What Have We Learned? the Scientist, the Twins, and the First Human Gene Edit
Two years on from the birth of the world’s first tailor-made babies
In 2018, a Chinese scientist’s good intentions lead him to become the first in the world to perform an internationally banned and ethically-fraught procedure: modifying the DNA of two human embryos. The “He Jiankui Affair” resulted in the imprisonment of three scientists, the birth of healthy twin girls, and a new wave of regulations surrounding the control of gene-editing technologies. With six months until the first of his collaborators is released from prison, what has the global community learned from this event — and where do we go from here?
As many families have done this year, my holiday season was held indoors, making the most of streaming services in the on-going effort to self-isolate. While binge watching a show focusing on a young woman’s discovery that she is one of many experimental clones, my sister posed a question. “How realistic is this?” As a physicist, she often finds Science Fiction to be hilariously inaccurate. Although humans have not been cloned, the existence of people with edited DNA is a reality. As I began to explain the event, I realised that, despite its importance, the He Jiankui Affair has mostly slipped off the radar. Which it really shouldn’t have.
So, two years on, what has become of the major players? And did we really learn anything that might prevent the same mistakes from happening again?
The first instance of gene-edited humans occurred in 2018, sparking international controversy and debate. During my postgraduate studies, I remember my class of 30-odd 20-somethings responding to the news of the “CRISPR-baby” incident. It was a topic we had been learning about that same semester, and one some of my fellows were trying to perfect in bacteria as part of their ongoing research. Like the majority of ethics boards across the globe, we were shocked at the use of this novel technology in human embryos carried to term, before the necessary regulatory steps it unequivocally needs.
In 2018, the use of the CRISPR-cas9 gene editing system in human embryos was internationally banned. Although many parties were excited about its potential therapeutic applications, the moratorium on its use in humans was supported by one of the technology’s creators. This ban mainly cited concerns over the unexpected effect altering the human genome might have on future generations. Any genetic change made in this manner is irreversible, and inherited by all of that individuals descendants. With wide-spread clinical use, it could alter the course of our species. The technique was relegated to the laboratory bench, requiring further investigation before any government or scientific body would sign off on its use in a clinical setting.
Despite the moratorium, a few experiments slipped through the cracks. A combination of factors, among which lax regulatory oversight in China has been chiefly blamed, resulted in the editing of non-viable human embryos in 2015. Before the destruction of these cells, the scientists involved concluded that the use of the technology had been successful, but inefficient, and highlighted the need for further work before the protocol could be used in any clinical applications.
Enter He Jiankui.
The road paved by good intentions…
In November, 2018, He Jiankui posted five videos to his Youtube Channel, outlining his success in performing CRISPR-cas9 mediated ‘gene surgery’, ahead of the Second International Summit on Human Genome Editing, in Hong Kong. His experimental subjects — or perhaps you might say patients — were the fertilized embryos of Chinese couples, selected to take part due to the father being HIV-positive, and the mother negative. Although the couples consented to IVF using gene-edited embryos, the following investigation revealed some concerning facts.
- The consent forms that this couple, and six other couples, signed were incomplete.
- He was charged with forging the necessary ethical approval documents. The hospital denied every giving ethical approval, which He claimed to have received.
- Doctors were not informed about the nature of the embryos they were responsible for implanting into mothers.
- SUStech, the Shenzhen university where these procedures took place was unaware of the project, or that it involved human infants, despite funding it. Dr He acknowledged hiding his research from the university.
“What could these parents hope to gain?”, you might ask. In all likelihood, He Jiankui promised them that his procedure could prevent their future children from becoming infected by HIV, a life altering disease. HIV is an infection which incorporates itself into the host’s DNA and slowly disables their immune system. Couples where the father is HIV-positive can choose to undergo IVF to conceive. IVF allows for a procedure known as ‘sperm washing’, which will lower the risk of transmission to the child during conception. While this form of transmission is incredibly rare, there is some risk of transmission through bodily fluids in the daily lives of these families. It is understandable that these couples might have looked for a more permanent solution.
Some members of the population are naturally immune to HIV. They possess a mutation in the gene CCR5. The CCR5 protein normally acts as a ‘doorway’ to the cell, which HIV uses to infect a host. People with a version called CCR5-Δ32 are protected from this infection, as the CCR5 protein is non-functional. By modifying the DNA sequence of CCR5 to mimic that of CCR5-Δ32, He Jiankui intended to make his patients immune to HIV for life. You have to admit: it’s a compelling prospect. This procedure would require He to deactivate the CCR5 gene in both embryos while they were each only a single cell large.
For those interested, here’s how it works.
In essence, the CRISPR-cas9 system can loosely be described as ‘cut and paste’ on a molecular level. The cas9 protein, which was taken from the immune systems of bacteria, is normally capable of cutting DNA in routine repairs. In conjunction with a synthetically created string of ‘guide RNA’, a form of DNA made up of one strand as opposed to two, the cas9 protein can be directed to cut any area of the human genome which matches the sequence of the guide. Once cut, the cell will attempt to heal the broken DNA. This can be done in two ways. The cell can use its own resources to repair the damage, which can result in an incorrect DNA sequence and a non-functional gene. Or, the cell can use a synthetic string of DNA provided by scientists to fill the gap, adding new or different functions to the gene. As He Jiankui only wanted to disable CCR5, he performed the former.
“For a few children, early gene surgery may be the only viable way to heal an inheritable disease and prevent a lifetime of suffering… Their parents don’t want a designer baby, just a child who wont suffer from a disease which medicine can now prevent… Gene surgery is, and should, remain a technology for healing…” — He Jiankui, Nov 2018
In early November, 2018, “Lulu and Nana” were carried to term. He Jiankui described himself as proud of what he had done.
So what’s the catch?
Although He claimed his procedure to be a success, other researchers disagree. Scientists who were able to examine He’s records were concerned that Lulu’s and Nana’s embryos may have been at the two cell stage at the time of the procedure. This means the gene surgery may only have affected one cell, leaving Nana a ‘mosaic’ of half CCR5 edited and half normal cells. Additionally, CRISPR-cas9 is not perfect. Continued errors with guide RNA can lead to ‘off-target mutations’, where the system cuts DNA somewhere else in the genome to unknown affect. Evidence of these off-target mutations was reported by independent observers in at least one of the twins. These unintended edits are now permanent changes, affecting these children and any of their future offspring. These concerns started a wildfire of outrage. And rightly so, when you consider that researchers suggest off-target mutations could cause defects, disabilities or even cancer.
Amazingly, independent observers could not confirm that either Lulu or Nana received the CCR5-Δ32 mutation. The technique used by He Jiankui resulted in mutations occurring near this site. Yes, the mutations the received did inactivate the gene, but not in a way that occurs naturally in the human population. CCR5-Δ32 is well-studied variant, and any other form of CCR5 inactivation won’t automatically lead to the same level of HIV immunity. He Jiankui can only predict that the gene surgery he performed will prevent HIV infecting the cell. His justification of his work — that ∼100 million healthy people have the non-functioning CCR5Δ32 allele — certainly doesn’t apply to his patients.
To summarize: the gene surgery that He Jiankui claimed he would perform to benefit his patients, was not the surgery he gave them.
This is not the first time China has been beset by scientific scandal. These ethical oversights further prevent China from becoming the scientific powerhouse it desires to become,tarnishing the reputation of the research it produces. With more than 100 Chinese scientists denouncing He’s work within days of his announcement, China exhibited a hard-line response, supporting growing dissent for the project.
“…the theory is not reliable, the technology is deficient, the risks are uncontrollable, and ethics and regulations prohibit the action.” -Scientific Ethics Committee of the Academic Divisions of the Chinese Academy of Sciences
In November, 2019, a year from the publication of his results, He Jiankui was convicted of forgery and unethical conduct. Following a closed court case, in which He plead guilty, he was sentenced to three years imprisonment and a fine of 3 million yuan. This sentence was down from a possible ten years imprisonment, reduced due to the healthy nature of the children. His collaborators, Zhang Renli and Qin Jinzhou, were sentenced to two, and one and a half years, respectively. Qin is slated to be released in six months.
Two years on from the announcement of their birth, “Lulu”, “Nana”, and their parents, remain anonymous. The court heard of the birth of a third child during 2019, who has also remained anonymous.
Under the ethical lens
An excellent feature in Nature, Inside the circle of trust, perfectly encapsulates the most damning elements of this event. I highly recommend it as further reading; it lays out, in detailed and extensive terms, the many systemic failings which allowed
- He’s lab recruited people who were desperate, and supplied them with incomplete, or false information about the support for his work.
From all accounts the He lab recruited couples from an HIV support group in China. Whether these couples were searching for a permanent solution to HIV transmission, it cannot be denied that He Jiankui sought out a specific audience for his pitch. People who were desperate. Those who had faced discrimination due to their condition. The kinds of future parents who would embrace an unknown procedure recommended by a highly reputable and charismatic doctor. As He Jiankui describes, one HIV-positive father had “lost hope for life” over fears that his children might suffer the same treatment. It was He’s moral duty to inform his patients of the full picture. Their vulnerability, stemming from ignorance of scientific practice, was abused. He claimed that this procedure would become common place in the future, used to heal preventable disease. Considering that He did not follow through with the most basic tenant of his promise — to emulate HIV immunity which occurs in nature — the best we can hope for is that this family is completely unaffected. There are certainly worse scenarios.
2. The use of CRISPR-cas9 was unnecessary.
The embryos that He edited were healthy. They had no genetic diseases. The chance of these children becoming infected with their father’s HIV during conception were incredibly low. The ‘early gene surgery’ which He describes as being necessary to prevent undue suffering (quoted above), plainly does not apply here. HIV is a manageable condition. It is common sentiment that He was ‘criminally reckless’ for the sake of scientific advancement and personal prestige — and not the health of families, as he claims. With the pressure to succeed, many scientists in China adopt a “do first, debate later” mentality. We can only speculate as to why He Jiankui chose to go ahead with this ethically-fraught, and prohibited approach, when many established managements are available. Perhaps for the novelty of calling himself the first? The Chinese courts certainly thought so.
[He Jiankui] defied government bans and conducted the research in the pursuit of personal fame and gain. —
3. He Jiankui could not have done this alone.
Although He Jiankui’s actions have been described as ‘rogue’, it is obvious that this cannot be the case. Aside from the two collaborators who were sentenced alongside him, He had an extensive international network. From studying at Rice University in Texas, to researching at Stanford University in California, He’s USA ties ran deep. He’s PhD advisor, Michael Deem, is listed as being present during the signing of consent forms. The results of an investigation into Deem’s compliance were never made public. While many of He’s old colleagues have been cleared of any involvement, many of them quickly changed their tune on his achievements. Quotes, such as the one following, are revealing of a small but informed support group.
“I certainly don’t approve of what [He] did.” — Stephen Quake, He’s Stanford Associate, to Science magazine
“Wow, that’s quite an achievement! Hopefully she will carry to term …” — Quake, in emails to He.
Although many of the ethics boards and funding bodies in China deny knowledge or involvement, the closed nature of the court case provides no answers to the international science community. Before going silent in early 2019, He continued to defend his work, and the legitimacy of his approvals. It can only be concluded that regulations and colleagues failed to prevent this affair. No one wants to admit their involvement. It cannot be denied the science community should have done better, and must commit to doing so in the future.
“ [He was] thrown under the bus... Everyone ran for the exits, in both the U.S. and China. I think everybody would do better if they would just openly admit what they knew and what they did, and then collectively say, ‘Well, people weren’t clear what to do. We should all admit this is an unfamiliar terrain.’” — William Hurlburt, Bioethicist at Stanford University
What have we learned?
As an emerging scientist, this far-from-complete list of ethical failures is enough to make my stomach turn. The best outcome of this debacle is that He Jiankui’s work is viewed for what it is — an example of a few people taking unnecessary risks, gambling with the lives of innocents, and tarnishing the reputations that we in the biological sciences work so hard to keep. To be clear, CRISPR-cas9 is not an unethical system. Like anything, it is a tool with the power to harm, or heal. As stated by Dr. Collins, Director of the NIH, USA, it is “profoundly unfortunate” that the first instance of this technology in humans was so irresponsible. With tools such as these, further work to understand and regulate them is always required — a hurdle that should not be prematurely overcome by any individual or company. International transparency, between both governments and scientific institutions, would have prevented much of these events from occurring.
So where does that leave us? In response to this affair, China drafted harsher regulations of gene editing in human embryos. The revised codes include experimentation with human genes or embryos as a violation of a person’s right to physical well-being, freedom, privacy and dignity. The USA did the same. On the other hand, there are even those who believe that they could perform these experiments ‘the right way’, and that CRISPR in human embryos should be an immediate reality. It is becoming clearer that since the invention of the technology in 2015, the world is heading towards an inevitable crossroads where it will become important to answer some critical questions.
“‘How will it happen? How do we control, or can we even control it in any reasonable sense of that word? And what will the impact be on society going forward?’” — Jennifer Doudna, University of California, Berkley
In my opinion, the use of CRISPR technology to edit the human genome is not a question of ‘if’, but ‘when’ — and more importantly ‘how’. Once the global community is ready to reassess CRISPR in a clinical setting, there’s nothing like a healthy dose of patience, honesty, and willingness to admit that we aren’t ready yet.
Ella Williams (MSc) is a graduate of the University of Otago, double-majoring in Neuroscience and Genetics. Her postgraduate degrees focused on fetal brain development in obese mothers, and expanding newly identified intellectual disability disorders in children. Merging her childhood love of creative writing with science, she hopes to break into science communication — particularly in the fields of gene-editing, LGBT+ genetics, and mental health. Her work can be found at ellamwilliams.medium.com/.