Wednesday, August 09, 2017

So, what is this CRISPR thing anyway?

There has been a lot of attention paid to CRISPR - and particularly to the ethics of its use - in the wake of the recent announcement of a successful American experiment to edit the DNA of human embryos.
CRISPR is no longer new technology, but its use in the human genome remains controversial, and this particular study - which involves editing the genes of early-stage, viable, human blastomeres in order to correct for a genetic mutation that often leads to heart failure (hypertrophic cardiomyopathy) - pushes the technique past even recent Chinese advances in the field. The edited embryos in this study successfully eliminated the mutation, and also avoided any incidence of "mosaicism" (i.e. where only some of the desired cells are repaired).
This kind of "germ-line editing" (genetic manipulation of embryos, eggs or sperm) is much more contentious than "somatic editing" (genetic manipulation of grown body tissues), largely because of the possibility of introducing errors or leaving "stowaway" mutations that will go on to affect future generations. But this Oregon Health & Science University suggests that successful, eror-free, germ-line editing is in fact quite possible, at least for certain specific heritable disease-causing mutations. Which of course raises the question of "should we?" and, if so, under what circumstances, for which diseases or mutations, etc. The "designer babies" argument and all that.
This is a huge debate for medical ethics, which the serious press is all over at the moment, and I don't have the time or energy to go into it all here. But what I did want to look at, at least briefly, is just what CRISPR actually is, because I think there is a reasonable amount of confusion, or at least misunderstanding, about it.
Part of the confusion is due to the popular media's insistence on calling it a "technology", and the use of the phrase "molecular scissors", which is a useful analogy but not quite accurate. All of this gives the impression of a kind of man-made machine or tool, perhaps something involving nanobots, which is really not the case.
So, without getting TOO technical, what is CRISPR really?
CRISPR is shorthand for CRISPR Cas9. CRISPR is an acronym for "clusters of regularly interspaced small palindromic repeats", specialized sections of DNA that include repeated sequences of nucleotides, interspersed with "spacers" (in the case of bacteria, bits of DNA from viruses that previously attacked the bacteria). So, CRISPR itself, then, is really just bits of bacterial DNA, not too exciting in itself. The "molecular scissors" part is actually the Cas9, a "CRISPR-associated" protein or enzyme that is naturally capable of cutting (chopping up and destroying) strands of foreign DNA by binding to two CRISPR RNA in a "double-stranded break".
Thus, the whole CRISPR-Cas9 process is actually the natural defense mechanism of single-celled bacteria and archaea to foil attacks by viruses and other foreign bodies. It was the achievement of a few very clever humans in 2012 to realize that this same simple process could be used to manipulate (or "edit") the genomes of other, more complex, organisms, including humans. The rest, as they say, is history.
So, the bacterial CRISPR-Cas9 process can be used as a kind of tool, effectively tricking a cell's natural DNA repair mechanisms into introducing the required changes (e.g. cutting out genetic mutations that lead to diseases). It is absolutely not a tiny pair of nano-scissors, or a microscopic programmable machine
But it sure is cool.

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