CRISPR Is Not Immune To The Development Of Resistance Genes
A Science Enthusiast
Depending on your point of view about biotechnology, recent revelations about the effects of CRISPR on organisms could be good or bad. As a science writer for Bioscription, I take the news as a little of both.
So, what happened? Recent research between the University of Kansas and Cornell University has discovered that the usage of a gene drive, a system whereby genetic modifications are spread to other members of a population down the genetic line, does not come without its complications.
This sort of technology has multi-fold uses, even if it is currently still being developed. It could be used to give a person and later a population resistance genes to a deadly disease or it could be used to wipe out a species of deadly mosquitoes, like Aedes aegypti that spread horrible pathogens like dengue fever, chikungunya, and Zika.
Obviously, with humans, it would be a very slow process indeed. Such a desired change would be far more advantageous if just applied directly to each member of the population.
But for faster breeding species like mosquitoes, a gene drive would prove far more effective. Or so we thought.
The original problem in challenging A. aegypti included the issue of introducing a gene change that would damage the fitness of the modified individual. The forces of natural selection would, pardon the pun, naturally result in the changed mosquito not passing on its genes. There are even genetic factors that control for this by purposefully stripping out genes that lower fitness. This was a primary concern when using genetic modification in A. aegypti.
More research, however, resulted in the idea of tying the modified gene to so-called “selfish genes”, components that are far more likely to be passed on and dramatically increasing the spread of the modified gene. With this plan, scientists were able to overcome the fitness cost of the change by increasing the inheritance chance.
This is, essentially, what a gene drive is. A modification that isn’t positive for the individual or the population, but is forced to be passed on thanks to tying it to selfish genes.
The only other issue was being able to specifically place the genes next to the selfish genes to force this conservation. But you can likely guess what oft-discussed technological innovation solved that problem.
Yes, it’s our old friend, CRISPR-Cas9.
Resistance To Change
However, now we come to the new research and the new complication that has arisen. Using a genetic framework and modeling system, the researchers were able to determine that resistance to CRISPR modifications are not only possible, but also inevitable. Especially in fast-breeding organisms like mosquitoes.
So, does this mean that the idea of gene drives need to be tossed before they have even begun to be used? No, not quite. Not at all, in fact.
The same study also lays out other options, such as engineering methods with CRISPR that would significantly lower the resistance chance. It would still be inevitable, but it will take far longer. Next, the way in which the gene drive is introduced into a population will play a huge role in how quickly resistance forms. Models of the population to be modified are a necessity before any gene drive technology is to be rolled out.
A Directed Assault
Lastly, CRISPR techniques must be honed into one specific type of genetic repair when doing the modification. After inserting, changing, or removing the desired gene, CRISPR just allows the normal DNA repair systems to fix the broken strands of the genome.
What is desired is for the homology-directed repair option to be used by the cell, where it compares the genome to a template. This reduces the chance of mutations and resistance genes forming.
The other method is nonhomologous end joining, where the broken strands are just pasted back together with no care for genetic sequence. This has a huge chance of changing the genetic code and creating resistance.
Finally, multiple different CRISPR constructs should be created that can be swapped out via gene drives in a population as resistance inevitably forms, essentially repeatedly introducing modifications to cause the same desired effect every time an individual in the population develops a way around the prior modification.
That way, a change like making mosquitoes resistant to dengue fever so they can’t contract it and pass it on to humans will be retained in the population as a whole.
A Lengthier Consideration
At first glance, it would appear that this new research conclusion severely damages the potential for gene drives, but in reality, all it does is increase the need for prior thought and readiness to be made before using one.
And I think even the people against biotechnology can agree that increased planning is a good thing.