A Crack in Creation [Book Review]

So if you have you been listening to some of the most hyped up scientific discoveries in the last decade, you have probably heard of CRISPR (no E) and it’s potential in gene editing technology. And as you can guess, this book is on that technology. The book gives you a good description on the technology, how it works, and its application in the first half. Then it continues with an ethical conversation on its possible portfolio of applications in the second half. This section, personally, was almost overly-detailed to the point of me losing interest in the subject……….but I’ll get to that.

But first the fun part: the technology.

CRISPR (cluster regularly inter-spaced short palindromic repeats). I actually have no idea what “palindromic” means, but we don’t really have to. It just means that there’s a sequence of identical sequence of repeated genes in the genome. They are never spaced throughout the gene, just in a designated section.  And between these sequences are copies of viral DNA. It’s basically a library that the genome references when it needs to identify what is “foreign DNA” (typically viruses).

How do we apply these CRISPR genes for gene editing?

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We don’t. I don’t know why we keep calling it CRISPR, but here’s probably the reason:

The cell as a whole manufacture proteins of various functions and types. Mostly any action that a cell can do is dependent on the functionality of some sort of protein (or in most cases, A LOT of proteins). And the cell’s self-defense system is one of them. Specific proteins will create unique “tags” of DNA from the CRISPR genes, and other proteins will utilize these “tags” to hunt down matching DNA and cut it up.

The last part is the significant aspect of the whole CRISPR system: the protein that utilizes a tag to cut up DNA. We just want that protein, typically known as Cas9 (Crisper ASsociated protein #9).

We don’t need the CRISPR genes, just the Cas9 proteins that attach to the tags created from other Cas proteins.

Jennifer, both the author of this book and “finder” of the Cas9 protein’s potential, initially noticed that for Cas9 to function naturally it needed two pairs of genetic code to function: the strand to bind to the virus DNA and the second to bind to the protein itself. Natural selection wasn’t efficient enough to just make one gene strand that could do both…….so that’s what her team and the following major publication demonstrated:

1 protein + 1 gene strand = 1 precise cut

It’s not 100% precise, but it’s pretty darn close compared to the previous technologies available. And since we can just have bacteria make more of the protein, it’s dirt cheap (relatively to biochemistry standards, that is). And if you make two types of Cas9-encoded proteins, you can cut two locations and remove a subsection of DNA from the system.

Note that Cas9 doesn’t fix anything; it just cuts DNA. If you want to add DNA to the genome, it gets a little more sketchy. We don’t have any specific biochemical tools that say “put x gene in y location.” Scientists just utilize the cell’s own DNA repair mechanism (more proteins) to either stitch the genes (either referencing a floating template gene, the partner chromosomal pair, or just haphazardly) back together. So some genetic diseases are easier to cure than others, in the case of adding vs. deleting genetic information.

Note: I don’t know if it’s a field yet, but I love the idea of “protein engineering.” Currently, we just see what mother nature already makes, and we research what else we can do with these products. Wouldn’t it be nice if we could use quantum biological physics to build a protein model from scratch to do X, and just inject DNA into a protein to manufacture the desired “artificial” molecule? That’s the scientific breakthrough that I am waiting for!

And that’s how Cas9 (CRISPR technology) works. Part II is about integration. Which starts out technical, but drags out into being ethical.

Cas9 has already been used on a lot of applications, though most of them have only been in research labs. Food, animals, human cells. Finding a target gene and cutting it. If you want to add genes, you inject the cells with template genes for the body to use as a repair blueprint. And that’s how you replace an A with a G (or a lot more than that). It’s a lot easier to do when there are less cells, like a sample of bone marrow or a single germ (egg/sperm) cell.

The coolest method of implication that the book talked about is the gene drive. For a gene drive to work, the newly implemented gene also codes for the Cas9 protein and “gene tags” itself! If one chromosome has this gene, it creates the Cas9 protein and ensures the paired chromosome also undergoes the same edit. This guarantees that its offspring/kids/baby kittens will get one of those genes during reproduction, edits the other parent’s inherited genes, and the cycle continues until the entire population inherits the “driven gene(s).” This is one way to kill the mosquito population: female sterility. The males can still inherit the gene and produce with the unaffected females until there’s no more fertile females left….. and the whole population just collapses! We just need to make one mosquito with the gene drive and let it free!

And that brings us to the ethical issues. A technology so easily accessible, financially and technically (there’s simple lab kits available now). Could it be used to target a specific ethnicity with a specific genetic trait? Would a single edited creature bring the downfall to a major staple in the food chain (or food web if you prefer)? Does this bring into similar disputes against GMO (genetically modified organisms) and its human-consumed products?

This book goes on for ~50 pages of continuous questions, details on international meetings, social opinions, and related technological disputes. A major lash back on the technology was when a group in China (it would be China) did the first Cas9 edits on a fertilized human egg cell [Yes, it passed China’s ethical standard boards, and the cells wouldn’t develop anyway due to an intended flaw in the genome. But in the name of Science, anything goes ……. I guess]. A lot of questions, and not a lot of answers. Whatever answers we do have are very opinionated and dependent on our upbringings, beliefs, and possibly our current mood.

Just like politics…..

But you can never tell what is good until it actually happens. You can’t make a statement until you have data on the subject. And that’s the scary part; we may overshoot the technological harm an idea might bring BEFORE we can detect and the situation becomes irreversible.

But Jennifer (the author) also brings up her own, and quite compelling, opinions for the utilization of the Cas9 protein. While this procedure does cause an artificial edit in the gene, it is far more controlled and occurs significantly less than what occurs naturally in your own body. There’s random breaks, radiation edits, chromosomal twists and recombinations, and even “jumping genes” that move on purpose (please don’t ask me why). And while there may be some ethical dilemmas that we face, the main drive behind this technology is overall positive (mostly for mankind; not for the mosquitoes). And there may be a time where we ask ourselves if it’s ethical NOT to edit an embryos genome so it can live a happy, healthy, and self-fulfilling lifestyle!

There’s also an underlying fact that I truly appreciate the author bringing up within the last chapter. The technology behind CRISPR was not something that was a direct action to discover a specific tool. No one said, “I want a better gene editing tool”……research, research, research……..”Eureka, I’ve done it!” CRISPR has been known for a long time now, and the discovery of the proteins that utilize it have been known (but their underlying reactions and workings were not). Jennifer didn’t even know much about CRISPR until someone approached her and asked if they could use her genomic expertise to help solve their questions on these CRISPR associated proteins. So while Jennifer and her team did publish the first paper on the understanding and application of the Cas9 protein, a lot of additional thanks have to be given to those that enabled her research group to go in that direction.

In the end, research is about discovering an area and seeing what comes up. Sometimes it gives you lemonade, sometimes it gives you lemons. But I’ll tell you what… most of the time it just gives you lumps of rocks. And it’s hard being a scientist for that reason.

A big thank you to all researchers out there in the world! Even though most of you don’t find things as “awesome” as the Cas9 protein, we at least know that those areas don’t contain any groundbreaking technology. And it’s all thanks to you [and trust me, I’ve been there].

 

Also……..F#@k mosquitoes.

 

 

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