HIV resistant embryos thanks to CRISPR?

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas (CRISPR-associated system) 9 gene editing tool has been used to edit human embryos to make them resistant to HIV, and it’s making headlines. This isn’t the first time we’ve seen CRISPR-Cas 9 in mainstream media, and it surely won’t be the last. The imminent fear for some seems to be that this gene-editing technology will lead to designer babies and sci-fi dystopias discussed in books such as Huxley’s “Brave New World” and movies such as the star studded “GATTACA”.  How realistic are these expectations? And how efficient is this technology really?

What is CRISPR-Cas9?

CRISPR-Cas 9 originates from bacteria and archaea, where it works in adaptive immunity. It functions by integrating sections of invading foreign DNA and then expressing RNA structures (crRNA and trRNA) which can target this DNA specifically in the case of a future infection. The Cas 9 enzyme is guided to the foreign DNA by the crRNA and tracrRNA, and cleaves the DNA which disables it. Research has discovered that it can be used in humans and that by combining the crRNA and tracrRNA to form a guide RNA the system can be programmed to target desired DNA sequences. This allows for the CRISPR-Cas 9 system to be applied to create genetic changes that can aid research or even activate, repressor or help visualize a specific gene. Find out more about the system here. The McGovern Institute for Brain Research at MIT have created a great four-minute video to summarize how CRISPR-Cas9 functions and you can check it out here.

The study

The study: “Introducing precise genetic modifications into human 3PN embryos by CRISPR/Cas-mediated genome editing”has gotten a lot of interest recently. It was published May 2016 in the Journal of Assisted Reproduction and Genetics by a group of Scientists from China. They applied CRISPR-Cas 9 that was targeting CCRF receptor genes in embryos that were rejected from IVF clinics. The CCRF receptor has been found to be integral to letting HIV into cells, so removing this gene and receptor would make the cells resistant to HIV. The benefits of this genetic modification are clear, but how successful was this study?

Efficiency

With current IVF methods a couple will have only around one to three embryos are suitable for implantation, and even then some of these do not survive. In one of the experiments in the article, of the 45 embryos that were tested, 26 survived, but only 4 had the desired genetic ‘mutation’. Such a low level of efficiency would not be viable because currently there are so few embryos to start off with. It must be considered that the unwanted embryos from the IVF clinic did include ones with multiple chromosomes, and this could’ve affected their survival and the efficiency of the CRISPR-Cas 9 system.

‘Mosaic’ embryos

One caveat of the modified embryos was that not all the cells carried the modification. This could’ve resulted from the CRISPR-Cas 9 system only acting upon the cells after the first replication and therefore not all of the DNA had the desired ‘mutation’. These ‘mosaic’ embryos, if developed, could lead to offspring that do not have enough successfully genetically modified DNA for them to actually be resistant to HIV. To overcome this difficulty, the CRISPR-Cas 9 system should be inserted into the embryo as quickly as possible and then destroyed or removed before replication occurs. Alternatively, the genetic change could be made in stem cells which are then specified into egg or sperm cells.

Off-target mutations

Although the study claims that there were no unintended mutations in the embryos, they only tested 28 sites of the genome. The great benefit of CRISPR-Cas 9 is that it is arguably more specific than any genetic engineering method used before e.g. zinc finger nucleases. However, this does not mean that it is without faults. Wu et al. (2015) reviewed some studies on the sensitivity of CRISPR-Cas9 and found that many factors can affect the specificity of the system ranging from the target sequence length to the structure of the CRISPR-Cas complex. It is important to keep in mind that even if there are off-target effects these don’t necessarily have to have functional consequences. The lack of reliable whole genome screenings to test for mutations limits are knowledge of the effects the system might have. Similarly the effects of removing genes that may be needed for other processes, unknown before, can lead to unwanted diseases. The last thing that is wanted is for the offspring to have a worse disorder than the one that was ‘healed’.

Where do we draw the line?

Although there is a lot more fine tuning of the specificity and efficiency of CRISPR-Cas 9 needed before this genetic engineering is applied to our offspring, the discussion of the ethics behind it has already begun. One difficult question often arises: where do we the draw the line between treatment and enhancement? For example would improving intelligence, lowering cholesterol and having 20/20 vision give people an unfair advantage and lead to the rise of ‘designer babies’? It’s difficult to say. Our lack of knowledge of the complex genetic systems involved in these are also holding us back.  The regulations of the genetically modifying human embryos varies around the world and has sparked predictions of where the first ‘CRISPR baby’ will be born. But there seems to be a general consensus that this should be the last port of call and certain parameters must be met before allowing parents to use this method.

Future outlook

The screenings of IVF embryos before implantation already exists and work, so why complicate things? It seems that curiosity and the desire to see how far we can push what is humanly possible is pushing this research forward. Although this passion can lead to incredible cures of diseases it will be necessary to do so in a careful and well thought out manner. Making it a gene editing ‘space race’ as suggested by some can lead to a lax of controls and premature experiments, which can ultimately hurt humanity.

Beyond the first ‘CRISPR baby’ the genetically altered DNA could be inherited and affect the germ line. This raises issues with evolution and inheritance of genes that may seem healthy in first generations, but turn out to be harmful in the future.

Before any of this proceeds it is vital for us to understand our genes more fully, and improve the CRISPR-Cas 9 system to work efficiently and precisely.

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