a very big moment in this issue. What was that like for you?

JEFFREY KAHN: Yes. It felt like we were experiencing history, living through a historic event. That meeting, as you rightly pointed out, was in Hong Kong, and because it was right after Thanksgiving we all left on Friday or Saturday after Thanksgiving and arrived on either Saturday or Sunday. I think whatever day the meeting started, the day before this announcement happened, we were all physically already in Hong Kong. In fact, I was not only attending, I was a speaker.

Everybody on the program was staying in the same hotel, including Dr. He, and so we all saw each other. This announcement happened, and it turned what we thought was going to be a little bit of a humdrum meeting into this electric atmosphere, as you rightly intuited.

There was a lot of talk in the hallways and in the breakfast room, and "JK"—as he's called in English—was around, and everybody was saying: "What in the world? Why did not you tell anybody you were doing this? How did you keep it secret? Why do you think it was acceptable to do?" He was very defensive, and then he disappeared. We were all in the same hotel, as I said, and then he wasn't there anymore.

The meeting began, and there was a scramble to figure out how to deal with this. This announcement happened, as you pointed out, not through a journal publication or a presentation submitted in advance to a conference, but rather through a series of YouTube videos and two articles, one in the MIT Technology Review, and one in an Associated Press story, so there was no typical scientific discussion.

There was a lot of question about whether it was even appropriate to give him a spot on the program to talk about this, because you don't give a platform to unethical research. That was one of the concerns. The other was: "Well, we're all here. He clearly released it at this time for a reason. This is our opportunity to quiz him, grill him, and call him to account. If we don't do it now, we may never see him again."

So the decision was made by the planners—I wasn't part of the planning group—to alter the program a bit and create an hour on the program for him to make a presentation. Up until the moment he walked on the stage, it wasn't clear that he was even any longer in Hong Kong, because he disappeared, as I said.

He was announced. There were 300 or so journalists alone in the room, and it took a while—it seemed like a few minutes, but it was probably a minute and a half—between the time he was called to the podium and he finally strode out from one of the side doors onto the stage, and there was audible gasping. It was really one of these electric moments.

That was the only time there has been a presentation of the "data" because he showed PowerPoint slides, but there has never been a publication of that data. Everybody—including me—had their cellphones out, their mobile phones out, and were taking pictures of each of the slides as they were presented, because I think we all thought, This is probably the only chance we'll have, and that became true.

After his presentation, there were two members of the planning committee sitting on either side of him who then effectively grilled him in public about why he did it, why he did it this way, why he thought this was a good idea. He was very defensive and thought that he—at least he said—had followed rules, which seemed patently absurd to all of us in the room.

He did not comport himself terribly well, I would say, in answering the questions. And then he disappeared, and he literally has not been heard from since.

That has caused the international science oversight, science policy, ethics, and genome-editing community to scramble about what to do about this. We can talk about what happened before that, because there had been a fair amount of work and criteria articulated and recommendations made, which we thought would have prevented Dr. He's actions, but obviously they weren't enough.

ALEX WOODSON: Let's talk about that. So this surprised you and surprised a lot of people in the community when this happened. You didn't have any idea that this was being worked on in the run-up to last November?

JEFFREY KAHN: Yes and no. Among the things that are important to understand about the story is Dr. He is not a charlatan. He was—and I guess in some sense still is—a member of the community of scientists who are working on genome editing using these tools. It was known that he was using these tools in human embryos but only in vitro, only in the laboratory. He would make presentations at small meetings about his work.

What he did not disclose—but was doing all the time he was giving these presentations—was that he was implanting embryos which he had modified into women to get them pregnant. That was the shock. It wasn't as if he was working on a desert island someplace. People knew he was doing this work, but he lied, he kept secret the fact that he was implanting these embryos into women.

That was the shocking part, all in the context of an international commission—which I had served on—convened by the National Academy of Sciences in the United States, the Royal Society in the United Kingdom, and the Chinese Academy of Sciences in China, interestingly enough, and with membership from all over the world, which made recommendations about when, if ever, it would be appropriate to go forward with clinical trials of genome editing in human embryos.

Ten criteria would have had to have been met, which he ignored. It wasn't like he didn't know about that. He was part of the community of people who were paying attention.

It's a question about what do you do when somebody in the community acts out. He's a rogue versus a charlatan, which is an important distinction. It's really hard to control rogues is the upshot. Among the things you have to ask of the governance processes that are now being worked on it is what, if any, effect they will have on that kind of behavior, and how would it work?

ALEX WOODSON: Yes. What happened after this? I know you're a member of the International Commission on the Clinical Use of Human Germline Genome Editing. That's a different commission than the one you were talking about before?

JEFFREY KAHN: It is.

ALEX WOODSON: I know you're working through this, and there's the World Health Organization (WHO) committee that we can talk about. What has been happening in the past year to make sure something like this doesn't happen again?

JEFFREY KAHN: Maybe to even go back a little further—and I'll be quick—because you mentioned that Hong Kong was the second, the first International Summit on Human Genome Editing was in 2015, and the second was in 2018. In between was the committee I mentioned a second ago, which issued its report on Valentine's Day, February 14, 2017. So sandwiched in between was an 18-month-long process of an international expert committee being convened, and we met numerous times in Washington and Paris, if I remember correctly, and issued this report, which we thought would have answered the question.

Then, the 2018 summit was to take stock of what had happened, mostly in the scientific community, between the 2015 summit and the second in 2018, and then this announcement from Dr. He. It made everybody think that the 2017 report that I mentioned wasn't explicit enough, which is the short answer to your question.

Some people have decided that the answer to the question is we need to be more explicit and answer the question about what nuts and bolts—stepwise process—would have to be met in order to go forward with this use in a clinical context. The WHO convened a commission because of its stature as an international body related to health to answer that question about the specifics for all of genome editing in humans. Then the commission on which I serve was convened by the science academies of 35 countries to focus only on the question of germline modification in humans.

The work of those two commissions is ongoing. The one I'm on is supposed to finish its work around April, and that report will then be taken up by the WHO and somehow included in their deliberations and hopefully their recommendations. So in some sense, these two commissions—the WHO and the one that I'm serving on—are seen as a little bit of a do-over of the 2017 commission that issued its report, or at least a deeper, more detailed articulation than the 2017 report did.

ALEX WOODSON: You just got back from London. You were meeting with this commission that you were mentioning. You talked about it in kind of broad terms. What specifically are you looking at to make things a little bit more explicit to govern gene editing in a more close fashion, I guess you could say?

JEFFREY KAHN: Yes. It's really to articulate the steps and the policy process and the regulatory processes for a clinical trial going forward using this technology in a human embryo, so very specific.

The earlier recommendations had been much more about principles for governance, with the idea being that you can't create international directives. We don't have a mechanism for that. So you need to create guidelines or guardrails or something to that effect, with the idea being that individual countries would then take up the job of making regulation.

That didn't happen, partly because there wasn't that much time, and now we're trying to actually put more meat on the skeleton effectively and say, "You would need to go through these steps, in this order, with this kind of result in some kind of confirmed way with an international oversight body saying, 'Yes, it's time to move from step one to step two and from step two to step three and so on.'"

We haven't articulated what those steps are, and I shouldn't talk about what the deliberations are until we're done, but that's the work. We're going to actually be much more down in the weeds, as it were, of articulating what a clinical trial approach would look like and with some expectation that any country that would allow that research to go forward would follow that stepwise process.

ALEX WOODSON: To go back to the 2017 report, which as you said was a little bit higher-level, that's the one where there were seven principles for the governance of human genome editing?

JEFFREY KAHN: Exactly.

ALEX WOODSON: I think you said that in some sense the work you're doing now, the work these commissions are doing now, is a bit of a do-over of this report, but I assume that these principles are still very much things that should be followed for scientists and researchers. I don't think we have time to get through all of them, but are there any that you'd like to highlight that you think are especially applicable now, a year after the incident in China?

JEFFREY KAHN: I think they all remain applicable, and the idea was, "from principles derive responsibilities." The way that happens is pretty society-specific.

Among the principles are that individuals get to decide for themselves about control of one's body. That's a very high-priority principle in the United States and other liberal democracies, and not so much in China. China might say, "Okay, yes, we acknowledge that people should decide for themselves about some things," but not in the way that in civil societies, like the United States or the United Kingdom, that's a very highly protected priority.

The idea was, "We will articulate these seven principles." It's about: be careful going forward; fairness in terms of access to the technology as well as the way the burdens and benefits of the technology are distributed. These are all pretty high level and hard to argue with. It's activating them, turning them into things that we would do, which we thought needed to be left to the countries, that it wasn't for an international committee of experts to articulate that. No one would accept it, for one, and second, it didn't seem appropriate.

What we learned was that it's not enough to do that. To articulate high-level principles is insufficient to get the job of governance done. Not that we were trying to do governance, but it showed where the gap or gaps might be.

It's true. There are significant gaps in governance for this kind of technology applied to humans. In fact—and we can talk about this—there is really only one model in the world of a governance system that's ready for this, which is in the United Kingdom. Everyone else in the world is going to have to create something pretty much new.

ALEX WOODSON: What is the United Kingdom doing? Connected to that, I was watching a talk that you gave about a year and a half ago. You said that the United Kingdom does a much better job of public engagement than the United States does on this issue. Maybe those two are connected.

JEFFREY KAHN: They are.

ALEX WOODSON: What is the United Kingdom doing, and how could that point the United States in a better direction?

JEFFREY KAHN: Those are really good questions. I should say that public engagement was among the principles that we articulated in the 2017 report. And those words, everybody nods and says, "Yes, that makes sense," but it's very hard to think about how to do that, hard in a country of 300 million, like ours. Think about how to do that in China, where they're pushing 1.3 billion. We can say "engage the public," but doing that is a little more challenging to figure out.

The United Kingdom has had a longstanding oversight body called—it sounds a little Orwellian, but bear with me—the Human Fertilization and Embryology Authority (HFEA), which was created when the first in vitro fertilization (IVF) birth happened, Baby Louise Brown. People may remember the first IVF baby.

They made what turned out to be a very prescient decision to have a regulatory authority, whose job it is to review applications for license to create a human embryo for any purpose, whether it's for implantation to help a woman get pregnant or for the purpose of doing a particular kind of research. Without a license from the HFEA, you may not go forward in the U.K. context. It's easier to create something like that in a system where there's a National Health Service, like there is in the United Kingdom, but even in the private sector—there is a private health care sector in the United Kingdom, and there is reproductive technology in the private sector in the United Kingdom—those practitioners also have to apply for and receive a license from the HFEA to go forward.

That has created a mechanism by which even controversial kinds of reproductive technologies—and maybe it would be important to say at this point genome editing applied to human embryos is a combination of gene-transfer or gene-therapy techniques and reproductive technology in combination, so the HFEA would be invoked—but even controversial kinds of reproductive technologies like genome editing in embryo would be something that they could review and decide whether to go forward and do so in a very controlled way, like one at a time: "Here's one license to do this once. Let's see how it goes. Until such time as we are confident about the way it went, we won't issue another license."

In the United States we don't have a mechanism like that, so at the moment, as I mentioned before, the Food and Drug Administration in this country is prohibited from receiving even an application to start a clinical trial for anything that would modify a human embryo in a way that would lead to a heritable—an inherited—genetic change. So it couldn't be done.

But let's assume that at some point that is lifted. Once it's through the FDA process in this country, it's out in the public, and there's very little that our system can do to control its use in whatever way practitioners think is appropriate. It's sometimes thought of in the drug world as "off-label" prescription. Physicians as professionals have a lot of discretion about, "I think this drug would be good for you to use with this diagnosis," even though the label doesn't say it's approved for that.

We have a bottleneck to get through that FDA process, but once you're through the bottleneck it's out; the genie is out of the bottle. The HFEA in the United Kingdom has a way to control in a very careful way a much longer pipeline, if you want to think about it as a metaphor like that.

ALEX WOODSON: Is part of what you do talking to policymakers, talking to people connected to government, to try to follow the U.K. model or do something similar?

JEFFREY KAHN: Or at least learn the positive lessons from the U.K. model.

ALEX WOODSON: Yes.

JEFFREY KAHN: You asked me before about public engagement, which I didn't answer. That's another piece. The HFEA has a mechanism—and they have used it actually relatively recently for a very controversial reproductive technology called mitochondria replacement, which I and many others think is a heritable genetic change which is introduced to an embryo through the genetic contribution of effectively two women to make one egg, which is then fertilized and implanted.

To go forward with that, they decided that they needed to do a significant public engagement undertaking, and they did it. Over the course of more than a year, they went all over the United Kingdom, they held townhalls, they did radio programs, they had websites, they did all sorts of stuff and got feedback from the public in a way that it would be hard to argue wasn't a robust discussion with interested members of the public, and then they decided to go forward, and how they went forward was influenced by what the public input was.

Public engagement can be anything from, "Let's have an exhibition at the science museum," where you teach people or people learn about science, but that's more like science communication, to "Let's ask them what they think." If you do the latter, ask people what they think, you have to be clear about what you're going to do with the answers.

I think part of what people in positions of authority when it comes to policy making in this area is "be careful what you wish for," because if you ask people, they'll answer you, and then you have to be willing to follow through in some way about what they've told you. If you just say, "Thank you very much for your opinion," and do something you would have done anyway, that's not public engagement. I don't think we've figured out quite yet how to take stock of public opinion and public input and how it should influence what we do as a matter of science policy in this country—and most others, actually.

ALEX WOODSON: I'd like to end with a philosophical question that will probably be very difficult to answer, but that's okay.

JEFFREY KAHN: I hope not. I'm a philosopher by training, so that's going to make me look bad if it's too hard for me to answer.

ALEX WOODSON: This is something that Dr. Klitzman brought up, and it's something I've seen mentioned in many places. Dr. Klitzman used the example of the issue of abortion in the United States, something that we don't have consensus on.

I think gene editing will fall into a similar category once this technology is maybe more known by the public. I don't think everyone is always going to agree on the right cases to use it. And look at the world: You're going to have different countries that have different thoughts about this and different ways of doing it. How can we do anything close to governance when there's not going to be any consensus over these deep ethical issues?

JEFFREY KAHN: That's a great question. One thing we did not talk about—we can do it now—is what kind of line drawing would you engage in if you were trying to craft governance in this area?

Among the things that people working on ethics and gene therapy have talked about for a long time is, it's one thing to cure or prevent or avoid disease, it's another thing to enhance traits, which sounds good. Everybody can get their head around that. It turns out to be a much harder thing to define what falls into which of those two categories.

I'll credit one of both Dr. Klitzman's and my colleagues, Alta Charo at the University of Wisconsin Law School, who was one of the co-chairs of the 2017 Commission, who said, "Sometimes you don't have to know exactly when the sun sets to know when it was light versus when it's now dark, and so let's focus on the things we know fall into the two big categories."

If we were to say, "You can only use this technology to prevent a life-threatening disease which you know will befall the person if they have this genetic mutation," that would be a way for us to answer. That would be hard for people to argue with.

You want to also make sure that what you're doing is what you think you're doing in a way that's pretty close to 100 percent predictable. You can't say, "Well, 90 percent of the time it's going to work, and another 10 percent we're going to get an off-target mutation, and that's just too bad." We can't accept that in the context of a heritable genetic change.

If you add together "how precise and certain do we have to be" with "where the limits should be about the line between preventing disease versus enhancing somebody," you start to see where the line would be drawn. That feels like something that most parts of the public should be able to get behind.

The other thing to say is that this falls into the same kind of philosophical discussion as abortion in the following way, which is, it's about reproductive control and how we should think about individuals making decisions about their reproductive futures. What's interesting is in the use of reproductive technology we don't put obstacles in front of people in the way we do when we talk about abortion. There is bipartisan support for IVF and other technologies that have followed on IVF to help people where IVF isn't sufficient.

In some sense, this technology is just a follow-on to IVF followed by intracytoplasmic sperm injection, which is one sperm injected into one egg, which also sometimes invokes pre-implantation genetic diagnosis, which is biopsying the embryo as it's developing in vitro outside the body, and you do genetic testing on that before you implant it. So there are these follow-on technologies, and we have not said: "That's it. That's too far, and people shouldn't be allowed to do that for philosophical reasons."

I think it's going to look more like reproductive technology than it is like abortion. That's my prediction. We'll see whether that's borne out.

In some cultures, fooling around with human embryos will not be accepted or acceptable. Germany is one where they just won't accept that, and that owes to the terrible history of the Third Reich and how they have implemented policy to make sure they never do anything unethical in relation to human beings again. Italy likely will I think have a hard time as a matter of policy because of the very strong Roman Catholic influence in their government and their governance.

I think you'll have those cases, but that's not going to be special for genome-editing tools, that's just about reproduction. I think it will look a lot like how we think about reproductive technology in the places where those technologies are permitted.

ALEX WOODSON: I know I said last question, but just one more: What should people who are interested in gene editing and the governance and ethics of it be looking for in the next year or two? Are there more conferences coming up? Are there papers to look out for? What should we be watching for?

JEFFREY KAHN: Those are great questions too. The meeting that I just came back from in London, half of it was a public workshop. That will continue. The WHO committee—and I don't remember whether we have one more, but I would watch for that. The next meeting I know is going to be in Washington in January for my commission.

There's a very healthy literature already starting to come out in relation to these questions, but it's sort of prospective because the governance work is happening, so a lot of it is trying I think to steer and influence what the thinking is about the people who are sitting on these commissions.

And I would say watch for the media because Dr. He may have gone quiet and under the radar, but there are others. There's a guy in Russia—Denis Rebrikov is his name—who has suggested that if the Russian government either permits it or doesn't make it impermissible, he's willing to offer genome editing of embryos to people who want to come to Moscow and have him do it.

I would say watch to see what happens in this space. He is not just in an implicit way but explicitly thumbing his nose at some of these governance efforts. It's like, "Try to control me. Good luck with that." I think that's part of the evolving story here. How successful will governance be? I think, is something to watch for.

ALEX WOODSON: Okay, great. Thank you so much for talking.

JEFFREY KAHN: It has been my pleasure.