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Post-Pandemic Scenarios – XLVII – Synthetic Biology 2

Schematic representation of the many variants of CRISPR to change the DNA and the RNA. Different Cas are being used depending on the type of action desired. More Cas will likely be found in the coming years, broadening the toolkit for gene editing. Image credit: Gavin J. Knott and Jennifer A. Doudna, AAAS Science

CRISPR-CasX

The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) – Cas  (CRISPR Associated Protein) system was discovered, and invented, in the last century, the first reference is found in an article in 1987. The CRISPR was discovered in bacteria: they are short DNA sequences that bacteria have inherited from viruses (bacteriophages – literally bacteria eaters) that infected them. Rather than being killed by the viruses these bacteria hijacked part of their DNA and used it to recognise those virus and destroy them using an associated protein, Cas, that would chop the virus DNA into pieces. Conceptually it is very similar to a vaccine and it provides immunity to the bacteria.

The crucial feature of CRISPR-Cas is its ability to cut the DNA/RNA strand in specific (desired) points. Once the DNA is broken a set of codons can be inserted / removed changing the “instruction”. If the change takes place at the DNA level it will become part of the cell code (and possibly will be inherited by offsprings), if it takes place at the RNA level it will only be effective for a limited time (the RNA is used to code a certain protein and then it disappears). Several “Cas” have been discovered (the first was Cas9) and they serve different purposes (look at the graphic). CRISPR-CasX are already used in a variety of field, from agriculture (creating GMO) to environmental care (e.g. modified bacteria are used to remove oil spills from the sea). More recently CRISPR-Cas has been used to create mRNA vaccine (if you are interested in this area watch the video I have enclosed. It is a long one but it guides you to understand the various aspects of using CRISPR for vaccine).

The FTI’s report foresees a growing application of CRISPR-CasX to healthcare that by the end of this decade will make possible to address pathologies that so far have been out of our curing capability like congenital blindness, muscular dystrophy, Alzheimer’s disease, and sickle cell anemia. Some form of cancers might also be addressed with CRISPR-CasX. It seems science fiction, manipulating the cell DNA to tech it how to fight a specific disease. Yet it is science.

In 2020 for the first time CRISPR-Cas9 has been used to treat a person with a genetic condition leading to blindness by inserting the appropriate “instructions” in that person’s retinal cells.

The big issue with using CRISPR-CasX is that biology is not like engineering. In the latter you can replace with certainty a specific “cog”, in biology you are statistically replacing / deleting a specific DNA/RNA strand, meaning that in the millions of replacements most will be on target but a few will miss. What happens to those missing? Most likely nothing of concern but there is always the potential of unexpected side effects. More than that. We know of course that a given strand of DNA is responsible for an undesired effect (a genetic disease) and by replacing it we will fix the problem. However, most of the time (at least today) we are not sure if that particular strand was also involved in other biological processes, so that once it is remove/updated we are fixing a problem but we may create a new one. As an example, many animals (ourselves included) have a gene (Hox gene) that results in the formation of five fingers and five toes. It would be possible (and most likely happened many times in Nature) to change it and get 6 fingers – an additional thumb might come handy in doing some repair job, wouldn’t it? The problem, and the reason’s why we do not see people with 6 fingers is that the Hox gene is also involved in our reproduction process. You change it and you get six fingers but you are no longer able to generate offsprings (hence any random variations of that gene will not be transmissible to further generations).

The evolution is the coming years will follow two paths:

  • discovery of new Cas that can be used to better operate on some DNA/RNA strands (be more precise and focussed, fewer missing), thus allowing the replacement/deletion of different specific parts of the genome;
  • understand the relation between the genotype and the phenotype, using AI, so that we can be sure of the implications deriving from changing part of the DNA/RNA strand. Notice that changes in the RNA are less impactful since they are restricted to that specific individual, whilst RNA changes could propagate to offsprings…

All DNA manipulation is fraught with ethical issues and there is no clearcut dividing line between what should be permissible and what should be banned. It is more of a grey fuzzy area and more than this, it is an area that shifts over time.

About Roberto Saracco

Roberto Saracco fell in love with technology and its implications long time ago. His background is in math and computer science. Until April 2017 he led the EIT Digital Italian Node and then was head of the Industrial Doctoral School of EIT Digital up to September 2018. Previously, up to December 2011 he was the Director of the Telecom Italia Future Centre in Venice, looking at the interplay of technology evolution, economics and society. At the turn of the century he led a World Bank-Infodev project to stimulate entrepreneurship in Latin America. He is a senior member of IEEE where he leads the Industry Advisory Board within the Future Directions Committee and co-chairs the Digital Reality Initiative. He teaches a Master course on Technology Forecasting and Market impact at the University of Trento. He has published over 100 papers in journals and magazines and 14 books.