Ethical concerns surrounding CRISPR, and the emerging world of precision health
May 4, 2021 · IDSN 540 · Processes and Perspectives
On the ethical concerns that attach to germline CRISPR editing — off-target effects, consent, and the He Jiankui case.
Do you support or disagree with Dr He?
He Jiankui’s experiment into embryonic gene editing was irresponsible and unethical. He imperiled a nascent technology by prioritizing personal fame over scientific rigor. He resisted the advice of experts and moved quickly with a controversial experiment that has endangered the health of three children when there was no medical need.
What are the most pressing ethical concerns regarding Dr He’s gene editing of human embryos?
The most pressing ethical concern of He Jiankui’s gene editing was that through the process of editing, the twin girls became mosaics and their future health is in jeopardy as a result. Additionally, it is unclear what governing body in China will provide genetic screening and health monitoring for these children and their descendant’s in the future.
What do you think are the most pressing ethical issues associated with germline gene editing in general?
The most pressing ethical issue of germline editing through CRISPR Cas9 is off-target effects that can occur during an initial edit of an embryo, through the lifespan of the individual whose genome has been edited and later through to the progeny. The implications of future off-target effects are difficult to anticipate and pose health risks.
Another key ethical concern of germline editing surrounds informed consent. While a child’s legal guardian is responsible for making health decisions on their behalf until they have become old enough to have autonomy around personal health decisions, this issue becomes complicated when it comes to gene editing. A parent has a moral obligation to ensure their child is able to live a healthy life, but this process should not violate the rights of a minor who might disagree with their parent’s approach to eugenic selection.
An additional ethical concern surrounds social justice, access and commercialization of CRISPR technology. IVF is an expensive procedure that tends to benefit a group of people who are affluent and competitive with one another. The possibility of introducing CRISPR gene editing to this process would likely exacerbate social inequities.
Should germline gene editing be pursued?
The scientific community should continue to pursue research and technologies that help to heal humanity of inherited diseases that cripple and kill children, however it would be unethical to pursue clinical procedures in children that would be inaccurate, unpredictable, and irreversible.
What genes were edited?
He Jiankui’s highly secretive and controversial experiments were focused on editing a gene in the human embryonic stem cells of an unborn children during the germinal stage of In Vitro Fertilization with the intent of introducing them with immunity to HIV. He Jiankui’s objective was to edit the CCR5 gene and introduce the Delta 32 mutation which would provide an element of immunity to HIV by preventing the glycoprotein complex at the surface of HIV from binding at the CCR5 co-receptor of immune cells. What is publicly known about his research at SUSTech Shenzhen, is that there were three babies whose embryos were edited and all three may have had ended up with inconsistently edited CCR5 genes as well as off-target effects.
How were they edited?
The harvested human embryos of the mothers who participated in Jinakui’s study were edited during the process of IVF by Embryologist Qin Jinzhou, who injected each fertilized egg with CRISPR-Cas9 protein including sgRNA instructions to knockout the CCR5 gene. The translated transcript of Jinzhou’s video documentary indicates that the Cas9 protein did not immediately edit the single-celled zygote. Instead, Jinzhou describes that the editing process took time to unfold, “By the time the egg becomes three to four cells, the gene surgery is already finished.”
Why were those genes chosen?
The medical need behind He Jiankui’s experiment has been questioned by the scientific community, however Jiankui’s stated goal was to enable parents infected with HIV to avoid cultural stigma and have children with immunity to HIV. Jiankui’s gene editing experiment was convoluted, because the process of sperm washing during IVF eliminates the possibility of HIV being passed to progeny. The CCR5 gene was chosen for editing because a certain variant of HIV can infect an immune cell when it is able to bind to both the CCR5 co-receptor and the C4 receptor.
What were the DNA outcomes?
It is difficult to know fully, because there are conflicting reports on the details of Jiankui’s un-published manuscript and Michael Deem, the most senior scientist involved with this research, has distanced himself, remaining largely silent about the details of Jiankui’s work. Currently, there is only information about the twin girls. Details around the DNA edits of the third baby from another mother have not been made public.
According to Charles Gersbach, Jiankui removed both copies of the CCR5 gene in both chromosomes one of the girls, but on the other girl CRISPR had left CCR5 unedited on one allele and deleted more than expected on the other allele. According to Walter Isaacson, CRISPR was injected into a single cell, but it didn’t not edit until later within a subset of cells. As a result of editing that was not done uniformly, both children became mosaics. This DNA outcome meant that their systems were not resistant to HIV and they were now subjected to unknown health risks.
Did the experiment work?
The experiment did not work as planned. The CRISPR-Cas9 system was not able to edit the single-celled zygote properly. The edits were not done on time, in a uniform way, nor without off-target effects. Jiankui’s gene editing procedure made both children mosaics.
What is mosaicism?
According to Stanford Children’s Health, Mosaicism occurs when there is an error in cell mitosis and cells within a zygote are different from one another (having differing chromosomes). The result of mosaicism causes a person to have two or more genetically differing sets of cells in their body. Mosaicism can lead to serious health disorders.
How could this scientific plan backfire?
This scientific plan was flawed conceptually and logistically. The research was flawed because there are variants of HIV that do not rely on CCR5 to infect immune cells. While the HIV variant R5 Tropic relies on CCR5, the X4 Tropics and dual tropics pursue infection via CXCR4 and CD4. In 50% of individuals, HIV changes preference from CCR5 to CXCR4. Additionally, Jiankui He was aware through his research in monkeys that Cas9 takes time to find its target and greater efficiency occurs when injecting Cas9 closer to fertilization. For unknown reasons, Cas9 did not immediately introduce edits to the zygote. Instead, several cells had divided before the edits happened.
It’s unclear if He Jiankui’s goal was to protect the twin girls from incidentally contracting HIV from their father at some point during their lives (should they encounter his blood randomly), but if so, germline editing for this reason seams extreme considering the father’s viral load was already low and managed by HIV drugs.
During this research, He Jiankui violated many of his own ethical principles for gene editing by pursuing an edit that would provide a “vanity” benefit. When questioned by Robin Lovell-Badge about research on CCR5, Jiankui He said that he was aware of the research around mutations to CCR5 that conferred cognitive benefits in mice.
Ultimately, the biggest problem with He Jiankui’s experiments is that his gene edits may lead to health consequences for both girls due to mosaicism as well as the off-target effects. Now that Jiankui is in prison, who is responsible to ensure that the twin girls remain healthy? Who is financially responsible for the medical consequences of this flawed experiment? What psychological impact will this have on the girls if they find out they were a part of this experiment? Who will ensure the identities of the twin girls will remain hidden from the public?
Knowing that these girls have been put at risk, will the Chinese healthcare system take proactive steps to protect them from any future health issues or will they observe them as subjects within a science experiment similar to what happened during the Tuskegee Syphilis Study in the 1930’s.
Were there off-targets?
The edits created an off-target effect in one of the twin embryos that appears to be of little consequence in the immediate term for this child. During his presentation in Hong Kong, He Jiankui described the off-target effect as follows, “The other edited embryo showed one possible off target of a 1bp insertion in an intergenic region on chromosome 1 (chr1:69754212).” What is not known at this point are how expansive the heritable off-target effects will be across future generations. If the CRISPR-Cas expression cassette remains active in future progeny the risk of emerging off-target effects becomes greater. During He Jiankui’s research on monkeys, it was discovered that a second micro-injection of Cas9 24 hours later would reduce mosaicism and therefore if this methodology was used in the twin girls, it would signify a greater presence of CRISPR-Cas expression cassettes needing to be monitored for activity.
How were the off-targets analyzed?
Early in the process, Jiankui’s team conducted sequencing on both parents to provide a baseline and then conducted analytics to predict possible off target effects that might occur in the children. This data informed the sequencing Jiankui performed on the hESC’s to conduct a Preimplantation Genetic Diagnosis by Sanger Sequencing. They used this information to gain consent from the parents to proceed with the implantation of both embryos (with uneven editing and the single identified off-target effect). During the pregnancy, the team continued to conduct tests and after birth they did sequencing of the umbilical cord blood. Based on this sequencing, Jiankui believed that there were no novel cancer mutations in both girls.
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Sources
Lydia Goff, December 14, 2018 Gene-Editing Human Embryos: What, How, Why?
The He Lab Gene Surgery in Embryos: An Embryologist Explains How It Works
Antonio Regalado, December 3, 2019 Why the paper on the CRISPR babies stayed secret for so long
Christian Hoffmann, Oct 15, 2007 The epidemiology of HIV coreceptor tropism
Donald E. Mosier, March 2009 How HIV changes its tropism: evolution and adaptation?