The moratorium Jennifer Doudna called for when she invented CRISPR-Cas9 in 2012 is set to continue as an international commission concluded there is still insufficient evidence that precise genomic changes can be rapidly made to the germline without undesired changes.
The commission, which comprises 18 members from 10 nations, was formed in the aftermath of the 2018 International Summit on Human Genome Editing where Chinese scientist He Jiankui shockingly announced that twins had been born following editing he had performed on early embryos. At the time, and still currently, it was illegal in much of the world to use a genetically engineered embryo to establish a pregnancy. In China, it is prohibited under a 2003 ministerial guidance to IVF clinics. He has since been sentenced to prison.
While the report maintains the need for continued research and extensive conversation before any country permits germline editing of human embryos, it does provide a tentative framework for how this could look in the beginning.
If a nation decides to allow heritable human genome editing (HHGE), the report says the technique should be limited to serious monogenic diseases, which result from the mutation of one or both copies of a single gene. Common examples of these diseases include cystic fibrosis, thalassemia, sickle cell anemia, Huntington’s disease and Tay-Sachs disease. However, the report says this should only be done for persons whom have no option for having a genetically related child that does not have the serious monogenic disease. If there is a chance some biological children will not inherit the disease, the commission cautions against CRISPR-Cas9 for many reasons, chief among them being a healthy embryo could become affected.
Serious monogenic diseases above situation is the only for which the report provides a “responsible translational pathway” from preclinical research to application in humans. The commission does account for a second category where genome editing may be appropriate, but certain parameter must be met. In this case, a person(s) wishing to have a child must have a 25% or less change of unaffected embryos, and have attempted at least one cycle of preimplantation genetic testing without success.
The commission did identify four additional categories of potential uses of HHGE, but said it was impossible to forge a responsible translational pathway in these cases:
- involving other monogenic conditions with less serious impact
- involving polygenic diseases
- involving other applications of HHGE, including changes that would enhance or introduce new traits or attempt to eliminate certain diseases from the human population
- with special circumstance of monogenic conditions that cause infertility
“It is not possible to define a responsible translational pathway applicable across all possible uses of heritable human genome editing (HHGE) because the uses, circumstances and considerations differ widely, as do the advances in fundamental knowledge that would be needed before different types of uses could be considered feasible,” the report explains. “Clinical use of HHGE should proceed incrementally. At all times, there should be clear thresholds on permitted uses, based on whether a responsible translational pathway can be and has been clearly defined for evaluating the safety and efficacy of the use.”
If HHGE moves forward, pre-clinical and clinical data will be critical to its success. Preclinical data must prove safety and efficacy, including that the intended edit was successful and no other modifications occurred. A proposal for clinical use should include plans to evaluate human embryos prior to implantation, including through a biopsy performed within 5-9 after fertilization at the blastocyst stage. Monitoring during pregnancy and long-term follow up of resulting children and adults will also be vital to the success of HHGE.
Lastly, the report recommends the establishment of multiple regulatory bodies to oversee HHGE progress, including at least one per nation, an independent, multidisciplinary International Scientific Advisory Panel, as well as a second international body to focus specifically on the societal implications of HHGE.
The commission’s report will inform the World Health Organization’s expert advisory committee on human genome editing, which is developing governance mechanisms for both heritable and non-heritable human genome editing research and clinical uses. The WHO advisory committee is expected to issue its guidance later this year.