CRISPR Babies: He Jiankui's Unplanned Legacy

On November 25, 2018, the MIT Technology review published an article. It was titled, “EXCLUSIVE: Chinese scientists are creating CRISPR babies.” The title reads like a nerdy tabloid, bringing to mind the long history of the alarm over scientists’ activities in China and other countries, which is often couched in xenophobia and racism. The headline also seems to prey upon the widespread fears following the development of CRISPR-Cas9 gene editing technology. In the years following the announcement of CRISPR technology, there was a widespread panic that spread throughout the world. People were concerned that gene editing would be used in unethical ways. Think pieces speculated about the horrifying innovation of “Designer Babies,” gene-edited babies who would have selected-for desirable traits. There was concern that the technology would usher in an age of increased socioeconomic inequality-- due to the rich being able to afford these premium “designer babies”-- as well as warranted fears that this would result in the next wave of eugenics. Countless other articles, however, denounced the moral panic. They called it a scaremongering tactic (Bailey) and reported that scientists were unconcerned about the possibility (Yong, Buhr, Belluck).

However, Antonio Regalado’s article was not, in fact, a trashy, speculative gossip article. It was a thoroughly-researched piece of investigative journalism, and the evidence was undeniable. A Chinese scientist, He Jiankui, seemed to have plans to eliminate a certain gene in human embryos, causing them to be immune to “HIV, smallpox, and cholera” (Regalado). The worst fears of designer baby alarmists had come to fruition. We had entered the era of the CRISPR baby.

In a series of YouTube videos posted shortly after Regalado’s earth-shattering article, He Jiankui, also known as JK, himself steps in front of the camera. Sharply-dressed and sitting in a brightly-lit biology laboratory, JK placidly tells the camera that the world’s first humans with CRISPR-edited genomes have been born (He). Smiling peacefully, he continues to assure viewers that the twin girls, pseudonymized Lulu and Nana, are healthy, and that the parents are beside themselves with joy. Most incredibly, the girls were successfully genetically altered to be immune to HIV infection (He). JK’s reassurances fell largely on deaf ears. From the moment scientists read the title of this video, they were bursting with questions. How did this happen without any of us knowing about it? Is JK telling the truth? Where is the peer-reviewed research, the scientific evidence, the proof of ethical conduct? Who is He Jiankui?

He Jiankui: Entrepreneur of Research

He Jiankui (JK) is an entrepreneurial, savvy man. He grew up in a small town in China in a poor farming family (Cohen). He made frequent trips to a local bookstore to read a textbook his family could not afford to buy. JK received his bachelor’s degree in physics in China, then his PhD in biophysics under Dr. Michael Deem at Rice University. In 2011, Deem introduced JK to Stephen Quake at Stanford, under whom JK proceeded to do postdoctoral work in genome sequencing and the bacterial CRISPR system. After working at Stanford, he applied to be a researcher at SUSTech, a new university in China whose president wanted to bring in “high-quality research” and “entrepreneurship,” which JK appreciated (Cohen). Clearly, JK had luck selling himself as a blossoming scientist with a sharp intellect and big ideas. He had a self-proclaimed “start-up” or “entrepreneurial” mindset (Cohen). When JK arrived at SUSTech in 2012, he began doing genomics work. Shortly thereafter, as CRISPR-Cas9 began to make the news, his fascination with gene editing began.

CRISPR-Cas9 is a relatively new gene editing technology that harnesses a facet of the rudimentary bacterial immune system. It is revolutionary due to its ability to target specific gene sequences, snip them, and add in new sequences or delete existing ones. It does all this more accurately and for a much lower price than any previously available technology. Immediately after its invention in 2012, scientists realized it would inevitably “revolutionize gene therapy” (Sanders). However, the “designer baby” moral panic dominated public discourse around CRISPR, and for good reason. Many worried that the tech would be used to pick and choose human traits in embryos. CRISPR could usher in a new wave of eugenics movements. That is why scientists, ethics boards, and governments have almost universally condemned or outlawed germline editing. This is editing of the sperm or egg cells, or the very early embryo, in which the edits made can be passed down through the generations. Making heritable changes like this is widely seen as risky and morally unsound due to the lack of knowledge about the technology, as well as the ability to select for “favorable” traits. By editing very early embryos, He Jiankui induced changes in the twins’ germline cells. This means the changes he made could be passed on to the twins’ offspring, and could persist for generations. JK did this despite widespread consensus that it should not be done. Hence, the horror and disbelief from the scientific community.

Not only did He Jiankui break a major rule followed by all researchers of gene editing and gene therapy, but he did it for reasons that weren’t worth the risk. His goal was to make HIV-immune babies, born to HIV positive fathers, by knocking out the CCR5 gene. This gene encodes a protein which JK describes in his YouTube video as “the doorway through which HIV enters to infect people” (He). This is an oversimplification. Though CCR5 is the main pathway used by HIV to infect a certain type of immune cell, the T cell, there are other pathways, both in T cells and other immune cells like macrophages (Greely). Additionally, CCR5 has other functions in the cell that are not completely understood. The effects of CCR5 deletion are unknown, and could be harmful in any number of ways (Greely). This is all assuming that JK succeeded in creating the mutation he set out to create, which is by no means a certainty. CRISPR had never been used in this way, so there were myriad things that could go wrong, including off-target effects or unpredictable erroneous changes (Greely). Any mistake, or a combination of them, could result in serious problems any time at any point in this embryo’s future life, both in the womb and beyond. Even if the experiment did proceed exactly as planned, the only potential benefit would be partial immunity to a largely avoidable and treatable virus (Greely). The risks were immense, and the scientific community agreed that it was a foolish, reckless, and dangerous thing to do.

A Stubborn Man’s Dream

Steve Lombardi, whom JK and Deem reached out to for investments in a genomics business, described JK as “your classic, incredibly bright, naïve entrepreneur—I run into them all the time… I just thought, ‘Okay, it’s probably early, and he wants to make a splash.’ It wasn’t the right sort of splash, but he made one” (Cohen). He Jiankui wanted to make history. JK actually spoke to several scientists who were more established in the gene editing field than himself about his ideas. Most dissuaded him. JK was trained as a biophysicist, not a geneticist, and more established scientists had a low opinion of his work (Begley and Joseph). In many of those discussions, JK brought up the scientists who had won the Nobel Prize for the first “test tube baby,” and who had made countless families happy (Begley and Joseph). His apparent obsession with this story makes it clear who he wanted to emulate. He wanted to be the name associated with the next big “splash” in the field. JK attended a conference shortly after the bomb dropped. Before his presentation, he spoke with Jennifer Doudna, one of the creators of CRISPR-Cas9. He told her that he did not plan to mention Lulu and Nana at all, which shook Doudna (Begley and Joseph). She described him as having “an odd combination of hubris and naivete” (Begley and Joseph). He was proud of his work, confident that it was groundbreaking. Yet, at the same time, he seemed “not understanding of the explosion he had caused,” said Doudna (Begley and Joseph). He went to dinner with Doudna and other scientists attending the conference. When they asked tough questions about his methods and his ethics, he became angry and stormed out of the restaurant (Begley and Joseph). Clearly, he had expected a certain reaction, and that wasn’t it. It became apparent to him that the glory he wanted wasn’t coming. That everything those scientists had warned him of when he came to them, proud and confident but still wide-eyed and excited, was coming to pass.

He Jiankui failed to listen to his heroes. Though he looked up to the CRISPR experts and geneticists he consulted with, he disregarded them when they advised him against his ambitious and dangerous experiment. Science is, fundamentally, a collaborative effort. While there are the names we remember as the innovators, the parents of new fields, or the researchers who made breakthroughs, science primarily builds on itself slowly over time. Every breakthrough we remember is built on mountains of research done by names that history does not remember. JK’s obsession with being the next big thing-- winning a Nobel Prize, going down in history-- shows that he did not take this essential tenet into consideration. JK had heroes, but rather than humbly working to build up more knowledge on top of theirs, he wanted to emulate them. He went about it all wrong. Rather than engaging in a collaborative, transparent process, he worked in secrecy, with disturbing ethical shortcuts.

Secrecy and Fraud

As it turned out, the germline editing was only one of many wrongdoings JK committed in the process of his great experiment. The entire affair was shrouded in secrecy and misconduct. His disregard for ethical conduct was evident from the start, when he failed to obtain informed consent from the research participants (Greely). In consent forms, the language around the planned CCR5 mutation was overly technical and difficult to understand, and there was no mention that this experiment would be the first of its kind (Greely). The form forbid patients from attempting to share information about the study or replicate the results (Greely), a demand in line with JK’s obvious desire to be the “first” and to make scientific history. The fathers who participated in this study were HIV positive, which presents another set of ethical and legal concerns. In China, people with HIV are not allowed to seek “assisted reproduction,” which includes in vitro fertilization. Given this, JK’s experiment may have been the only way for some of these couples to receive IVF treatment and have children. If this is the case, not only was JK’s experiment illegal in more ways than one, but there is even less possibility for legitimate informed consent.

It seems that JK got away with doing this experiment because somehow, miraculously, nobody knew about it. SUSTech, the assisted reproduction centers, and the hospital’s Medical Ethics Committee all seemed to be in the dark about the nature of this study (Greely). Not only did JK lie by omission, but he may have intentionally and actively committed fraud. Since those with HIV are forbidden from assisted reproduction and IVF, there has been speculation that He had uninfected men take blood tests and claim to be the real participants in the study (Greely).

The secrecy was so great, in fact, that for over a year after the news broke, there were still questions left unanswered. The primary one was whether or not Lulu and Nana truly existed. Due to the frenzy of media attention and investigations, both by the universities of those involved and legal entities, after the announcement, “real proof” took quite some time to surface (Regalado). Though a manuscript detailing the experiment and its results was submitted to Nature, it was not published due to concerns about transparency. Until December 2019, all the public had to go on was He’s word, both from his YouTube videos and his speech at the conference shortly after the announcement. Additionally, JK had not been seen or heard from in months at that point, making it difficult for anybody to get clarifying information (Regalado). On December 3, 2019, Antonio Regalado, the same reporter who wrote the MIT Technology Review article that broke the story, published snippets of JK’s manuscript. Alongside the piece was an article explaining how he got hold of the story (it was sent from an unnamed source), and why it hadn’t been publicly available before. While the world at large, including scientists, seem to have come to the consensus that JK at least thinks he edited the CCR5 gene of these girls, the manuscript “will not assuage skeptics” according to Regalado. The consensus is that an independent scientific effort is needed to investigate whether JK did what he said he did, and whether the results were as he suggested (Regalado). Regardless, the world seems to be giving him the benefit of the doubt-- he tried to perform germline editing. How successful he was, nobody is sure.

The intentional misleading of everyone around him suggests that he knew his activities would be frowned upon. Perhaps he believed that when he finally dropped the news, with a timing and secrecy “that made the rollout of Beyonce’s ‘Lemonade’ look amateurish” (Begley and Joseph), all his misdeeds would be forgotten.

Forgotten, they certainly were not. Ultimately, He Jiankui and two collaborators, Zhang Renli and Qin Jinzhou, were given fines and sentenced to time in prison. The court found that they had “deliberately violated national regulations on biomedical research and medical ethics, and rashly applied gene-editing technology to human reproductive medicine” (Normile). He Jiankui surely shook the world with his discovery, though it was not in the way he clearly intended to. He made great strides in creating the dreaded “designer baby,” which could be disastrous for future endeavors involving this technology. Whether we like it or not, the field of gene editing will always have to contend with He Jiankui’s dark legacy looming over it. Hopefully, this dark page of scientific history can be overcome for a more ethical future.

Sources

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