20. CRISPR and gene therapy to fight diseases
CRISPR – Clustered Regularly Interspaced Short Palindromic Repeats- is a series of DNA chunks discovered in bacteria in the last decade of the 1900. Researchers found out (a bit later) that these were remnant from bacteriofagi (nasty bits that eats bacteria from the inside, even bacteria get sick!) that infected bacterias and where killed by the bacteria reaction. The killing resulted in a sort of immunity (the bacteria got vaccinated) so that if another fagi invaded the bacteria it was recognised and duly killed using a protein associated to the DNA sequence Cas – CRISPR associated protein). There are quite a few of proteins that can be associated and scientists decided to call them with a number.
They also discovered that a particular protein, Cas9, was pretty good in the editing of a DNA string in vitro and started with experiments. After a while they realised that CRISPR-Cas9 can be used as a tool for gene editing and a whole new slate of possibilities opened up (the 2020 Nobel Prize in chemistry was awarded to Charpentier and Doudna for their contribution is establishing this technique).
As shown in the graphic on the side (click on the link to get a readable size) CRISPR-Cas9 can be used, as bacteria do, to kill a gene by chopping the DNA strand at the point where that gene is contained. The cell will patch it up stitching the broken strands together but in doing so it will lose some parts of the original gene, thus disabling it. However, CRISPR-Cas9 can also be used to insert a new chunk of DNA as a replacement of the disabled gene. In the previous case the cell will no longer be able to produce a certain protein (and that may be good if that protein was creating problems, as it is the case in some genetic disorders) whilst in the latter the new gene can provide the instructions needed by the cell to produce a protein (again, some genetic disorders derive from the inability of cells to produce a certain protein).
In practice, scientists now have a tool, CRISPR-Cas9 allowing them to manipulate the DNA to get a specific result. As in anything having to do with biology (differently from mechanics) the process has a statistical flavour. On the average you get the result you are looking for but there are cells where this is not achieved, where the cut is not occurring where it was planned or the insertion does not work out the way you wanted. However, as long as the majority of the operations have a positive result you are good (not all cells, as an example, will have the capability of manufacturing that protein but if a sufficient number will the genetic disorder can disappear).
This lack of absolute precision is also the ground for several scientists and ethicists to object on the procedure. By altering the DNA of a living being you may set up a clicking bomb that could lead to unexpected consequences (one of the issue here is that we don’t know how the genotype – the instructions contained in the DNA strands- results in a phenotype – in the actual living being. A single gene is often involved in many traits of a living being and conversely a given trait my involve several genes and the truth is that at today’s level of knowledge we do not know the relationships (or better, we understand just a tiny fraction). Hence the opposition to modify the code of life -better be cautious than sorry.
On the other hand, it is evident the potential advantages that this technology may offer, starting with, obviously, the cure to genetic disorders (there are some 6,000 known today). Once perfected (i.e. becoming more accurate and predictable) could also be used to improve a living being (this is something that occurs in Nature over million of years of selection process and that science can make possible in e few weeks…). We have already seen this technology applied to create bacteria with specific characteristics (like the capability to adsorb heavy metals to clean up a polluted area). Here again we are faced with a Pandora’s box: once we open the lid of genetic modifications the possibilities are huge but are we sure we want to explore them (and who is going to decide what is right or wrong)?
The CRISPR-Cas9 was practical tool the first technology for genetic modification but in the last ten years several others have been found, each one having specific characteristics that would make it useful in a given application. Also, scientists have discovered a way to apply the genetic modification to the RNA, rather than the DNA. This is somehow better since the modifications will not propagate to the offsprings, therefore limiting the concerns (although not completely clearing them). A person with a genetic disorder may be cured through RNA modification but that will require continuous intervention since the new cells (and we keep changing our cells) will be affected by the disorder since their DNA will not have been changed. Additionally, the baby born from that person will have a chance of inheriting the disorder. Hence in case of genetic disorders a DNA modification is the way to go. In case of “augmentation” using the RNA path would probably be better.
CRISPR can also be used as a sensor and a team of researchers at the Gladstone Institute of Virology have developed a test, that is awaiting for FDA approval, that uses it to detect with high precision the presence of the Covid-19 virus. Interestingly, the test has been designed as do-it-yourself so that people can run it at home, by picking up some saliva from their mouth. Interestingly, as shown in the figure, part of the processing takes place in a microfluidic chip connected to a smartphone, in charge of the heavy computation and display of result.
This Megatrend is foreseen that progress will continue at a fast pace throughout this decade and will result in cure for hundreds of genetic diseases by the end of this decade.