A year since China's gene-edited baby scandal, here's how the technology has advanced

South China Morning Post Dipublikasikan 04.12, 16/12/2019
A year since China's gene-edited baby scandal, here's how the technology has advanced

In late 2018, Chinese researcher He Jiankui roiled the scientific world by announcing he had helped make the world's first gene-edited babies, altering the DNA of Chinese twin girls Lula and Nana to try to make them resistant to HIV, the virus that causes Aids.

The scandal brought attention to the scientific, ethical, social and legal challenges of research into gene editing, with a panel convened by the World Health Organisation (WHO) director general saying in March that it would be "irresponsible" for scientists to use gene editing for reproductive purposes. Beijing has since tightened its laws on genetic engineering, drafting new rules in the past year to tackle the previously loosely regulated sector, although it is too early to tell if these can be effectively enforced.

Gene editing is intended as a more precise way to do gene therapy, and has been tried in adults to treat diseases without much controversy as the DNA changes do not pass to future generations.

But while experts generally believe that gene editing could benefit human society, they have called for stricter regulation and ethical scrutiny as the technology develops.

Earlier this month, He's original research was made public for the first time by MIT Technology Review to show how He ignored ethical and scientific norms in creating the twins using a gene-editing method called CRISPR.

The Chinese biophysicist's manuscript made claims of a medical breakthrough that could "control the HIV epidemic", but it was not clear whether it had even been successful in its intended purpose " immunising the babies against the virus " because the team did not in fact reproduce the gene mutation that confers this resistance.

A small percentage of people are born with immunity because of a mutation in a gene called CCR5. While the team targeted the right gene, they did not replicate the "Delta 32" variation required, instead creating novel edits whose effects are uncertain.

Most scientists think using it to alter the genes of embryos is too risky at the moment because of the danger of damaging other genes and because unknown DNA alterations could be passed on.

Editing genes by CRISPR resembles editing a book, as the technology's co-inventor Feng Zhang, a biochemist at the Broad Institute of MIT and Harvard, put it at an event two years ago. It involves two major steps: cutting the targeted double-stranded DNA off, just like locating and removing a typo in a sentence, and inserting a desired one, he said.

This technique, while efficient and customisable, has limitations too. It could introduce accidental or "off-target" mutations that can alter the function of a gene and may result in genomic instability. Ethically, it has the potential to create unfair social advantages by turning embryos into stronger, healthier, and even more intelligent people.

Chinese biologist He Jiankui at the Second International Summit on Human Genome Editing at Hong Kong University in 2018. Photo: SCMP / Sam Tsang

Nonetheless, the past year has seen the technology being advanced by scientists worldwide.

In October, a team led by CRISPR co-inventor Zhang's colleague David Liu described a way to upgrade the technique to achieve "much lower off-target editing" with "fewer by-products" through a method they called prime editing. This could, in principle, correct up to 89 per cent of known genetic variants associated with human diseases, according to an academic paper published by the team.

"The potential of CRISPR will definitely be extended further, and the hope is really that it will have more benefits to human society," said Alan Wong Siu-lun, an assistant professor at the School of Biomedical Sciences of the University of Hong Kong.

Doctors around the world have continued experimenting with using CRISPR to treat human diseases, achieving slow but sure progress.

Earlier this year, a 34-year-old American woman underwent an experimental treatment for sickle cell anaemia, a type of blood cell disorder, that involved genetically modifying her cells with CRISPR. Preliminary findings showed positive effects, but researchers cautioned that it was "too early to celebrate" as the results involved just one patient who was only recently treated, NPR reported. The project is designed to eventually enrol up to 45 patients in the US, Canada and Europe.

A group of Chinese scientists transplanted edited stem cells into a patient that had HIV and leukaemia. The process saw some success " the leukaemia went into complete remission and there were no adverse effects related to the edited genes over an observation period of over 19 months " but the researchers, in a paper published in September, said further research was needed for the approach as there were limited results on the CCR5 gene targeted as a cure for HIV.

CRISPR has also been used to edit animal genes. In December last year, weeks after the He Jiankui scandal, scientists at northeastern China's Jilin University announced gene-edited "mutant pigs" with resistance to classical swine fever. By July, the team had successfully created 40 different genetic modifications in pigs using CRISPR, Science reported.

In February, scientists in Italy began experimenting with modifying the genes of mosquitoes, in an effort to eradicate malaria. The genetically modified mosquitoes are designed to quickly spread a genetic mutation lethal to their own species, but this is not without controversy " environmentalists have expressed concern about unforeseen effects on the environment and argued that it might have devastating impacts, such as eliminating important pollinators for crops, according to NPR.

So far only one researcher, Russian molecular biologist Denis Rebrikov, has publicly revealed plans to produce gene-edited babies like He's team.

Rebrikov announced his intentions to implant embryos edited with HIV resistance into women, by targeting CCR5 " the same gene the Chinese team worked on " just months after He's experiment rocked the scientific world. The Russian scientist initially said he would conduct the experiment by the end of this year if he could get government approval, but by October decided to switch his focus from HIV resistance to treating deafness, according to a Nature article.

"With a new such study under consideration in Russia, appropriate regulation is urgently needed," Jennifer Doudna, a UC Berkeley biochemist and co-inventor of CRISPR, wrote in the Science journal in November.

Scientists around the globe have been trying to "build a viable path toward transparency and responsible use of CRISPR technology", according to Doudna. The regulations that arise in this area should be "thoughtfully" crafted "without stifling" the technology, she wrote.

The scandal surrounding He threw Beijing's oversight of medical ethics into stark relief. Although China banned genetically modifying human embryos for reproductive purposes in a 2003 guideline, no penalties were stipulated. In the past year though, the National Health Commission drafted a rule that all "high risk" biotechnology, including gene-editing, would need cabinet approval and that those in breach would face warnings, fines, lifetime bans from research and even criminal charges.

In June, the cabinet also issued a new rule to regulate all "genetic resources", stipulating a fine of up to five million yuan (US$710,550) for collecting, storing or using human genetic resources to carry out scientific research without proper permissions.

In July, the top reform committee of the ruling Communist Party approved a proposal to establish an ethics commission for science and technology, although details have not been released.

"The Chinese government has reacted quickly by drafting guidelines on genetics studies," said James Cai, an associate professor who researches human genetics and data science at the Texas A&M University.

However, Cai expressed concern about the practical execution of the rules or guidelines, as well as the running of the national ethics commission: "Chinese people and government are notoriously known to not follow written rules at all levels mindlessly."

Using a genetically engineered embryo to establish a pregnancy is illegal in the US and much of Europe. The WHO, in a statement in July, advised regulatory or ethics authorities to "refrain from issuing approvals concerning requests for clinical applications for work that involves human germline genome editing". A month later, the organisation approved the first phase of a global registry on human genome editing, a step towards greater transparency of such trials.

As for the case that set off the controversy, a document purportedly approving the ethical aspects of He's experiment, featuring seven signatures and a Shenzhen hospital stamp, was circulated online after the scandal broke. But the official probe stated that this document was fabricated, and some of the doctors who supposedly signed off on the approval said they did not recall doing so.

An official investigation in late January preliminarily concluded that He acted alone out of a desire for fame and would be punished for any violations of law.

Not much else is clearer one year on. One Chinese researcher informed about the investigation recently told the Post that authorities could be hesitating to release further findings because of the breadth of the scandal. People involved in the research did not respond to enquiries by the Post on He or the twins' whereabouts, or said they did not know.

The Chinese researcher was last seen in late December in Shenzhen, on the balcony of a flat in his university under guard by a dozen unidentified men, according to the New York Times. Weeks later, his employer, the Southern University of Science and Technology, fired him.

The fate of a possible third gene-edited baby, who He alluded to in a presentation last year, is unknown. But William Hurlbut, a Stanford University physician who had been in communication with He, said in July this year that the birth was nearly at term.

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