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By Gary Evans
Chinese twins born in 2018 face a future fraught with potential health complications after a rogue gene-editing experiment that “basically broke every single principle of ethical medical research,” an expert on the case tells IRB Advisor.
“This is a cautionary tale for everything that can go wrong scientifically and ethically,” says Kiran Musunuru, MD, PhD, MPH, a cardiologist and the director of the Genetic and Epigenetic Origins of Disease Program at the University of Pennsylvania. “This experiment on unborn human beings — which is effectively what it was — does not meet the definition of a clinical trial.”
Musunuru reviewed a copy of the unpublished research paper obtained by the MIT Technology Review.1,2 The lead researcher, He Jiankui, announced in November 2018 at a scientific meeting in Hong Kong that he had genetically modified twin embryos. Then, at the Southern University of Science and Technology in Shenzhen, China, Dr. He said he used CRISPR-Cas9 to edit the human genome to confer resistance to HIV infection.
The experiment shocked many in the scientific community, who cited widespread agreement that there were too many unknowns to proceed with CRISPR in human research subjects. Dr. He faced legal consequences from Chinese authorities, but his fate is unknown, Musunuru says.
“His lab was closed immediately, and he was under house arrest for quite a while,” he says. “Whether he is still under house arrest is unclear. The Chinese government has stated publicly that he violated laws, although it is not clear what he violated and what were the penalties.”
Dr. He announced the babies were born healthy in a video posted online but the details are scant. Some remain skeptical of the research and its purported outcomes.3,4 Based on the genetic information in the unpublished paper, Musunuru says the experiment may lead to downstream harms to the children.
“CRISPR is like fire,” he said. “If you are very careful and keep it well-controlled, it can do a lot of good. If it gets out of control, it can cause a lot of harm and damage.”
The World Health Organization (WHO) formed an oversight panel in the wake of the incident, calling for a “central registry on human genome editing research to create an open and transparent database of ongoing work.”5 (For more information, see the story in the May 2019 issue of IRB Advisor.)
“The WHO has convened a committee, and the National Academies of Medicine and Science in the U.S. have convened a commission with international representation,” Musunuru says. “Their goal is to create a regulatory framework. Here’s the problem: They don’t actually have the legal power. It will be up to individual governments to decide whether they want to adopt the recommended regulatory framework into their laws.”
IRB Advisor talked to Musunuru about the experiment in more detail in the following interview, which has been edited for length and clarity.
IRB Advisor: The researcher has stated that the experiment, performed in conjunction with in vitro fertilization, was justified because the father was HIV-positive. What was the risk of transmission of HIV from the father’s sperm, had the gene editing not been performed?
Musunuru: There was basically zero chance that they were going to get it from the father. During in vitro fertilization, sperm are washed, so there is no possible HIV transmission there. As we all know, HIV is not transmitted through casual contact. Just living with an HIV-positive father is not going to give you any risk of getting HIV. The other issue is that the HIV-positive father was on therapy and his viral load was suppressed. It is not like it was active. You worry slightly more if the mother is HIV-positive. If she has an active virus then there is the possibility of transmitting during pregnancy or more likely in childbirth because there is the exchange of bodily fluids, blood, and so forth (although medication also will suppress viral load and prevent transmission [in that case]).
I would say that if there had not been [gene] editing, the twins’ chance of contracting HIV would be essentially the same as the HIV prevalence in China, which is 0.1%. Even if they did get HIV, there is therapy so the chance that it would actually proceed to AIDS and suffering in their lifetimes is very low. There probably will be an HIV vaccine developed during their lifetimes.
There is no justification [for gene editing] because there was very little benefit. That is important because if there is very little benefit, then the whole notion of beneficence gets thrown out the window. You have to ask, do the benefits greatly outweigh the risks? If there is basically no benefit, then any amount of risk is not acceptable.
IRB Advisor: Can you speak to the risk of the gene editing in this case?
Musunuru: We know that CRISPR has a tendency to be messy. It’s not easy to control. You can make edits at the place that you want in the gene in question. In this case, that is the CCR5 gene, which, when turned off, confers resistance to HIV. But the problem is it is very hard to control. [Dr.] He put CRISPR into the single-cell embryo, the zygote that was made from the sperm and the egg. It quickly starts to divide into two cells, four cells, eight cells. Different cells can get different edits. You end up with a situation called mosaicism — the body of the child is a patchwork of different cells with different edits. You might think you are protecting against HIV, but some number of cells in the body may not have edits that are protective. HIV could still gain a foothold and cause problems. You don’t know that you are actually getting the benefit that you think you are. With HIV, there was no risk anyway, so the point is kind of moot.
The other aspect, which is more worrisome, is that this tool, CRISPR, can be sloppy and edit other genes inadvertently. It’s more of a theoretical concern that if you may hit a tumor suppression gene or another gene, the kid is at [increased] risk of cancer, heart disease, or whatever. There can be directly harmful consequences of the gene editing because you are introducing a mutation that causes disease rather than helping. You mix the two — mosaicism and potentially harmful mutations — that makes it hard [to justify]. When the kid is born, you take a blood sample, you scan it with genome sequencing, and you think everything is fine. But, in fact, there could be some cells deep in the body that have harmful edits. They are not present in all of the body, but some are present in some of the body.
IRB Advisor: Are these mutations inheritable?
Musunuru: Some of these potentially harmful edits could get passed on to the next generation. This is a technology that is far from being perfected. To put it lightly, [Dr. He] was both arrogant in thinking he had a full grasp of it, and he was incompetent because, from what we know looking at the information that is available from the embryos, CRISPR was messy. There was mosaicism and off-target effects. The children could still have potential downstream harmful effects. If one of the kids gets cancer as a teenager, is it because of the [gene editing], or were they just really unlucky? We’ll never really know. This is the problem if you just go in willy-nilly and do this.
IRB Advisor: You note that CRISPR can create unintended consequences, even if the experiment goes as planned.
Musunuru: Let’s say that everything worked perfectly. He turned off the CCR5 gene. They are resistant to HIV even though they weren’t any at any particular risk. The problem is that turning off the CCR5 gene has multiple affects. You get resistance to HIV, but you become more susceptible to other viral infections — West Nile, tickborne encephalitis. You may say those are rare, but the other big one is influenza, which is very common. The evidence is that people who have this gene naturally turned off, because they were born with the mutation, are actually more susceptible to having a bad outcome if they get infected with the flu. They can get very sick, or die. If one of [the children] gets the flu — and they probably will because everyone gets the flu at some point — they might die from it because of the [gene] editing.
IRB Advisor: Were these potential adverse consequences addressed as part of informed consent?
Musunuru: None of this was covered in the informed consent document — or the travesty of a document that was called informed consent. There was some potential for harm, and very little potential for benefit. I can’t imagine any IRB allowing this to go forward.
The informed consent document reads like a contract. It talks about all the rights the research team retains — publicity, intellectual property, and basically the patients are waiving rights to those things. There is active coercion, as it says if the patients discontinue the trial at any time they have to pay back everything that they received. If they don’t do so in 10 days they have to pay the equivalent of a $15,000 penalty, which is higher than the annual average income of a Chinese national. That is beyond the pale. Participants have to be able to withdraw from a study at any time for any reason without any penalty.
Financial Disclosure: Author Melinda Young, Medical Writer Gary Evans, Editor Jill Drachenberg, Editor Jonathan Springston, Editorial Group Manager Leslie Coplin, and Physician Editor Lindsay McNair, MD, MPH, MSB, report no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Nurse Planner Kay Ball, PhD, RN, CNOR, CMLSO, FAAN, is a consultant for Ethicon USA and Mobile Instrument Service and Repair.