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Researcher defends creation of CRISPR twins, fails to quell controversy

A Chinese researcher who helped create the first genetically modified babies in the world first publicly disclosed the details of his work to an international audience of scientists and ethicists, and revealed that another baby with of these genes would be expected next year.

Lulu and Nana, two binoculars whose DNA was modified with CRISPR / Cas9 to disable the CCR5 Jiankui said on November 28 that the gene involved in HIV infections may soon join the group. Another woman participating in a genetic modification trial to make children resistant to HIV infection is in early pregnancy, he said. at the Second International Summit on the Modification of the Human Genome, held in Hong Kong.

He conducted the experiments largely in secret – not even the Southern University of Science and Technology in Shenzhen, China, where he worked until he took a leave of absence unpaid in February aware of the study. He apologized for "unexpectedly disclosing information about his work," a confusing assertion because he had given interviews to The Associated Press and recorded several videos online. A manuscript describing the work is being revised in a scientific journal, he said.

Controversial experiences

In the presentation, he claimed that his experiments aimed at disabling the CCR5 The gene could help vulnerable children, especially in developing countries, to avoid HIV infection. "I sincerely believe that this is not just for this case, but for millions of children who need this protection because an HIV vaccine is not available … I am proud. "

But his first public explanation failed to allay the controversy over his actions (SN online: 11/27/18).

Producing babies from genetically modified embryos is "irresponsible" and goes against the consensus established by researchers in 2015 after the first international summit on human gene editing, said David Baltimore after the presentation of Hey. "Personally, I do not think it was medically necessary," said Baltimore, a Nobel laureate who had a decisive influence over the definition of the policy on DNA research and chairing the committee's research committee. 39, organization of the summit.

There are many ways to avoid HIV infection that does not require risky hacking of DNA. And scientists are not convinced that editing human embryos with CRISPR / Cas9 is safe or ethical.

Public scientists lined up to ask He how he had recruited patients for the study, informed them of the risk and consequences of the research, and explained why he had done the work.

"I suppose you are well aware of this red line," said Wensheng Wei of Peking University in Beijing, echoing more widely the sentiment of many members of the scientific community. "Why did you choose to cross it? And hypothetically, if you did not know, why did you do all these clinical studies in secret? He did not answer the question.

Pierce in the details

He added that he and his colleagues had begun experimenting with unsustainable mice, monkeys and human embryos to perfect the editing technique. In this preliminary work, the CRISPR edition of the CCR5 gene did not produce any undesirable changes in other genes, what scientists call "off-target" modifications. Out of 50 human embryos published in one experiment, only one had a potential untargeted edition. Researchers can not tell if this untargeted modification was caused by CRISPR / Cas9 or if it is a genetic tweak inherited from one of the parents of the embryo.

Lulu and Nana's parents were one of seven couples recruited from a group of HIV-positive patients to participate in He's study. A consent form posted on its website views the research as an HIV vaccine development project. The baby's father is HIV-positive, but the virus is at undetectable levels in his blood. The mother is not infected.

He and his colleagues performed in vitro fertilization after sperm washing to remove any remaining trace of the virus. CRISPR / Cas9 protein and an RNA that guides the protein to the CCR5 gene were injected into the egg with the sperm. When the resulting embryos turned into a blastocyst, a step just before implantation in the uterus, when the embryo is a ball of about 200 cells, the researchers took several cells. The team examined or sequenced three to five of these cells' DNA for proof of editing. A total of 31 embryos from the seven pairs reached the blastocyst stage. Of these, about 70% had modifications to the CCR5 gene, he said.

The embryo that developed in Lulu contained an edition that mimics a natural mutation that helps protect some people from HIV. The initial tests also revealed evidence of an untargeted change, far from any gene of this embryo, he said. The embryo that developed in Nana had a small suppression in the CCR5 gene that would eliminate five of the 352 amino acids of the protein produced by the gene. Scientists do not know if this change would prevent HIV from entering the cells. Nana's embryo has no detectable off-target changes, he added.

He left it to parents to decide to implant the published embryos, knowing that one of them could undergo further modifications and the other would not resist HIV. The couple decided to implant both embryos.

After the girls were born, he and his colleagues sequenced the baby's umbilical cord blood cell DNA and determined that Lulu had no untargeted changes, after all.

Unanswered questions

But the researchers who attended his presentation are not convinced that he has presented enough evidence to verify that the edition was successful and did not damage other genes. Previous research has shown that some embryo cells can be incompletely edited or evaded, creating a "mosaic" embryo (SN: 9/2/17, p. 6).

There would be no way to determine whether each cell of an embryo is altered in the same way without looking at each cell's DNA separately, says molecular geneticist Dennis Eastburn, who was not at the top. In addition, traditional sequencing methods do not detect all the possible off-target changes that CRISPR / Cas9 editing could produce in the DNA of an embryo, says Eastburn, co-founder and scientific leader of Mission Bio in South. San Francisco. To find DNA rearrangements, for example, researchers should perform what is called long-read sequencing that can cover large parts of a chromosome.

Even more disturbing is that he chose to implant embryos to establish a pregnancy, all without consulting scientific experts, ethicists and government regulators, says chemical biologist David Liu.

The moment he decided to implant a modified embryo to create a human pregnancy was "the critical moment when his study passed from a study on the human embryo that raised the eyebrows, but not unprecedented, similar to others in China and other countries, to a deplorable study. a calamity, "says Liu, a researcher at Howard Hughes Medical Institute at Harvard University and Broad Institute of MIT and Harvard.

He claims to have consulted with several other experts, including some in the United States, before continuing his study. His university and the Chinese authorities have launched an investigation into his work. Rice University of Houston is studying the role that one of its researchers, Michael Deem, could have played in research.

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