The rapidly expanding field of gene editing had another breakthrough this week, which was excitedly reported in the news  as a potentially revolutionary new way of treating genetic disease. Is this a real possibility, or just hype? And what have the researchers done that’s so special?

I’ve blogged before about CRISPR gene editing: this is the technique that has been transforming a lot of molecular biology research. It allows you to specifically target a section of DNA and change the sequence: a guide RNA is molecule is used to target the CRISPR enzyme, which cuts the DNA double strand in two. The cell’s own repair mechanisms stick the ends of the DNA back together.  It’s powerful, cheap and easy. A key application would be to correct disease-causing mutations. But there are drawbacks. Currently, you’d have to do it in an embryo, and it’s much less efficient at correcting mutations than simply “knocking out” genes (rendering them effectively inactive).

There are actually two new methods published in the last couple of weeks in Nature and Science, one based on editing DNA, and one RNA.

You are probably aware that your DNA contains four “bases”; every three letters code for an amino acid, the building blocks of proteins, of which we have about thirty. In your double-stranded DNA, the two strands complement each other, with the bases joining up with a partner on the opposite strand: A (adenine) pairs with T (thymine), and G (guanine) with C (cytosine). When you make a protein, the DNA strand unravels and a messenger code is made to the gene you want, this time from single-stranded RNA: again, this contains bases which pair to those in the DNA, forming a complementary sequence. These are the same bases, except that instead T, RNA has U (uracil). This mRNA is then translated into the amino acid code of proteins.

With regards to DNA editing, a previous study(1) was able to use a system to mediate the direct conversion of C to U thereby effecting a C→T (or G→A) substitution. The most recent one(2) can do a more useful change, going in the other direction, converting T to
C or A to G. This is important because deamination of cytosine, which happens spontaneously in cells, is a common cause of point mutations: it changes a C-G pair to a T-A pair, and is estimated to be responsible for half of all disease-causing human “point” (i.e. single base change) mutations.

Another study (3) uses a system which performs a similar conversion, but for RNA
instead of DNA. It turns an A into inosine (I), which is read as a G by the cell’s protein building machinery. As it will only work for the RNA of a gene being copied, it will cause a temporary correction of a disease-causing mutation without permanently altering the DNA of the genome (which is what is inherited). If you could work out a delivery system (a thorny problem in itself), you could theoretically give this to adults, not just engineer embryos. It’s also potentially a lot safer because it’s not permanent – you could try an RNA therapy and if it doesn’t work, discontinue it with no permanent changes to your genes.

Base editing is not just potentially useful for medicine, of course but, as CRISPR itself, for engineering crops or eliminating invasive species, and potentially also for DNA-based storage systems.

I’ve included a figure below, and explanation, taken from reference (4) which summarises how these systems work.

gene editing summary
From Science magazine, 2017, ref. (4).

Figure: Conventional CRISPR uses a guide RNA (gRNA) coupled with an enzyme called a
nuclease, Cas9, that together attach to a specific stretch of DNA bases; the nuclease then snips the double helix. A cellular repair mechanism rejoins the cut DNA ends, but occasionally inserts or deletes bases, which renders the DNA code into nonsense and can knock out a targeted gene. To correct a mutation, the system must also introduce a strand of “donor” DNA that has the correct base and then use another cell-based repair mechanism called homology directed repair (HDR), which works poorly in non-dividing cells. In the DNA base editing studies, a “dead” Cas9 that can unzip the DNA helix but not cut it is fused with the gRNA. An enzyme (TadA) is also tethered to it, which performs the base change. The dCas9 was also modified to nick the unedited strand, which stimulates the cell’s DNA repair mechanism into converting the G that originally paired with C into an A that pairs with the new T. For the RNA editing system, the gRNA is fused with a different dead nuclease, dCas13, and a natural enzyme (ADAR) that converts A to I in RNA, and the RNA simply functions as if it had a G in that position.

These are all in vitro methods at the moment: it will take more work to get them to the point where they could be useful in humans, but it’s an important step forward.

What are the implications of being easily able to edit human DNA? Will we end up with a society of engineered X-men mutants? Well no, because for one thing most of them break the laws of physics. I can well see this becoming the new drugs cheating at sports events, however: there are known mutations that increase muscle mass, for example.

What about so-called “designer babies?” Possibly. Humans may engineer traits into their offspring that they find desirable. What is considered desirable will be very culturally and politically loaded. This would probably be the preserve of the rich, if it was not strictly regulated. If it became easy to do, and we could find genetic changes that would cause the effects we want, then it may be the case that in a more distant future people will change their genes much as they modify their bodies externally with tattoos, piercings etc.

Twenty years ago a thoughtful and clever science fiction film called Gattaca was released, in which people were judged from birth on the basis of their DNA and their futures assigned accordingly. That society featured genetic haves and have-nots, and your capabilities were assumed to be pre-written in your genetic code. So, are we going to end up in the future of Gattaca? Well, I hope that we won’t make the mistake of assuming you can predict someone’s potential completely from their genetic makeup, although I can well imagine a totalitarian government of the future using that as a pseudoscientific justification to control people and place values on them (as the Nazis did with outward physical characteristics, and colonial powers did to the peoples of the lands they invaded).

But are we heading for a society of genetic haves and have-nots? Of course we are. Wait, you were expecting me to say no? Or something qualified like, “Well there are obviously important ethical considerations but as long as we have strict controls and do proper tests….blah blah blah.” I’m sure we will have strict controls, at least to start with. I’m equally sure that if it becomes easy, then unscrupulous people will at best use it in a cavalier fashion without assessing risk. But that’s not the point: the whole world already exists in a society of haves and have-nots, and more or less has done ever since we developed agriculture. We live in a world where people regularly starve, where whole countries are riven with violence and warfare, where vast swathes of the population are treated like chattels at best and cattle at worse. Genetic technology won’t create this, and it won’t change this – it will simply slot in with it, as every other technology has done, from writing to the internet, from contraception to chemotherapy. Most of what we have learned from DNA so far actually opposes the prejudices humans construct: there’s no biological justification for racism, for example, However, there is a danger with genetic engineering, because our genes are fundamental to our identity as humans, in a way that external technological applications like mobile phones never will be. It will create, potentially, classes of people who ended up being regarded as “less than” in an even more extreme way than exists today.

If we don’t want this to be another thing that the rich have and the poor don’t, or that is used to oppress others, then it’s our societies we have to change first; it’s dealing with the basic problems – things like providing safe drinking water and educating women, both of which would massively improve millions of peoples lives – for which there is depressingly little political will at times. Changing these core inequalities and the systems which underpin them is taking so long to achieve that the rapid pace of gene editing will solve problems of genetic disease long before we solve the more fundamental problems of our nature.

 

References

(1). Komor et al, 2016. Programmable editing of a target base in genomic
DNA without double-stranded DNA cleavage. Nature. doi:10.1038/nature17946

(2). Gaudelli et al, 2017. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature, doi.10.1038/nature24644.

(3). Cox et al, 2017. RNA editing with CRISPR-Cas13. Science. DOI: 10.1126/science.aaq0180

(4). Cohen, 2017. ‘Base editors’ open new way to fix mutations. Novel CRISPR-derived technologies surgically alter a single DNA or RNA base. Science.  doi:10.1126/science.aar3226

Featured image: still from Gattaca, Columbia Pictures, via IMDB.

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