By Gary Evans, Medical Writer

A World Health Organization (WHO) panel formed in the wake of highly controversial human embryo research in China is calling for the creation of a “central registry on human genome editing research to create an open and transparent database of ongoing work.”1

After an initial two-day meeting in March, the WHO committee agreed “that it is irresponsible at this time for anyone to proceed with clinical applications of human germline genome editing,” according to the organization’s statement. The panel “has invited all those conducting human genome editing research to open discussions with the committee to better understand the technical environment and current governance arrangements, and help ensure their work meets current scientific and ethical best practice.”

Plans call for the committee to gather information from a wide range of sources with the goal of developing recommendations for “a comprehensive governance framework that is scalable, sustainable, and appropriate for use at the international, regional, national, and local levels. The committee will solicit the views of multiple stakeholders including patient groups, civil society, ethicists, and social scientists.”

The lone U.S. member of the panel is R. Alta Charo, JD, Warren P. Knowles Professor of Law and Bioethics at the University of Wisconsin. She declined comment for this story when reached as the panel readied to hold its initial meeting.

In originally forming the panel, WHO stated that “the recent application of tools such as CRISPR-Cas9 to edit the human genome have highlighted the need for the development of standards in this area.”2

At a meeting in November 2018 in Hong Kong, researcher He Jiankui announced he had genetically modified twin embryos to make them resistant to HIV infection. Although the research community was initially skeptical, a Chinese state media report later confirmed that the gene-edited twins babies had been born.3 The report noted that Dr. He “seriously violated” regulations and could face charges. The researcher claimed to have used CRISPR-Cas9 to disable the CCR5 gene that makes the protein HIV needs to enter cells. As this issue went to press, the incident remained under investigation by various authorities and there was still some confusion about what exactly had transpired.

“Dr. He says he created two kids. I assume he did, but who knows?” says Robert Klitzman, MD, director of the masters of bioethics program at Columbia University in New York City. “I think this WHO panel is needed. There are risks in doing this research now, and one issue is rogue researchers. Someone could do this this in their lab in another country.”

There will be those who seek out gene-edited human embryos, opening a path of global dispersement for research conducted without adequate oversight and regulation.

“We have global reproductive travel now,” Klitzman says. “There are only three countries where you can buy and sell human eggs, which are Russia, India, and the United States. People come from other countries, and laws vary between countries. If something is offered in a particular country, people may go there to get it done.”

The risks of this type of research include “off-target” effects of gene editing. “A researcher may try to take out just one part of a gene but accidently affect other nearby genes. Dr. He has been criticized for not being more precise in the DNA affected,” he says.

There also could be unintended consequences if researchers edit a gene without realizing it has more than one function.

“You don’t want to be knocking out a gene that causes cancer if it turns out you are going to have [increased risk] of intellectual disabilities,” Klitzman says. “We don’t know enough about these possibilities, I would argue.”

Another issue is long-term effects, which would have to be tracked over time to see whether the gene editing had some downstream consequences for the baby. For example, researchers are looking at the long-term risks of intellectual disabilities in babies born via in vitro fertilization (IVF), he says.

“The baby is born and is OK, but eight years later when they are in the second grade, you start to see problems,” Klitzman says. “We need to have follow-up over time once this [gene editing] begins to happen. You don’t want to roll this all out at once. We need to be very cautious in doing this research on embryos.”

‘The Very Core of Who We Are’

Craig Klugman, PhD, is a bioethicist and member of the IRB at DePaul University in Chicago. IRB Advisor asked him to comment on the implications of this emerging research for U.S. IRBs. This interview has been edited for length and clarity.

IRB Advisor: How significant is the formation of this WHO oversight panel for human embryos in gene-editing research?

Klugman: It’s needed because of Dr. He’s announcement. There had been an unofficial moratorium on gestating embryos that might be edited on an international level, and clearly asking people to volunteer to do something was insufficient.

The WHO recognizes that research is going to go ahead and there are a number of groups around the world who are doing gene editing work. At the same time, they recognize that this is a very fundamental issue of importance to all human beings. It is at the very core of who are and what our future will be. We need to look at this from an international perspective. This is not something that a single country is going to be able to say, “In our country, without our political borders, this is what is acceptable and this is what is not.” It really does need to be worldwide effort because any [human genome] changes could have repercussions all over the globe.

IRB Advisor: One of the risks cited is genetic changes that can be inherited by future descendants. Is this research on the horizon?

Klugman: That is very likely. In genetic engineering, we say there are two types of cells — somatic cells and germ-line cells. We could take a born person and change a cell in their body on the gene of an organ to make up for a disease state. Maybe they don’t produce a [needed] protein or maybe they produce a bad mutation. That could be fixed, and it would just remain in that one individual. But in germ-line engineering, we are changing things in cells that could be passed on to future generations. This is more challenging because in some of the work we are seeing, we don’t know if it will be passed on or not, but there is a high likelihood that it will.

IRB Advisor: The WHO is moving rapidly on this, but there is some concern that the proverbial genie is now out of the bottle.

Klugman: There is a lot more international collaboration happening. Even if somebody on your campus or in your institution is not doing this research, they may be working with people who are in other countries. In some sense, there’s a lot of national pride in doing research. Now that we know this work is going on in other countries, it is likely more researchers in the U.S. are going to be interested in doing this.

There is a group in Oregon already working on human embryos; they were just not planning to gestate the embryos after the gene editing. There is a group in New York that just announced they were interested in doing this. I think we are going to see that this is an area of research that people more and more are going to jump into in order to see themselves as competitive in the international scientific realm.

IRB Advisor: You note that Dr. He consulted with several researchers — including some in the United States — although they may not have known he was actually going to proceed with gestation of gene-edited embryos. What are the implications of such consultations for IRBs?

Klugman: From what I understand, U.S. IRBs were not involved because no research was conducted at their institutions, nor did the researchers participate in conducting the research in China. They were just consulting on it. Under the regulations we have, you don’t have to let an IRB know if you are just consulting because there are no human subjects in consulting. It raises an interesting question. The IRB is about protecting human subjects, so if you are not working with human subjects it doesn’t fall under an IRB. Academic freedom says you can work on anything you want, especially if you are just talking ideas with someone. So it’s one of those things that, as it happened, would not have fallen under the IRB at the institutions where the consultants were located.

IRB Advisor: With more interest now in this research, is the Common Rule sufficient to prevent such an extraordinary incident from happening here?

Klugman: The short answer is no because under the U.S. rules, an embryo is not considered a human subject. So institutions that do a lot of embryo research have established what are called Embryonic Stem Cell Research Oversight (ESCRO) committees. Those are bodies that do a lot of this work and have been set up, often voluntarily, to take a look at this. But under the Common Rule, these are not human subjects. They are also not animal subjects, so they don’t fall under either.

I think IRBs need to — even though it is my understanding the Common Rule does not require them necessarily to review this work — talk to their institution about how to ensure that there is some review in this area.

IRB Advisor: Could this WHO panel resolve this somewhat and make recommendations that would be helpful in the U.S.?

Klugman: Yes, but remember the Common Rule does not have a great effect outside the United States, so they are probably not going to look at the U.S. specifically. There is only one person from the U.S. on the WHO committee. I think they are going to look at the broader issues of rules and guidelines internationally. I don’t think they are going to drill down to the regulatory details because they just can’t do that for every international audience.

IRB Advisor: It seems the recent research in China was a call to action.

Klugman: I think the difference here with what we saw in China is if you are doing embryo research — and you are not planning on transplanting it for gestation — it wouldn’t fall under the IRB.

What happened in this particular case is the transfer of an edited embryo into a woman who wanted to be a mother. So, there is a question whether that would come under IRB or not because in IVF, there are no human subjects if you are just doing an IVF transfer. Does an edited embryo change that? If it does, it becomes a new way of looking at things that previously were just a clinical judgment.

IRB Advisor: How do you think that conundrum should be interpreted?

Klugman: I would want to see more [IRB] oversight in that circumstance. Doing the work in the laboratory is one thing, but transferring the embryo into a woman for gestation is another step. There is a difference between finding knowledge and creating a human being.

IRB Advisor: This case seems to reinforce the perception that expected research norms can be suddenly exceeded.

Klugman: This is not the first case of research being done that people have questioned. We have our historical examples of human subject research abuses, but it is usually with already-born people. The embryo occupies a strange position, at least in the U.S., where it is not a person but it is more than just a cluster of cells or tissues. How you think about that may depend on your politics and your religious beliefs, with the exception of these ESCROs, which are a great model. I think we are presented with a unique challenge at this point in time.

REFERENCES

1. World Health Organization. WHO expert panel paves way for strong international governance on human genome editing. March 19, 2019. Available at: https://bit.ly/2FpRciV.

2. World Health Organization. WHO establishing expert panel to develop global standards for governance and oversight of human genome editing. Dec. 14, 2018. Available at: https://bit.ly/2G44AZ2.

3. Ramzy A, Wee SL. Scientist Who Edited Babies’ Genes Is Likely to Face Charges in China. New York Times Jan. 21, 2019. Available at: https://nyti.ms/2UMdmB5.