Wednesday, Mar 29, 2017, 7:07 PM CST – China

Society

Genetic Modification

A Step Too Far?

A research paper involving genetically modified human embryos and published in a Chinese science journal has provoked an international backlash, though domestic coverage has been muted. NewsChina tries to find out why

On April 18, 2015 when the Beijing-based, English-language science journal Protein & Cell published a Chinese research paper on genetic modificaton of human embryos – a paper previously rejected by the more prestigious international journals Nature and Science – the world of science reacted strongly to the ethics behind the project.

Huang Junjiu, associate professor of cell biology at Sun Yat-sen University in Guangzhou, was lead author of the controversial article, which is titled “CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes.” According to the paper, research conducted by Huang and his team on abnormal fertilized human zygotes proved their theory of the “inefficiency and infidelity” of the clustered regularly interspaced short palindromic repeat (CRISPR)-associated system (Cas), one of the leading genome modification tools currently used by cell biologists.

Ineffective

The research conducted by Huang’s team attempted to modify the gene responsible for beta-type thalassemia, also called Mediterranean anemia, a hereditary blood disorder particularly common in China’s southern provinces. The research team used CRISPR/Cas9 enzymes (or “molecular scissors”) to target and remove specific DNA sequences in a genome, replacing them with artificially engineered nuclei.

Since this technology has given scientists the ability to replace “faulty” genes, or specific DNA sequences responsible for genetic diseases and disorders, as well as to “erase and repair” genetic information, CRISPR/Cas9, which is relatively simple to use and generally very efficient, has, since 2012, been widely adopted by global cell researchers working on developing both human and animal applications, with some institutions even attempting to modify animal embryos.

In early 2014, the science journal Cell published an article by a group of Chinese researchers documenting a breakthrough in precise gene modification in monkeys using the CRISPR/Cas9 system. The article claimed that use of this system was an efficient and reliable means to genetically modify animal cells.

However, it was not until Huang and his team described applying this technology to the modification of human embryos that CRISPR/Cas9 began to dominate headlines worldwide. Huang’s team used discarded abnormal embryos, chosen because they contained tripronuclear (3PN) zygotes due to the ova being fertilized by two sperm and donated by a local fertility clinic. Their investigation showed that the CRISPR/Cas9 system had a low success rate when applied to these embryos, causing a surprising number of “off-target” mutations instead of cleanly removing and replacing the single genes responsible for the related blood disorder.

Instead, Huang’s team observed multiple mutations in the subjects which could, were the embryos brought to term, have led to a number of further health problems. Rates of mutation were much higher than those observed in similar studies using mouse embryos or adult human cells, raising questions about the continued use of CRISPR/Cas9 technology in cellular modification.

“If you were to [subject] normal embryos [to this kind of testing], you’d need to be close to 100 percent [reliability],” Huang told Nature in late April. “That’s why we stopped. We still think [the technology] is too immature.”

Huang went on to say that his research team wanted to show their data to the world so people would “know what really happened,” rather than simply speculate about the effectiveness of CRISPR/Cas9 to modify the human genome.

Controversy

Despite the team’s deliberate choice of non-viable 3PN embryos obtained from fertility clinics, which would never be able to grow into a living human, a choice made due to ethical concerns surrounding using healthy embryos, Huang’s research still polarized international opinion.

According to Huang, his team’s paper was rejected by both Nature and Science “partly because of ethical objections.”

Germline manipulation (the artificial modification of DNA) remains a controversial strand of genetics, and is currently illegal in some European countries (such as the UK, Germany and Italy) as well as certain US states. Even advocates for further research admit that modifying the DNA profile of viable embryos that might be brought to term could have unpredictable results for future generations. Even though germline manipulation technology is still in the very early stages of development, fears are growing that, once perfected, it could allow geneticists to “grow” so-called “designer humans” with enhanced desirable traits.

Immediately after the publication of the paper, Edward Lanphier, president of Sangamo BioSciences in Richmond, California wrote an article in Nature calling for a moratorium on all research into human germline modification. “It underlines what we said before: We need to pause this research and make sure we have a broad-based discussion about which direction we’re going here,” he wrote.

Shirley Hodgson, professor of Cancer Genetics at St George’s University of London, wrote on ResearchSEA, a scientific news portal: “I think that this is a significant departure from currently accepted research practice... In the past all the gene therapy research that has been approved by regulatory bodies has been somatic, not germline, because of the potentially unpredictable and heritable effects of germline research.”

Professor Hodgson concluded that any proposal to conduct germline genetic manipulation on human embryos should be very carefully considered by international regulatory bodies before being taken seriously as a legitimate field of research.

Although criticism was widespread, the goals, if not the methodology, behind Huang’s research had some international supporters. Associate Professor Peter Illingworth, medical director at IVF Australia, commented on ResearchSEA that in his country it is standard practice to test embryos containing genetic material from known carriers of beta-type thalassemia. He admitted that actual modification of these embryos under the pretext of eliminating the disorder would be an enormous step forward, but only if the safety and reliability of such technology could be guaranteed.

In response to claims that it refused publication of Huang’s paper on ethical grounds, Science expressed in a printed response that its editorial board believes strongly that “the potential of genome editing must be viewed in terms of social mores and that the path forward must be developed through a consensus-building process.”

Domestic Voices

At press time, neither Huang Junjiu nor his only other named co-author, Zhou Canquan, responded to email or telephone requests for comment from our NewsChina reporter.

The conclusion to the controversial paper claims that Huang’s study conformed to the “ethical standards of Helsinki Declaration and national legislation” and was approved by “the Medical Ethical Committee of the First Affiliated Hospital, Sun Yat-sen University” where the embryos were obtained. Huang also claimed that the patients who donated their 3PN zygotes for research had signed informed consent forms.

According to The Paper, a Chinese news portal, a spokesperson for Sun Yat-sen University stated that debate concerning Huang’s paper was “a normal scientific debate” and the university would not comment on the issue.

While overseas science circles continued this debate, however, China’s domestic media and scientific community have remained largely silent beyond a handful of reports. Some have speculated that this silence is in part due to a generally tolerant attitude towards all varieties of scientific research in atheist China, where research and experimentation on human embryos is not subject to as many restrictions as in the West.

Chen Guoqiang, a professor of biology at Tsinghua University, told the South China Morning Post in late April that modification of human DNA is the key to curing many diseases, maintaining long-term health, retaining one’s youth and living longer. “[These things] will all be possible in the future and free many families from pain and suffering.”

Zhao Shimin, a biologist with Fudan University in Shanghai, echoed Chen’s opinions and denied any “ethical problem” with Huang’s study. He added that “modification of human DNA is inevitable. The technology has been used on plants, on animals, and the next step will be humans.”

Jiang Tao, senior engineer with the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, told NewsChina in June that the “general direction” of Huang and his team’s research was “correct.” “Considering how modern pharmaceuticals have helped to prolong human lifespans, it is harder to leave the eradication of damaging, heritable genes to natural selection.”

“Huang’s work aimed to get rid of harmful genes at a proper time, allowing couples carrying such diseases to have healthy babies. Thus, their work is absolutely moral in terms of its intent,” he added.

In Jiang’s opinion, human development is no longer a process of natural evolution, due to the intervention of modern medicine. His conclusion is that harmful genes can only be eradicated through high-tech methods, including genetic modification of human beings. The key point, in his view, is to find the appropriate time when such modification is both technically and ethically viable.

He added that while regulations in China prohibit human cloning, there is currently no legislation relating to the modification of discarded human embryos.

“As a scientist specializing in research on early-stage embryos, it is natural for Huang to shoulder the responsibility of solving the problem of hereditary genetic disorders. I understand his position in this case, and his research is serious science rather than the ‘publicity stunt’ described in certain media,” said Jiang. “Huang’s team chose early-stage, abnormal, donated embryos that would never have had a chance to survive. I don’t see any ethical violation.”

Since the first baby born through in vitro fertilization (IVF) in China was born in 1988, assisted reproductive technology (ART) has seen rapid development in the country, with an estimated 100,000 babies born through IVF in China alone, and some 5 million globally. During the IVF process, abnormal embryos, when detected, are often destroyed with the consent of the parents.

According to Wu Dan, a doctor from the Reproductive Endocrinology and Infertility Center of Beijing People’s Hospital, strict rules govern the handling of surplus and abnormal embryos created during IVF, with parents offered the choice to freeze them for future use, destroy them or donate them for medical research.

To increase success rates, most IVF clinics transfer multiple embryos at a time during treatment, a practice which inevitably leads to multiple fetuses and, consequently, terminations. It was not until 2003 when the Ministry of Health issued regulations on ART practices restricting the number for embryo transfers to no more than two for women under 35 years of age.

Wu Dan told NewsChina that improvements in domestic IVF technology have now led most embryologists to recommend single embryo transfers, adding that most surplus embryos are donated for medical research with the consent of the parents.

Commenting on Huang’s paper, Wu Dan expressed doubts as to whether his research was necessary. She told NewsChina that alternative techniques for embryo selection, notably pre-implantation genetic diagnosis, routinely applied during IVF treatment, are equally if not more effective than attempting to eliminate certain genetic conditions after the fact.

“I just do not yet see the need to correct a genetic defect in this way,” said Wu. “I suppose Huang and his team’s ultimate goal is to increase the proportion of viable embryos through genetic modification.” Wu added that if the modification process led to unintentional genetic modifications, then those responsible would be straying into unethical territory.

Despite the ongoing criticism, Nature recently reported that Huang’s team is continuing its work, and is now attempting to reduce the number of unintended mutations. However, the report claimed that Huang’s team is currently only experimenting on either adult human cells or animal embryos.

In mid-May, in response to the ongoing controversy surrounding Huang’s research using human embryos, some scientific bodies, including the US National Academy of Sciences and the National Academy of Medicine, have launched initiatives to develop guidelines governing experimental modification of the human genome.

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