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Targeted genome editing with CRISPR

This interview with Helen O'Neill at UCL, covers the topic of genome editing, using the powerful new technology of CRISPR.
CRISPR is an acronym that stands for Clustered Regularly Interspaced Short Palindromic Repeats. And this essentially refers to the appearance and the pattern of a genetic sequence. Cas stands for CRISPR associated and this refers to the protein or endonuclease which will work together with the sequence to cut invading bacteria. In essence comparing it to a pair of molecular scissors. We can cut out the regions that we don’t like or that we want to change and we can insert other regions of interest that we would prefer to have in there. If you think of the genetic sequence as a word, for example ‘sense,’ this word could be misspelt and still make sense if it was spelt with an S or a C.
If the S or C were replaced with a B it doesn’t make ‘sense’ or ‘sembe’ as a word. And this is comparable with genetics and genes. Sometimes you can have a missense mutation, which is still readable or in frame and this won’t cause a massive effect to the person or the tissue in, which it is active. If you have a missense mutation which can be a single base pair or letter, this could have a huge effect to the function of that gene and have a massive effect on the person. In other words, cause them a disease.
If we were to change that single letter and replace it or repair it, as we can do in CRISPR, this could effectively treat or cure that person. The difference between CRISPR-Cas and other methods of gene editing is it is quicker and easier and can easily be adapted in any molecular biology lab. It’s got amazing potential for both treatments and modifications to make things better. Where you have to draw the line is where it could be done to enhance something in a way that is beyond what would be considered a medical treatment and therefore stepping into an unethical territory. Changes that are made are made in somatic cells. These are the cells that live and die with us as a human.
They will not be carried on to the next generation. The ease of use of CRISPR in germ cells, in other words passing on that genetic changes that you make is something that needs to be noted. And this has certainly been highly spoken of in all forms in the ethics-based group and among the scientists. Some who think that it should not be used in any way to alter humans and others who believe that it must be used in humans in order to understand fully how we function. To date our studies, rely on working with altering and analyzing other species which no matter how close the species are they are still not humans.
So in order to understand fully how humans function and progress and work we need to work with humans. I think CRISPR will be used for all cell types and all therapies. I think it is an incredible tool that can be used for both treatment and prevention of disease. The fear among people is that if we make changes in the genome that will be passed on to the next generation we are yet to see the true effect that it will have. This technology is relatively new so the downsides have yet to be played out. We have already seen that there can be off-target effects, albeit minimal, but the extent or the range of these off-target effects is yet unknown.
So unless we do far more experiments to see and quantify and know exactly the changes that we are making within each individual cell or organism, and we are going to be limited in its application in humans. I think we need to be aware of the concerns but I don’t think that the scaremongering is justified when you look at the overall benefits that this technology could have on humans and treatments. If you look at any of the treatments that are currently in practice none of them are perfect. Take radiation for example, for cancer it has huge off-target effects and many unwanted effects also. It doesn’t alter your germline, it does damage your germline.
So this is why people who have cancer radiation therapy have to get their sperm or eggs frozen beforehand because it is going to damage to the point that won’t be seen in the next generation because they won’t be usable for the next generation. This technology, yes it has off-target effects but yes we are working on making the technology more precise. But I don’t think it is enough to warrant stopping its use. It needs to be explored fully because it has enormous potential as therapy. Using CRISPR to alter something from the germline isn’t too far from what we are already doing in altering our reproductive capabilities in the IVF clinic. So currently we already manipulate eggs, sperm, and the zygote.
We inject sperm into an egg to fertilize it. This is a highly invasive procedure to get the aim of having a baby. It is not too far away to say that along with injecting the sperm into that egg you could inject a CRISPR machinery to make changes in that zygote. We are already taking zygotes of potentially effected patients who might be carrying genetic alterations that would be harmful for the offspring and we take one cell from that zygote, bearing in mind, there is very few cells at this point within the embryo, again hugely invasive. And then we test these cells to see whether there is anything wrong with the zygote.
This is then implanted back in the mother if it is free of the mutation. You might argue that it would be easier rather than injecting the sperm in, waiting for the cells to grow, removing a cell, testing it implanting it back into the mother, to just say, “well, while we are injecting the sperm let’s put in some machinery that will correct any alteration.” It is less invasive.

When we think of bacteria, most of us probably think of the lurking menace of infection and disease. However, not all bacteria are bad. In fact, it could be that one particular bacteria-derived technique holds the key to a new era in molecular biology.

It has long been a goal in biomedical science to be able to edit the genome in order to correct such errors. And now, targeted gene editing is here, enabling the correction of a erroneous copy of a gene in order to restore normal function.

From 2012 to 2015 there was a ten-fold increase in scientific papers discussing a hitherto obscure technique called CRISPR, which stands for Clustered regularly interspaced short palindromic repeats.

This name refers to the unique organisation of short DNA sequences found in the genomes of bacteria and other microorganisms.

These sequences are arranged in partially palindromic patterns and form a crucial component of the immune systems of these simple life forms. Their function is to seek out and destroy any invading viral material.

CRISPR can be used to delete a sequence of DNA, or as in the below diagram, the CRISPR technique can be used to insert a new gene sequence into a host genome (adapted from Charpentier and Doudna, Nature, 2013).

The steps of genome editing with CRISPR

The key to understanding CRISPR is that it works like very precise molecular scissors. These scissors can accurately and reliably cut bits of DNA. This is technically known as the ability to induce directed breaks in the DNA.

Using these scissors to cut out a piece of DNA can be extremely useful. It can allow the cutting-out of a faulty gene; but more importantly, it can allow the introduction of a healthy copy of the same gene.

Because they are so effective at cutting up DNA sequences, they can be re-purposed by a synthetic Guide RNA sequence to interfere with the genome of the host as well.

That means that researchers can change the genomic target simply changing the targeting sequence present in the Guide RNA sequence.

One application of this is in the treatment of genetic diseases. By replacing the faulty sequence gene with the correct form of the gene, a single treatment might be sufficient to treat debilitating heritable diseases.

First demonstrated in 2012, CRISPR has now shown to be a precise, reliable and inexpensive way to edit the genomes of bacteria, plants, mice, rabbits, pigs and monkeys.

In 2016, Dr Kathy Niakan, who works at the UCL-supported Francis Crick Institute in London, became the first person in the world to receive a licence to use CRISPR on donated human embryos.

The future of human genome editing is here.

For your discussion: What do you think of the prospect of human genome editing? How would you strike the balance between the obvious benefits and the less-obvious but potentially fundamental risks associated with it?

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