One of the biggest stories of 2018 was He Jiankui, a researcher at the Southern University of Science and Technology of China in Shenzhen, announcing he had used CRISPR gene editing to modify the CCR5 gene in human embryos. He conducted the procedure in the context of in vitro fertilization for seven couples. One of those couples gave birth to a set of twins. A later announcement indicated there was another pregnancy.
The news was met with global condemnation for violating moral and ethical standards. The Chinese government, Southern University, Rice University in the U.S., and the U.S. National Institutes of Health (NIH) launched investigations.
Follow-up investigations by the Wall Street Journal suggest that He Jiankui’s story may be just the tip of the iceberg of sloppy and unmonitored clinical trials using CRISPR in China. WSJ cites clinical trials in China where the researchers and physicians lost contact with patients whose DNA had been altered, and in a separate case, an Indian man who was treated with CRISPR for cancer improved but died from a heart attack and stroke, despite having no history of cardiovascular disease. The Chinese physicians involved apparently did not investigate his death.
However, in light of He Jiankui’s international scandal, China’s health authorities appear to be cracking down on some of this research. Three physicians involved with CRISPR clinical trials in China told the WSJ that the government science and health ministries had contacted them recently asking for information concerning their ongoing trials. WSJ writes, “Unlike in the U.S., no federal body is overseeing these trials in China, meaning standards vary across experiments.”
Although China appears to be ahead in terms of clinical trials using CRISPR, there are ongoing trials in Europe and the U.S. CRISPR Therapeutics began treating patients with beta-thalassemia in Europe earlier this year. In October, the U.S. Food and Drug Administration (FDA) lifted a clinical hold and accepted the Investigational New Drug (NDA) application of its CRISPR-based gene edited product, CTX001, for sickle cell disease. In the U.S., there is only one trial, which is at the University of Pennsylvania for melanoma, sarcoma, and multiple myeloma.
One significant difference between these trials and what He Jiankui did was the European and U.S. trials treat a disease in adult patients for which there is a clear medical need. In He Jiankui’s trial, he modified the CCR5 gene in the embryos in order to potentially make them less susceptible to HIV infection. The fathers of all seven couples have under-control HIV infections. As such, there was little likelihood of the children being infected. In addition, any changes made to their embryo DNA affects their germlines, meaning if they decide to have children someday, they will pass those changes onto their offspring. Also, research is still early and not all side effects are understood, notably off-target effects, where the gene editing effects areas of the genome besides the target areas.
Researchers associated with the discovery of CRISPR expressed concern about the lack of clinical follow-up in the Chinese studies. Jennifer Doudna, a professor at the University of California, Berkeley, one of the inventors of CRISPR, told WSJ, “Since we do not fully understand the human genome and are still developing knowledge of CRISPR-Cas technology, we need to monitor the intended and unintended consequences over the lifespan of patients.”
Beijing science and health officials have declared that implanting a CRISPR-modified embryo into a human is illegal. Using the technique to modify the DNA of adults isn’t illegal in China or the U.S., but U.S. researchers have generally erred on the side of caution. For example, the WSJreports that the University of Pennsylvania took two years to receive clearance to go ahead with the trial from the FDA and its institutional review board. Additional laboratory tests were requested and the consent agreements between the patients and the university received additional scrutiny.
“Even then,” WSJ reports, “the university struggled to recruit patients for months afterward because the requirements were so stringent.”
Part of the U.S. trial includes following the patients for 15 years.
China, however, only requires that a hospital’s ethics committee approve the trials. Which is at least why, as of January 2018, there were about a dozen CRISPR-based clinical trials publicly announced in China. At that time, about 86 adults had been known to have been treated using CRISPR gene editing. Most were involved in trials by Anhui Kedgene Biotechnology.
Mandy Zhou, founder of Kedgene, told WSJ that one trial didn’t finish as planned and they had lost touch with one of the treated patients. Another Kedgene trial was performed at the Anhui Provincial Hospital. It involved 18 patients, many who have died as their cancer grew. The China science ministry asked for a report this month, the first time they had requested information. Reportedly, none of the deaths were related to the gene editing, although no data is available to verify that.
In a third Kedge clinical trial, at least 19 out of 21 patients treated this year have died. Wu Shixiuof the Hangzhou Cancer Hospital told the WSJ none of the deaths were related to the use of CRISPR, although no details were provided.
“Any death in any clinical trial must be fully investigated,” Doudna told WSJ, adding she is concerned “about reckless applications of genome editing that put the safety of patients at risk, damages the public’s acceptance of CRISPR technology, and could trigger a range of negative but permanent unintended consequences.”
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