he ethical storm that has been swirling around Chinese scientist He Jiankui, a 34-year-old associate professor of bio-engineering at the Southern University of Science and Technology (SUSTC), shows no sign of abating, weeks after his shock announcement at the end of November 2018 that he had used a gene-editing technique to modify the genome of twin baby girls, who were born in November 2018 in Shenzhen, South China’s Guangdong Province.
Lulu and Nana, born to an HIV-positive father and an HIV-negative mother, had been gene-edited using a technique called CRISPR-cas9 to disable a gene called CCR5, which would make them immune to HIV/AIDS, He claimed. CRISPR is described as being a bit like “molecular scissors,” which can snip or modify individual genes.
The outcry was instantaneous and the repercussions rippled far beyond the scientific community. A number of institutions, which He claimed had authorized his trial or had supported him, distanced themselves from the scientist, and SUSTC released a statement saying that the experiment was “conducted outside of the campus” and “seriously violated academic ethics and codes of conduct.”
A hospital in Shenzhen, which He claimed had approved his work, also denied knowledge of He’s research. HarMoniCare Shenzhen Women & Children’s Hospital issued a statement on November 27 emphasizing that the twins were not born at the hospital, it had never participated in the experiment, and the signature on the approval letter from the hospital ethics committee was fake.
He was unrepentant over the storm of criticism, and according to a video uploaded to YouTube by the South China Morning Post, he was “proud” of his work as he answered questions at the Human Genome Editing Summit in Hong Kong.
Nevertheless, Chinese authorities moved quickly to investigate, with the National Health Commission saying on November 26 that it had ordered officials to “seriously investigate and verify” He’s claims. Local health authorities in Shenzhen were also investigating. All research activities connected to gene-editing and He’s lab have been suspended. Even the World Health Organization (WTO) has withdrawn an application to register He’s work, Bloomberg reported on December 10. The Chinese site is a register for Chinese medical trials. It was rejected because “data cannot be provided.”
There are two types of gene-editing techniques: using somatic cells or germ-line cells. Somatic cell gene therapy involves transferring genes into target somatic cells of a patient, such as a bone marrow transplant. This technique is used to treat diseases such as hemophilia and cystic fibrosis, and it only affects the cells of the specific patient. In Lulu and Nana’s case, their cells were modified using germ-line cell therapy. Such modifications are heritable, and have ramifications for the offspring of the girls and give rise to enormous ethical considerations. Using CRISPR, He said he had modified the CCR5 gene in the twins to prevent the AIDS virus from being able to infect them.
There has been previous research and experimentation in this area. In 2015, Huang Junjiu, an associate professor with Sun Yat-sen University in Guangzhou, Guangdong Province, had also experimented with gene-editing embryos. The research team used nonviable zygotes and embryos that could not develop into a fetus, which had been donated by a woman who suffered a miscarriage. The result showed that out of all the 86 embryonic cells, only 28 were successfully altered. The 33-percent success rate generated widespread concern.
According to a video He posted on YouTube and Chinese video site Youku in November, only 44 percent of the gene-editing they did on embryos succeeded, meaning that the CRISPR-Cas9 tool is not reliable and is likely to result in off-target mutations and bring harm to humans. The rationale for gene-editing is to prevent disease, particularly congenital disease, which means that new healthy genes could be passed to the next generation, making offspring immune from inherited diseases. Based on this assumption, geneticists believe that gene therapy of reproductive cells will play an increasingly important role.
Nowadays, there are at least 4,000 single-gene inherited diseases, affecting over one percent of newborns around the world. In theory, reproductive gene-editing could prevent genetic diseases and ensure healthy offspring. Nevertheless, gene editing on embryonic cells generates higher risks and side effects than on somatic cells, and if there is a problem, it will echo through the generations. As a result, there is consensus, both in China and abroad, that there must be strict ethical regulations on embryonic gene-editing.
According to Rao Yi, a professor with the School of Life Sciences, Peking University, it is necessary to distinguish somatic cells from germ-line cells. Modification of somatic cells has an impact on
patients and their family members, but editing of germ-line cells is likely to impact others and even the human race. This means that while a family or individual can decide whether to undergo gene therapy on somatic cells, the issues surrounding the editing of germ-line cells are a matter for society as a whole.
Even so, gene therapy on somatic cells is also governed by strict ethical regulations, and it is also currently used as a treatment of last resort when all other medical interventions have failed. There have been many cases of patient deaths when gene therapy techniques were not sufficiently advanced, so the US Federal Drug Administration takes a cautious approach before it approves new therapies.
On the morning of November 27, 2018, more than 100 Chinese scientists working in the area of HIV/AIDS released a joint statement opposing He Jiankui’s trial. Zhang Linqi, director of the Comprehensive AIDS Research Center at Tsinghua University, told NewsChina that medically, the CRISPR therapy on the CCR5 gene cannot totally prevent HIV infection, as there are many ways a person can be infected with the virus.
Moreover, there are several effective measures to prevent the offspring of HIV-positive parents from contracting the virus. This includes using vitro fertilization, where doctors are able to “wash” the sperm before fertilizing an egg and implanting it in the mother’s womb. If a pregnant woman is infected with HIV, there are also medications to reduce the risk of mother-to-child HIV transmission to less than one percent.
“Even if the parents are HIV-positive, it is completely unnecessary to use gene-editing as a technique to prevent virus transmission,” Zhang said. “There is also no need to break ethical norms and cross humanity’s red line.”
What’s more, modifying the CCR5 gene is not 100 percent guaranteed to protect people from the HIV virus, said biologists. To begin with, scientists do not yet know the full range of CCR5 functions, therefore it is risky to modify the gene. According to existing studies, CCR5 has properties which make it resistant to viruses and tumors, and it therefore has an important role. Modifying it could have serious affects on the immune system.
Zhang told our reporter that the CRISPR technique has been known about for a long time overseas. It is not so sophisticated and is relatively easy to grasp, but it has many limitations and there should be further research in terms of off-target mutations, efficiency and long-term safety.
For either gene-editing on somatic cells or on germ-line cells, there is a complete set of regulations such as the Declaration of Helsinki, which was developed by the World Medical Association (WMA) in 1964. According to the WMA, it is “a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.” The rights of human subjects and their health must be protected, it stipulates. The Council for International Organizations of Medical Sciences (CIOMS), in collaboration with the WTO, has published the International Ethical Guidelines for Health-related Research Involving Humans, starting in the 1970s, which has been revised and updated several times, most recently in 2016. In China, the Ministry of Science and Technology (MST) and the Ministry of Health released guidelines on the ethics of research on human embryonic stem cells in 2003, which stipulates that embryonic cells are prohibited from being implanted into the wombs of human beings or animals. In 2012, the Chinese government released a regulation on the consent agreement to collect, preserve and utilize human genetic resources.
In 2017, the MST elevated genetic engineering involving gene-editing technology to high-risk research, requiring all scientific institutions to exercise strict management. Geneticists in China have organized a series of seminars on gene-editing and reached consensus on banning clinical experimentation using gene-editing for reproductive purposes.
In December 2015, the first International Summit on Human Gene Editing was held in Washington, hosted by the National Academy of Sciences and the National Academy of Medicine in the US, the Chinese Academy of Sciences, and Britain’s Royal Society. Participants discussed the scientific, ethical and governance issues on human gene-editing research. The summit gave the green light to undertake fundamental research on human gene-editing, including the study of gene sequencing inside human cells, research on the functions and risks of clinical applications and the biological study of human reproductive cells under the appropriate legal and ethical regulations.
Moreover, scientists at the conference agreed that it was “irresponsible” to conduct gene-editing on human embryos for reproduction, the “red line” that should not be crossed.
Huang Junjiu told our reporter that if gene-editing techniques are not 100 percent accurate, they should never be used in human embryos. “Right now, the CRISPR technique is not mature, and that’s the reason we stopped our research.” It is hard to predict whether Lulu and Nana will experience any future medical issues, or whether their offspring will be affected.
Kong Daochun, a professor at the School of Life Sciences under Peking University, called on the National People’s Congress, China’s top legislator, to ban gene-editing in humans to prevent other incidents of scientists abandoning all ethical concerns.
Zhang Linqi argued that scientists across the board have condemned He’s actions for his violation of basic academic ethics and codes of conduct. The gene-editing will leave an indelible and irreversible imprint on the individuals and their offspring, he added.
“It is a serious violation of a person’s genome, rather than being protective of individuals.”