Immunity... to CRISPR?

I suppose it won't be long before our cells start to get confused about their genomes - which sequence came first?

CRISPR, gene editing in general actually, has played an unexpectedly fundamental role in my project. It's been almost acting like a bridge that connects model system capabilities of C. Elegans to human neuroscience implications. What we haven't discussed very much however is crispr as its own stand-alone technology. Recently, researchers have been asking questions about and experimenting with various ways to use crispr for treating congenital defects such as cystic fibrosis. The concept of this immunotherapy, beyond of course the genetics side of things, is grounded in a vaccine-like mechanism. Every organ in our bodies has a group of cells called "stem cells." These are a special class of cells because they are always creating new cells to replace old ones. First, an immunotherapeutic injection with all the necessary genetic components would be delivered to stem cells for any specific tissue. Once the DNA of the stem cells is altered, then any mitotic (identical progeny) regeneration of cells will maintain the same genetic sequences. In theory, something like this sounds great - if it works, soon enough otherwise fatal diseases could be cured with the likes of a flu shot.

As with most things though, there's a catch... crispr operates through a bacteria called cas9. Now, what's your first thought when you hear or read the word "bacteria"? Probably not the most healthful thing. Turns out, our immune system reacts in a little bit of the same way. From birth, our lives present the physical substance of our bodies with a multitude of external pressures, challenges, and novel experiences. As we grow, our immune systems develop resistance to certain harmful things (types of bacteria included) - strong walls of protection against things that disrupt equilibrium or introduce the threat of disease. Oftentimes, this acquired immunity causes our bodies to be extremely resistant to any type of foreign substance. So you can guess that unless crispr were a little bit of fairy dust mingled with some abra-cadabras, our immune systems would be pretty suspicious upon their first encounter with the treatment. The biggest problem really arises due the fact that the cas9 bacteria can come from one of two places: Staphylococcus aureus or Streptococcus pyogenes. Briefly, Staph and Strep are both types of bacteria that almost everybody is exposed to at some point in their lives. You would think then, that since the body's already been exposed to these things, the immune system is already familiar, making the substance less of a threat. In reality though, and anyone who's had strep throat can back me up on this - these types of bacteria are (in usual circumstances) an extremely traumatic experience for our immune systems. So traumatic that they can't recover on their own - amoxicillin or an alternative antibiotic is often prescribed. With the help of medications and small-scale natural selection happening in our bodies, our immune systems develop a strengthened resistance against these bacteria.

I know this might be looking like unnecessary jargon right about now but stay with me, it is all quite important. Essentially, this means that the crispr cas9 gene splicing technology cannot be used for immunotherapy on anyone who has already been exposed to the staph or strep bacteria. Let me say it again, THE CRISPR CAS9 gene splicing technology canNOT BE USED on anyone who has already been EXPOSED to the STAPH or STREP bacteria... "uh-oh" was my first thought.

But reading and exploring all of this newfound information made me think about a certain disparity that exists between the functions of a model system and the degree of speculation that is often present. Sure, C. Elegans, mice, monkeys, and fruit flies are all genetically related to humans, making them quite fine model systems. But no matter how many nucleic acids you change or how many trait loci you translocate, there is no possible way to account for how humans are impacted by their environment. One of the things I often struggle with when thinking about gene editing is that its introduction into the nervous system is rather unlikely at the moment. Primarily, this is due to the separation between nervous tissue vasculature and everything else by means of the Blood Brain Barrier. But the other, more confounding factor lies in the fact that there isn't one single gene or even a group of genes that marks the existence of a neurological disorder or disease. Correlation and causation are hard to determine when there isn't any clear patterns. It seems then, that these complications are considered "multifactorial," meaning they're controlled by a very specific and unique combination of genetic components and environmental influences. My newest question then; how on earth does one replicate things like human interaction or a particularly stubborn strain of influenza on this random year of life in a simple little nematode? The sullen answer is, no one can.

You see, with the possibilities of model systems come a significant caveat - a model is never exact. But I will contend that a model system isn't supposed to be exact. If we can't understand something because it's too complex, then what good would an equally complex system do? It is absolutely true that we'll probably never be able to replicate these environment-human interfaces in any model system but that doesn't mean model systems are completely useless. They're the foundation of knowledge on that which is inaccessible inside of a human. The dangers with rejecting model systems come in two different forms of the extreme. The first is debunking any value at all. Such pessimism in biological research would get us nowhere. At the same time though, we should not place all hope in these limited organisms. Humans, at least if our lack of knowledge is any indication, house so so much more than a transparent and glowing worm can barely begin to suggest. When using model systems then, we ought to take everything with a grain of salt and realize that structure fits purpose. If the purpose of a model system is to show a smaller scale of what we can't see, then we can't disregard that key detail of "smaller scale" when assessing and reflecting on our results/findings.

CRISPR, in its infancy was probably one of the most promising treatment possibilities we have seen in quite a while. Although this immunity factor is definitely a little bit of a hiccup, it doesn't mean that the possibility of such a treatment is no longer promising. Oftentimes, figuring out what doesn't work can be far more valuable (and possible) than finding the one thing that does work. It's exciting stuff, these rapid medical advancements and increasingly prevalent work with model systems. But it's important to keep a few things in mind. There is a disparity between model and actual, such a fact must not be overlooked. Maybe it'll take time, more complex model systems, or even a reset button, but there is not a doubt in my mind that we will reach an answer. Progress is always present, we need only direct our questions towards finding it.