The second paper reporting gene-editing in nonviable human embryos from IVF clinics has been published in the Journal of Assisted Reproduction and Genetics. Using CRISPR/Cas9, the researchers attempted to introduce a genetic mutation that provides resistance to HIV infection, but only 4 out of 26 embryos were modified successfully. The authors say their work highlights the significant technical issues remaining before any therapy using gene-editing in human embryos could be developed.
Dr. Amander Clark, Professor, Department of Molecular, Cell and Developmental Biology at the University of California, Los Angeles (webpage):
Expertise: Origins of the human germline with an emphasis on understanding epigenetic reprogramming and inheritance.
“The paper is very similar to the previous work published in Protein & Cell, in that embryos not suitable for reproductive purposes were used for the experiments. The embryos used in this report inherited an entire extra haploid genome from the father, whereas normal embryos will only inherit one haploid genome from the mother and one haploid genome from the father. The consequences of this additional genetic material on the accuracy and efficiency of human embryo genome editing is unclear, and this paper provides no insight into this important question.
“Experiments proposed by Dr. Kathy Niakan in the UK will use viable embryos donated to research. Viable embryos donated to research are the only option for addressing the efficacy and improving the accuracy of gene editing in human embryos.
“The newly published work was performed with institutional ethics approval, and further confirms that the field does not have the correct technical know-how to begin proof of principle experiments to correct genes in pre-implantation embryos for therapeutic benefit. Critically, no gene edited embryos were used to make a baby. Making a baby from gene edited embryos by transferring the edited embryos to a woman’s uterus is a very bright ethical line that should not be crossed until the technology is proven safe and following an open discussion as to the benefit to society.”
Dr. Peter Donovan, Professor of Biological Chemistry and of Developmental and Cell Biology, University of California, Irvine (webpage):
Expertise: Molecular genetics of germ cell and stem cell development.
“This paper is the second publication to describe attempts at modifying the human germline. Previously a study had been published in the journal Protein & Cell in which another group edited a gene involved in the disease beta-thalassemia, whereas the new study attempts to edit a gene involved in HIV. Some people have naturally-occurring mutations in the CCR5 gene which render those individuals resistant to HIV infection. Thus, using gene-editing to create individuals with the CCR5 mutation would provide natural protection against HIV.
“The new study follows essentially the same path as the first study; using the CRISPR/Cas9 gene editing system in tripronuclear embryos that are discarded by fertility clinics. Patients attending such clinics gave permission to donate these embryos for research.
“The results are both comforting and disturbing. The good news is that the technique worked for this group in the same way that it did for the first group. This indicates the reproducibility of the science, an important part of the scientific process (showing it wasn’t a fluke the first time) and one that should inspire confidence in the public. However, this group of researchers also reproduced another finding described by the first group, namely that this type of gene editing also causes off-target effects.
“Notwithstanding the use of tripronuclear embryos that clearly aren’t the same as normal embryos that can develop properly, the salutary lesson is that there is still much to be learned about gene editing in human embryos before it is ready for prime time. Studies in mice and non-human primates will undoubtedly be informative but ultimately it will be studies like the ones just published using donated human embryos that will give us the most understanding.”
Dr. Debra Mathews, Assistant Director of Science Programs, Johns Hopkins Berman Institute of Bioethics (webpage):
Expertise: Bioethics and policy issues related emerging biotechnologies.
“This paper is clearly looking toward human reproductive uses of this technology, about which there has been insufficient national and international discussion and debate, both within the scientific community and between the scientific community and the general public, and about which there is no consensus.
“Even if it is ultimately determined in some jurisdictions that this technology is appropriate for use in human reproduction, it is unclear whether enhancement applications, such as introducing HIV resistance, will be among the approved uses. HIV can currently be both prevented and effectively treated, raising the question of whether it is an appropriate target for human germline genome editing, in particular in advance of applications to mitigate or avoid serious, early-onset disease.
“This paper, as with the 2015 paper, demonstrates the difficulties of applying CRISPR/Cas9 to human embryos, though imperfectly, given the triploid status of the embryos used, further raising questions about the scientific value of the work. Work on normal human embryos, focused on questions of basic human biology, is more likely to produce useful data.”
Dr. Perry Hackett, Professor, Center for Genome Engineering, University of Minnesota (webpage):
Expertise: Gene-editing techniques applied to both humans and animals.
“The results are very straightforward. The gene editing happened in triploid embryos which do not develop into viable fetuses, hence avoiding ethical problems. The efficiency with which the mutation in the CCR5 gene was introduced was not high, but was being attempted in cells with three genome copies. For medical purposes there would only be two genome copies.
“There were no detectable off target effects at the genetic loci which the researchers screened. This does not preclude other off-target events and whole genome sequencing would be required to resolve this issue.
“Ethical concerns around off-target effects may in fact be over-stated in the context of normal human genome instability. When families have their genomes sequenced – mom, dad and kids – the data suggests that normal human offspring have an average of about 100 new SNPs per child which are equivalent to off-target effects. Also, when similar work is done in animals the efficiency of the intended gene-editing is high and no off-target effects are seen after whole genome sequencing.
“The genie is out of the bottle and it’s just a matter of time (I predict just a few years) until gene editing, and especially the introduction of pre-existing mutations like in this paper, will be on par with current gene therapy efficiencies and safeties.”
Declared interests (see GENeS register of interests policy):
Dr. Perry Hackett: Dr. Hackett is Chief Scientific Officer at Recombinetics, a company that uses gene-editing techniques in animals but not humans.
No further interests declared.
‘Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing‘ by Kang et al, published in the Journal of Assisted Reproduction and Genetics on Wednesday April 6, 2016