Friday, December 10, 2021

The first children with germline-edited genomes are growing up: the CRISPR story so far

 Nature has the story:

The CRISPR children.  In China, the first children with germline-edited genomes are growing up.  by Vivien Marx

"Three years ago, the world was in uproar after a journalist broke the news about two babies born with genomes edited with CRISPR-Cas9. He Jiankui had been invited to speak in the session on human embryo editing at the Second International Summit on Human Gene Editing. Some of He’s advisors thought he should speak about the twins, while others advised him to wait until his manuscripts were published, and He was purportedly leaning toward focusing just on preclinical work. Then, when the news of the twins’ birth was revealed, he adjusted existing slides to address the news.


"The goal of these heritable gene edits was to generate HIV-resistant people, by introducing germline mutations into the C-C chemokine receptor type 5 (CCR5) gene, which encodes a co-receptor for HIV. This thinking was roundly criticized by researchers and ethicists because of a lack of a medical need given the availability of antiretroviral treatments.He’s rationale for germline editing was that the gene was well studied, that HIV remains a devastating disease and that HIV infection status leads to discrimination. The participants in this study were HIV-discordant couples: the wives are HIV negative and their husbands are HIV positive and being treated with antiretroviral drugs.


"As the chorus of criticism around the experiments mounted in the days after the announcement, He disappeared from public view. Some assumed he was given a kind of escort who accompanied him around campus and monitored him. In January he was fired from his university post, and apparently detained some time thereafter.The Chinese authorities initially touted He’s achievement, then backtracked, condemned the work and shuttered the lab. After a trial in Nanshan District People’s Court behind closed doors, He was sentenced to a fine and three years in jail for ‘illegal medical practice’, along with two members of his team.


"One key concern for the children is genetic mosaicism—a condition in which different cells from the same individual have different genomes. Such conditions can occur naturally during development, for example through post-zygotic mutations, when mitosis proceeds irregularly and mutated cells persist. It can also happen when, after an environmental insult, a DNA break is not properly repaired.


"Whitehead Institute researcher Rudi Jaenisch says that mosaicism is a major problem with current approaches to heritable embryo editing. When genome edits take place after a zygote has become a two-cell or multicellular blastocyst—as likely occurred in He’s experiments—the edited and unedited cells keep dividing.


"Adashi fears that, given how imperfect the gene-editing tools are, the type of genetic and genomic “mayhem” that can result might lead to the loss of entire chromosomes or pieces of them. “Basically they could have a scrambled genome,” he says about the girls. He points to several papers showing such damage when CRISPR-Cas9-based gene editing is performed in human embryos.


"Rather than edit embryos, both Jaenisch and Church think that if germline gene editing is ever considered, it would be more promising to, for example, edit spermatogonial stem cells that give rise to sperm. But for now neither heritable gene editing in embryos nor germ-cell editing are considered ready for application in people.

"What happened in He’s lab, says Musunuru, is a textbook ethics violation that should be extensively analyzed and discussed. To date, the manuscripts describing the work that led to the gene-edited children have not been published in a journal or placed on a preprint server (Box 2). But since the birth of Lulu, Nana and Amy, a host of reports about the safety and ethics of gene editing have been published.


"They may well grow up healthy, says Adashi. Considering the risks endured in their creation, that would be a wonderful outcome. But he worries that germline gene editing “has a significant potential to cause harm rather than good.”

“How and if it will manifest is unknown,” he says. It’s certainly no way “to start life.”



Monday, December 14, 2015

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