Towards Safer Gene Therapy with Calgary Undergrads

Genetic engineering isn’t easy. Sure, modern synbio techniques are easier than techniques of yore, but there are still a lot of challenges that researchers face.

Take gene therapy and precision medicine, for example. Very hot topics, because you can customize therapies to an individual person. You can account for the idiosyncrasies of an individual’s body, and minimize the likelihood of side effects or rejection.

After all, what better way to treat somebody than using their own cells? Why not treat genetic disorders by re-engineering your own cells and then putting them back in you?

Gene therapy still has a ways to go, though. Think of it like software engineering. Say you have a new module that you need to integrate into your app. You need to figure out where to put it so it doesn’t break the rest of the program, and you need to test it to make sure it works as you hoped.

Similarly, in gene therapy, you need to select a good site in the cell for your new gene, and you need to make sure the new system works without side effects. But you also have to consider how to physically get the new gene into the system so it can even be integrated at all.

This is where the University of Calgary iGEM team comes in. This team of eight undergrads spent the summer building a number of new tools to help researchers address these challenges.

Tools of the Trade

It’s a little complex, but there are three major components:

  1. Using CRISPR-Cas9 (I swear I’ll talk about it someday) to add a landing pad for the new gene. CRISPR is a powerful tool that cuts DNA at a target spot, inserts a new piece of DNA where it cut it, and then glues it back together. Imagine cutting a piece of rope so you can extend it with a new piece in the middle.
  2. Using a set of proteins called recombinases, you can then swap out the landing pad with your targeted gene. Why? CRISPR by itself can’t handle inserting large genes very well. Using the rope example, if your middle piece is too big and clunky, you can fumble and drop one of the two ends you cut. If you drop the end of a piece of DNA, this essentially breaks the chromosome in two. (Biologists call that “a Very Bad Thing.”)
    So what this two-step method does is use the landing pad in step 1 to mark a site where recombinase can do the job, instead. It’s like priming a surface for paint. You need the landing pad there or else the recombinase doesn’t work.
  3. Using something called chromatin-modifying elements (CMEs) to protect the DNA. This is especially important in eukaryotic cells like humans, animals, plants, and fungi. Eukaryotic cells are much more complex than prokaryotic (e.g. bacterial) cells and can silence a gene in other ways. The CMEs are used to insulate the new gene from these unwanted effects.

(Whew. That was a lot, wasn’t it?)

Most iGEM teams use bacteria, and use CRISPR-Cas9 to make small insertions or deletions in their sequences. That’s not quite similar enough to humans when gene therapy is involved.

The cool thing is that the Calgary team designed a new way to put large pieces of DNA into eukaryotic cells. That’s not done very often in iGEM. The goal is to provide the synbio community with this new set of tools so they can get better results working with model organisms that are better suited for gene therapy.

There are a lot of other things they did, including microfluidics design and an online software-scraping algorithm. Be sure to check them out, as well!

You can also follow the team’s adventures at iGEM on their Facebook, Twitter, and Instagram.

The team will be presenting their project at 12:00pm EST on Saturday, October 27th. Good luck, Calgary!

Photo credit: iGEM Calgary 2018

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