Human embryo gene modification – where do we draw the line?

20. May 2015
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Rumors of human embryo gene-editing have been floating around in the past few years, causing a great deal of ethical debates. Now, with the publication of a study from Chinese scientists reporting the genomic modification of human embryos, debates regarding the ethical implications of such work have been reignited.

Genetic engineering of human embryos has always comprised a heated topic of discussion, because of the ethical and safety concerns raised in the use of human embryos in scientific research. Advocates of human embryo gene-editing consider this possibility very exciting, since they believe that it can be used as a therapeutic tool to treat genetic diseases at an early stage, before a baby is born. However, others believe that using this technology would be unethical since the changes made to the human genome in embryos are heritable, and nobody really knows how these changes can affect future generations. Furthermore, gene-editing in human embryos could be described as opening Pandora’s box, a box said to contain all the evils of the world, since the potential uses of this technique are endless and not all of them are good or ethical. Unrestricted use of human embryo gene-editing could lead to requests from potential parents for ‘designer’ babies or even scientists trying to create humans with enhanced characteristics, described as ‘’superhumans’’.

Creating the world’s first genetically-modified human embryo

Even though there has been much talk and many rumors circulating about gene-editing in human embryos, up until now no one had actually published a study reporting human embryo gene modification. Now, Chinese scientists from the group of Junjiu Huang, a researcher from Sun Yat-sen University in Guangzhou, have reignited the debate about the use of human embryo gene modification, by showing for the first time, in the journal Protein & Cell, gene-editing in human embryos.

In this study – where the scientists used non-viable human embryos that can undergo the first stages of development, but cannot actually result in a live birth – attempts were made to modify the gene for β-thalassaeimia, a very common blood disorder in the mediterranean that can be fatal. Gene modification was achieved using the editing technique known as CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat (CRISPR)-associated system (Cas)). This method, in which the CRISPR/Cas9 complex binds to and splices DNA in specific locations, has been used previously to modify genes in model systems such as animal zygotes and human cells, and is believed to hold great promise for both basic research and clinical applications. However, up until now, there had been no previous reports of this method being tested in human embryos.

Using the CRISPR/Cas9 system, Huang and his colleagues set out to examine whether they could substitute a gene in a single-cell fertilized, non-viable, human embryo. Their assumption was that editing the gene at this early stage would then lead to the production of cells carrying the modified (healthy) gene, during later embryonic development. More specifically, they tried to replace the gene known as HBB that encodes for the human β-globin protein. Mutations in the gene lead to β-thalassaemia, a disorder that reduces the production of the iron-containing protein hemoglobin in red blood cells that carries oxygen to cells throughout the body.

The results obtained by the scientists carrying out this experiment showed that this method is far from ready to be used in gene therapy to treat genetic diseases. From the 86 embryos they injected, only 71 survived after 48hrs, which is the time required for the CRISPR/Cas9 system to act and for the embryos to grow to about eight cells each. From the 71 embryos that survived the CRISPR/Cas9 gene-modification, 54 of them were tested for successful gene-editing. It turned out that from these 54 embryos, only in 28 of them the DNA was spliced successfully and that only a small fraction of these contained the replacement ‘healthy’ genetic material. Considering the small percentage of success in this experiment, it is plain to see that this technique is far from being ready to use for gene-therapy, since in order to do that, the success rates would have to be near 100%.

Another hindering factor for using this method at its current state for the treatment of genetic diseases, as the researchers discovered, is that it also leads to a great number of ‘off-target’ mutations. In fact, the number of ‘’off-target’’ mutations they detected was much higher than that found previously in studies with mouse embryos or human adult cells. These ‘off-target’’ mutations are thought to be inserted by the activity of the CRISPR/Cas9 system on other parts of the human genome. This effect is a major safety concern in the clinical application of this method for gene-modification, since ‘’off-target’’ mutations that are generated can be harmful for the embryo.

Where do we draw the line?

The publication of this study, which was initially rejected by leading scientific journals such as Nature and Science due to ethical concerns, has raised new questions about whether there should be further restrictions put in place and research with human embryos more tightly regulated. The results obtained in this study clearly show that this technology is far from being safe and ready to be used for the treatment of genetic diseases. In order for this to be the case, scientists would need to have complete control over the DNA editing process and outcome. They would have to be sure that the disease gene has been eliminated and that the process is safe for the embryo and will not have any future implications. In any case, this study underlines the fact that where human embryo research is concerned we need to pause and think: Where do we draw the line?

References

Liang, P. et al. Protein & Cell 6 (5), 363–372 (2015).

Lanphier, E. et al. Nature 519, 410–411 (2015).

Baltimore, D. et al. Science 348, 36–38 (2015).

Ran, F. A., et al. Nature Protocols 8, 2281–2308 (2013).

Beta-thalassemia: http://ghr.nlm.nih.gov/condition/beta-thalassemia

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