Expert panel outlines steps before future ‘CRISPR babies’ attempts – STAT

Expert panel outlines steps before future ‘CRISPR babies’ attempts – STAT

Nearly two years after the birth of the first “CRISPR babies” stunned the world, an international group of experts on Thursday warned such human experimentation — in which the DNA of embryos is edited before starting pregnancies — should not be conducted because of unresolved scientific and ethical issues. But the group’s eagerly awaited report detailed the steps that scientists should go through before attempting to create gene-edited babies should countries ever greenlight the procedure.

The report also called for creating a pathway for researchers to raise concerns about genome editing pursuits they consider to be unethical. A number of scientists around the world knew in advance that a Chinese scientist was planning to start pregnancies with altered embryos in 2018 but failed to inform government or scientific authorities.

The international group echoed previous panels in determining that the world was not yet ready for gene-edited babies. But it also spelled out the circumstances when countries could ultimately decide to authorize such work if technical hurdles were cleared and societal concerns were addressed — namely, instances when it was the only way for a couple to have a healthy child without a serious genetic disease.

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“There are a lot of gaps in our knowledge and further research is necessary,” said geneticist Kay Davies of the University of Oxford, the co-chair of the International Commission on the Clinical Use of Human Germline Genome Editing, which was put together by the U.S. National Academy of Medicine, U.S. National Academy of Sciences, and the United Kingdom’s Royal Society.

The academies tapped the commission to develop guidelines for permitting “germline editing” following the global furor around the 2018 birth of twin girls whose DNA was altered with the revolutionary genome editor CRISPR while they were IVF embryos.

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Germline editing refers to changing the DNA of sperm, eggs, or early embryos — alterations that would be passed down to future generations. While it offers the promise of eliminating disease-causing mutations from family lines, scientists broadly remain opposed to its clinical use (meaning efforts to make babies, not editing embryos for research purposes without transferring them to a womb). They say researchers don’t have the technical capacity yet to guarantee that the edits occur as intended and are done safely. Others are opposed for ethical and moral reasons.

Germline editing is different from “somatic” editing — changing the DNA of adult cells as a way to treat genetic diseases — which is less fraught because somatic changes don’t get inherited.

Outside experts praised the commission’s work. While other groups have approached the question from a legal or ethical perspective, the commission delved “into the nitty-gritty technical issues that are very important to deciding when the world is ready to undertake heritable gene engineering,” said Nobel laureate David Baltimore of the California Institute of Technology.

The commission did not weigh in on the merits of germline editing or on the debate among experts over whether a global moratorium is needed. Instead, it sought to establish a baseline for when countries could consider giving clinical use a thumbs up and guidelines for what research teams needed to accomplish in their preclinical work to demonstrate they could safely move to a clinical application. It also said there need to be national and international mechanisms in place to ensure that preclinical requirements are met.

“They’ve outlined what it would take to make the decision,” Baltimore said. “And then it’s a matter of whether any country would want to or not.”

The first of the commission’s 11 recommendations says that germline editing should not proceed “until it has been clearly established that it is possible to efficiently and reliably make precise genomic changes without undesired changes in human embryos.” Because those criteria haven’t been met yet, the commission wrote, countries should not greenlight any clinical use of the technology. The concern is how to ensure that CRISPR systems make the desired edits in all of the intended cells while avoiding potentially harmful off-target effects — inadvertent alterations in the genome apart from the planned location.

“It underscores what really I think most researchers who think about this are aware of: There must not be any use of germline editing for clinical purposes at this time,” said CRISPR pioneer Jennifer Doudna of the University of California, Berkeley, who was not a member of the commission. “And the reason is the technology is just too early-stage and we don’t understand well enough how it works in human embryos.”

The commission’s report will now inform the work of a World Health Organization advisory committee, which is constructing a system to govern genome editing research. In a statement, the WHO committee said the new report “is an important contribution, including offering a framework for a potential translational pathway towards clinical application provided specific scientific, medical, and societal criteria could be fulfilled.”

When the Chinese scientist He Jiankui announced in 2018 he had created the CRISPR’d twins, he faced almost universal condemnation for undertaking such work prematurely and for skirting regulatory and ethical standards. But researchers also specifically criticized He’s choice of the gene to edit. Instead of aiming to correct a disease-causing mutation, He sought to alter a gene called CCR5 to protect the girls from being infected with HIV. (Their father had the virus.) Scientists argued there are other ways to minimize the chances of passing HIV to children, and AIDS is treatable.

The commission seemed to share those concerns about He’s target. In its report, the group wrote that if a country ultimately decided to allow clinical germline editing, it should restrict the technology only to fix mutations in single genes that cause diseases like cystic fibrosis, beta-thalassemia, sickle cell, and Tay-Sachs. The commission also recommended that embryos should only be CRISPR’d when parents had no other options for having a healthy child or had tried other options without success.

Would-be parents whose children might be born with a genetic disease, for example, can already make embryos through IVF and then, using genetic sequencing, identify and transfer only those embryos without the disease-causing mutation. CRISPR’ing embryos for a pregnancy should only be an option when that approach wouldn’t work for a couple, according to the commission.

The commission’s report also outlined the steps that national regulators should require from research teams once they’re considering clinical use of germline editing — a decision that should only be reached after broad public discussions about the societal and ethical implications. Researchers would need to demonstrate that the edited embryos develop in the lab the same as non-edited embryos and that the desired edits were made as intended across cells with no evidence of off-target effects. The embryos He CRISPR’d, on the other hand, contained a hodgepodge of edits other than those the scientist intended. Individual embryos also had cells that were edited in different ways, a concept called mosaicism.

“It was nice to see that laid out in a very, very clear fashion,” Doudna said of the detailed steps the commission proposed. “I don’t think anyone could claim they weren’t aware of what would need to be done.”

Researchers should also be required to monitor any pregnancies they help start with edited embryos and follow the children into adulthood to monitor their health, the commission said.

The commission’s final recommendation is sure to get scientists’ notice: It calls for “an international mechanism” for researchers to report concerns about genome editing work that “deviates from established guidelines or recommended standards.” He, the Chinese scientist, told a number of other scientists, including Americans, about his work or gave them hints about his plans. After the global outrage over the CRISPR’d babies broke out, those researchers said they had tried to steer He away from such a pursuit on their own but that they felt hamstrung because there was no international body to which they could ring the alarm.

By the time the twins were born, He had also started a second pregnancy with a third CRISPR’d embryo. Since then, a Russian scientist has indicated he wants to create gene-edited babies, and a number of scientists contacted He with questions. But so far, there have been no confirmed pregnancies or babies born from edited embryos. Still, scientists acknowledge the world lacks enforcement mechanisms to stop scientists who want to make the next CRISPR babies on their own.

“There will always be rogue scientists,” said Davies, the panel co-chair. But she added that she hoped having a “whistleblowing” route could address that.

The status and health of the twins — dubbed Lulu and Nana —  and of the third baby remains unknown. Late last year, He was sentenced to three years in prison for conducting an “illegal medical practice.”

Published at Thu, 03 Sep 2020 14:05:55 +0000