Excerpts from gene-edited baby research show it likely had unintended mutations, unknown side effects

As powerful a technology as CRISPR is, it also has the potential to introduce mistakes or unpredictable errors in important, sacred sites of a living subject's DNA.

Chinese biophysicist He Jiankui made waves in the news and scientific community when he announced in late 2018 that he tweaked the DNA of several embryos and helped bring three genetically-modified human babies into the world. His intentions were reportedly to make them immune to HIV infection.

The genes of twin babies, he had said, were edited while they were still embryos, before they were implanted into the womb. Now, the twins are at least a year old, possibly older. As more details questioning the rationale of his study emerge, it seems increasingly like Jiankui went further with the study despite knowing it wasn't working.

 Excerpts from gene-edited baby research show it likely had unintended mutations, unknown side effects

He Jiankui during an interview at his laboratory in Shenzhen in China. AP

Researchers familiar with the nuances of gene editing and CRISPR have different theories for as to exactly what to expect from Jiankui's 'targetted' changes. Yet, they are in agreement that the risk of unplanned mutations from the gene-editing procedure is high – and made worse by the fact that it just isn't predictable in the one-cell or few-cell stage of life.

The MIT Technology Review published snippets from the manuscript that Jiankui was apparently working on, with edits made to it as late as November 2018. Jiankui’s big announcement – which came in the form of an exclusive interview with The Associated Press and a YouTube video – came before the manuscript saw a peer-review or a review for publication in a scientific journal.

From the bits of Jiankui’s manuscript shared by Tech Review, it looks as if the experiment may have failed, and that Jiankui will have known that it did. The manuscript, titled "Birth of Twins After Genome Editing for HIV Resistance," is a 4,699-word record of research that, till date, remains unpublished, and rejected by a pair of esteemed journals Nature and JAMA. A second manuscript we also received discusses laboratory research on human and animal embryos.

More than a decade ago, a breakthrough trial on an American HIV-positive patient Timothy Brown, known as the "Berlin Patient," made him the first person medically cured of HIV. This, after he underwent a bone marrow transplant from a donor that has a mutation in the CCR5 gene. The gene supposedly lends a natural resistance to HIV infection in some people.

Chinese scientist He Jiankui claimed to have helped make the worlds first genetically edited babies: twin girls whose DNA he said he altered to remove HIV. AP

Chinese scientist He Jiankui claimed to have helped make the worlds first genetically edited babies: twin girls whose DNA he said he altered to remove HIV. AP

Evident in the manuscript excerpts is the likely possibility that Jiankui was not successful in editing the only gene his entire hypothesis revolved around – CCR5. His study also had implications for CRISPR technology, a gene-editing tool invented only seven years ago. It was known in the scientific community that CRISPR wasn’t 100 percent effective long before Jiankui’s announcement. CRISPR technology has undoubtedly transformed the accessibility of gene-editing technology, made it child's play, and the strategy is still prone to errors.

As powerful a technology as CRISPR is, it also has the potential to introduce mistakes or unpredictable errors in important, sacred sites of a living subject's DNA. Mutated, or incorrect DNA, can cause any number of problems in an otherwise healthy person's body – from developmental problems and serious neurological conditions to diabetes and cancer. And this would technically be the "side effect" of a supposedly hefty benefit – "HIV resistance".

Representational image

Representational image

It appears from the bits of the study Tech Review has published, that Jiankui and his team weren’t able to reproduce the mutation of a gene called CCR5, which lends resistance to HIV-1 – the viral strain that causes half of all AIDS infections globally. This was the highlight of his plan – the main claim that Jiankui clung on to in November 2018, to justify the use of gene-editing on multiple unborn children. It was his belief that his experiment would help "control the HIV epidemic", but his research didn't make room for the possibility that it would do... well.. nothing beneficial.

If it worked, Jiankui will have found a new way to prevent one form of HIV transmission – a big, big feat in the current global fight against the HIV epidemic. But if he didn't, which is all but likely at this point, his scientific career is rightfully behind him, and forever after. In 2018, a comment published in Nature Medicine suggested that editing DNA using CRISPR could easily harm other parts of the same organism's genetic code. These 'off-target effects' are also likely in the case of Jiankui's experiment, immunologist Philip Murphy, who helped discover the role of CCR5 in HIV infection in 1996, told the Science magazine.

Murphy, of the National Institute of Allergy and Infectious Diseases in Maryland, warned that the CRISPR edits made by Jiankui in the twins could harm them easily by producing an altered protein with unpredictable functions.

"This is a potential complication of editing that gets much less attention than potential off-target edits and effects," Murphy says.  “All of the CCR5 disease associations with the exception of HIV/AIDS need substantially more experimental support before one could handicap risks of CCR5 editing with confidence,” Murphy says. For instance, it's possible to accidentally disrupt the normal functioning of the living system that protects the skin from cancer, when the tool was used to edit something completely different.

In the case of Jiankui's study, his team of researchers found one new mutation in Lulu, which might or might not have been from the CRISPR experiment. There's no way of conclusively proving that for the time being. But Jiankui, knowing full well that a mutation like this exists in Nana's DNA, decided it was safe.

Gene editing as a technology still has a long way to go before being embraced in human trials. Image: Getty

Gene editing as a technology still has a long way to go before being embraced in human trials. Image: Getty

Many experts suspect that it's possible the babies both have CRISPR-induced mutations in their DNA that could harm their health at any point in their lives. Even if these off-target effects don't do them harm, there's research suggesting that a mutation in CCR5 can make people more susceptible to dying from the flu. There's no way of ascertaining what's likely to be the outcome from the (illegal) trail.

Jiankui had also resorted to a myriad of unethical practices, drawing criticism from scientists around the world, but also from within China. China's criticism and stern action came after the scientific community worldwide expressed their fierce criticism of He’s efforts, which have apparently bypassed what's typical in scientific convention and ethics at every turn.

So Jiankui's real contribution may have been entirely elsewhere – in drawing a bold line in the sand for genetics researchers everywhere, as to where the community collectively stands on gene editing in humans: we're just not there yet.

Also read: After CCR5 gene, scientists find second, rare gene mutation that protects against HIV

Scientists that edited babies' genes probably gave them a brain boost too: Study

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