Germline Genome Editing in the Clinic: International Commission Urges Caution

Ricki Lewis, PhD

August 15, 2019

The International Commission on the Clinical Use of Human Germline Genome Editing met for the first time on August 13 at the National Academy of Sciences in Washington, DC, to discuss establishing a framework to guide applications of the controversial technology. A report will be published in spring 2020.

Attendees were from the United States, the United Kingdom, China, South Africa, Canada, Sweden, Japan, Malaysia, and India. Kay Davies, PhD, of the University of Oxford, United Kingdom, kicked off the meeting by limiting expectations: "This is an information-gathering session. There will be no conclusions yet, and it would be a mistake to leave here today thinking otherwise." But that charge left plenty of room for intriguing discussion.

The Lead-up: The CRISPR Twins

This wasn't the first time experts have assembled to place CRISPR (clustered regularly interspaced short palindromic repeats) into perspective. In 2015, a summit organized by the United States, the United Kingdom, and China called for an ongoing international forum for further discussion and tracking, said Victor Dzau, MD, president of the US National Academy of Medicine, in the opening session.

In 2017, the National Academy of Sciences released a report on the scientific underpinnings of human gene and genome editing technology and potential uses and implications. "The 2017 report concludes that with stringent oversight, human germline genome editing could one day be permitted for serious diseases, but emphasis on any clinical use would be irresponsible at this time. It recommended setting overarching principles that should be used in governing human gene editing research. Since then, the science has moved rapidly forward, and new events necessitate revisiting of these issues," Dzau said.

The new events he was referring to regard He Jiankui, PhD, formerly of Southern University of Science and Technology, in Shenzhen, China. In November 2018, he announced the birth of twin girls whose genomes he had edited using CRISPR/Cas9 to remove the CCR5 gene so as to protect them from HIV infection, which their father has. He claimed to have been following the 2017 recommendations.

"I was there in Hong Kong in November 2018. The announcement changed the conversation significantly about human germline genome editing. Like many in attendance, I found it an incredibly disturbing presentation and news that was difficult to absorb," said Carrie Wolinetz, PhD, chief of staff and associate director for science policy at the National Institutes of Health, following Dzau's presentation.

His actions raised immediate alarms and a flurry of position statements from around the globe. "NIH [National Institutes of Health] leaders were clear in condemnation. We found the experiment to be highly unethical, irresponsible, and unacceptable in all sorts of ways. Shortly thereafter, NIH reiterated that we currently do not, cannot, and will not support gene editing in human embryos," Wolinetz said.

The August 13 meeting sought clarity about when germline gene editing might be feasible and appropriate. The morning talks explored the scientific challenges, and the afternoon presentations examined somatic genome editing as an alternative. Viewpoints from industry, regulatory bodies, and patients were expressed.

Basic Uncertainties

Eric Lander, PHD, professor of biology at the Massachusetts Institute of Technology (MIT) and the founding director of the Broad Institute of MIT and Harvard, exhorted the morning speakers regarding the complexity of germline genome editing. "Billions of changes to a human genome are possible. We need to understand that these changes are passed down through generations and consider the effect of these changes against different environments, genetic backgrounds, and other genetic modifications."

He added that once knowledge gaps are identified, if it is decided that an application is scientifically and medically appropriate and there is societal consensus, safety and efficacy will need to be evaluated.

Aravinda Chakravarti, PhD, director of the Center for Human Genetics and Genomics at the New York University School of Medicine, New York City, discussed choosing genes to target; Sarah Teichmann, PhD, head of cellular genetics at the Wellcome Sanger Institute, Hinxton, United Kingdom, discussed choice of cells; and Britt Adamson, PhD, of Princeton University, New Jersey, discussed optimizing the DNA repair mechanism to be deployed.

Chad Cowan, PhD, from the Harvard Stem Cell Institute, offered an example of CRISPR's exquisite specificity. He defined the technology as "breaking a genome and allowing the cell to fix it itself" and described knocking down the actions of a gene variant (PCSK9) that controls low-density-lipoprotein level in mice.

Warnings

A concern that the case involving the CCR5-deficient twins brought to the forefront is whether germline genome editing is necessary. The early afternoon session addressed alternatives, such as in vitro fertilization with preimplantation genetic diagnosis to select embryos without a specific mutation, as well as somatic (nongermline) editing.

The first patient to undergo somatic gene editing with CRISPR in a clinical trial (conducted by Vertex Pharmaceuticals), which was to address severe sickle cell disease, recently made the rounds of the media. Other gene editing strategies have been in clinical trials since 2009.

Denise Gavin, PhD, of the Office of Tissues and Advanced Therapies, US Food and Drug Administration, said that as a representative of the agency, she would not discuss germline modifications, only somatic ones. The speakers that followed did discuss the elephant in the room.

Bruce Levine, PhD, the Barbara and Edward Netter Professor in Cancer Gene Therapy at the University of Pennsylvania, related the state of germline genome editing to the proliferation of clinics offering questionable stem cell therapies. "How will we deal with the CRISPR clinics that are coming?" he asked.

Talk returned repeatedly to the impossibility of reining in renegades. "We all worry about the bad actor or someone going too fast or making poor decisions," said Vic Myer, PhD, chief technology officer at Editas Medicine.

"There are just some people for whom frameworks, laws, and regulations cannot help," agreed Sarah Norcross, director of the Progress Educational Trust in the United Kingdom.

Norcross speculated about the future of reproductive technologies in the United Kingdom, where such technologies have been pioneered. "An embryo with an edited genome might become a 'permitted embryo.' It could be used to establish a pregnancy, to avoid 'serious disease,' or similar wording," she said.

The UK's Human Fertilisation and Embryology Authority would regulate the technology, she added. "Clinics would need a special license to genome edit, and then need another license for each case."

Several speakers mentioned a moratorium on the technology. Said Myer, "We support a global moratorium on germline editing, from a company perspective."

It took decades for gene therapy to be approved, noted Levine, who was a member of the team that developed CAR-T cancer therapy. "We need many thousands of years of patient safety data. We will be nowhere near ready anytime in the next years or decades for germline editing. It is too huge a leap."

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