Chinese scientist He Jiankui claims to have used “CRISPR technology” to such an end. We can only hope for the health of the two childrenby Philip Ball / November 27, 2018 / Leave a comment
Photo: Gregor Fischer/DPA/PA Images The Associated Press and other outlets have reported that Chinese scientist He Jiankui, working at the Southern University of Science and Technology in Shenzhen, used genome-editing technology on human IVF embryos and implanted them in seven women, resulting in the births of two twin girls a few weeks ago. He made this sensational (in all senses) claim at a press conference in Hong Kong on 26th November, adding that “society will decide what to do next.” So far, the announcement, for which there is as yet no documented evidence, has been greeted with both scepticism and outrage. It is not clear where He did the research or with what funding; his university says that the research was not conducted there and had no official approval, and that He and his colleagues have been suspended without pay. 122 Chinese scientists have apparently put out a statement condemning the work and saying that it will damage China’s reputation for responsible research in this field (a reputation that, contrary to what is sometimes asserted, is largely justified). Quite aside from the ethical issues, should we even believe it in the first place? Stem-cell science and embryology are rife with false claims. Most notoriously, maverick doctors have claimed since the early 2000s to have created human babies by cloning, but never with any more credibility than we should attach to the announcement of that feat in 2002 by Clonaid—a company run by the Raelian cult, which happens to believe humans are descended from aliens. Rather more believable was the claim by the South Korean biologist Woo Suk Hwang in 2004 that he had cloned a human embryo to derive stem cells from it. Stem cells are the embryonic cells that may grow into any tissue type in the body. Hwang’s high-profile publication was found to be based on totally fraudulent results, and in 2009 he was given a two-year prison sentence for bioethical violations and embezzlement. Then in 2014 Japanese researchers led by stem-cell pioneer Yoshiki Sasai claimed to be able to convert the mature cells of adult mice, which had developed into a particular tissue type, back to fully versatile stem cells simply by exposing them to some kind of chemical stress, such as an acid. This result too was found to have used manipulated data. Sasai, although cleared of direct involvement in the apparent fraud, committed suicide. He’s claim, however, has a ring of truth. He is an academic with a respectable pedigree in the field, having studied in the United States at Stanford and Rice universities. His adviser at Rice, American bioengineer Michael Deem, says he collaborated on the work. (Rice authorities have said that they are now conducting an investigation into his involvement.) And unlike assertions about human cloning, there is nothing inherently implausible in what He has been reported as saying. The researchers say they used the technique called CRISPR-Cas9 to alter a gene called CCR5, which is involved in infection of cells by HIV. If the gene is inactivated, that might hinder the virus from entering cells. The aim, then, was to produce babies resistant to HIV, so that couples who carry the virus might have children (by IVF) without fear that AIDS would be transmitted to them. After a history of denial, China now recognizes that AIDS is a problem of epidemic proportions. The molecular machinery that carries out the gene editing—in effect replacing one gene with another (or another variant of the same gene) with pinpoint accuracy—was added to the embryos after fertilisation, and cells were removed from them a few days later for genetic testing to see if the CCR5 gene had been successfully modified. If so, the couples were offered the choice of using either edited or unedited embryos for implantation. He says that a total of 11 embryos were used for six implantations before a (twin) pregnancy was achieved. CRISPR-Cas9 genome editing, first introduced around 2012-13, is already being studied in human clinical trials to correct mutations in adults that cause single-gene diseases such as muscular dystrophy and thalassemia. Recent research on mice has shown that genome editing of particular cell types in the body can also be successfully achieved for fetuses before birth to avert diseases caused by faulty genes. But genome editing of early embryos is another matter, because any changes would then be passed on to offspring through the “germline”: they will appear not just in the cells of particular tissues but also in eggs and sperm, which arise later in development. What’s more, any editing errors made this early could have serious knock-on consequences for growth of the fetus. All the same, the CRISPR technique has been used before on human embryos, although not for reproductive purposes. In 2015 a Chinese team used it on non-viable human embryos simply to test if it would work; it did, but not with total reliability or accuracy). The following year, Kathy Niakan of the Francis Crick Institute in London became the first (and so far the only) person granted a license by the Human Fertilisation and Embryology Authority in the UK to use CRISPR on human embryos. Her group modified embryos just a few days old to find out more about genetic problems that can lead to miscarriage and other reproductive complications. Then in 2017 an international team led by reproductive biologist Shoukrat Mitalipov at the Oregon Health and Science University used CRISPR-Cas9 in single-celled human embryos to snip out disease-related mutant forms of a gene that causes a heart muscle disorder and replace it with the healthy variant. Unlike the earlier Chinese experiments, these involved embryos that could in principle continue to grow if implanted in a uterus, although that was never part of the plan. So He’s claims are believable, and both his track record and the detail with which he described his work lend credence to them. The next question is whether the work is safe. This is why the work has already been denounced as unethical by several specialists—because we have very little idea about safety. As I said, there are risks of off-target genetic changes, with unknown and inheritable consequences. What’s more, knocking out the CCR5 gene doesn’t seem very wise in the first place: even if that helps ward off HIV, geneticist Kiran Musunuru of the University of Pennsylvania told AP reporters that a lack of the functioning gene increases susceptibility to some other viral infections. This bears on another crucial question: will the treatment work anyway? One of the twins in the pregnancy apparently acquired only one copy of the altered gene (we have dual copies of our genes, one from each parent), which will not confer complete resistance to HIV. Besides, there are other ways now of treating HIV infection, so it is far from clear that this drastic and untested procedure is necessary. Questions are also being asked about whether He’s work observed proper protocols and whether the participants were adequately informed. In short, whatever the outcome of the affair, it is a terrible way to introduce genome editing into human reproduction. There are good reasons why the use of CRISPR for human reproduction is forbidden in all countries that legislate on it (including the UK), and is almost wholly rejected in principle by the medical research community. The risks are real and unknown, and they would be passed on to future generations. This is not to say that genome editing for human reproduction should be forever ruled out of court. In those relatively rare cases where a debilitating disease is caused by a single gene, and the consequences of replacing a faulty with a healthy version can be reliably predicted, there may be a place for it eventually. Some might argue that IVF was itself an equally untested procedure when it was first introduced for reproduction in 1977, and yet millions have now benefitted from that leap of faith. But medical ethics have moved on. Nothing is gained from pressing forward with a technique like this before society has had a chance to debate it adequately (the method is itself barely six years old) or researchers have been able more fully to assess the dangers. That’s all the more the case when the benefits of the treatment are unclear anyway, and where the embryos in question are healthy to begin with. Scientists working in embryology and gene editing have been almost unanimous in condemning the work. Jennifer Doudna of the University of California at Berkeley, one of the inventors of the CRISPR method, has responded to the news by saying “It is imperative that the scientists responsible for this work fully explain their break from the global consensus that application of CRISPR-Cas9 for human germline editing should not proceed at the present time… The work as described to date reinforces the urgent need to confine the use of gene editing in human embryos to cases where a clear unmet medical need exists, and where no other medical approach is a viable option… It is essential that this news not detract from the many important clinical efforts to use CRISPR technology to treat and cure disease in adults and in children.” If He’s claims are true, we can only hope for the health and welfare of the two children. They are the proverbial guinea pigs, exposed without consent to a burden and an uncertain future that they should not have to face.