Researchers Crack Genetic Engineering in 3-Dimensional Space

A new breakthrough in gene editing modifies the CRISPR technique to allow the movement of genes to specific locations in the cell nucleus.

Genetic engineering is a field that has, in theory, been around for many decades, yet in many ways, the field is still considered a new frontier by most scientists. This is because the ethical dilemmas it brings up and high-visibility failures of early human tests have for many years driven serious genetic research into the back rooms of academic institutions and the imaginations of science fiction writers.

Fortunately, all of that is starting to change due to a new technique in genetic editing you may have heard of… CRISPR.

Medical Technology

CRISPR Gene Editing Used on Mammals for the First Time

CRISPR (or “the CRISPR/Cas9 technique”) is changing the game. It is one of the biggest science stories of the past decade and will probably also be the biggest science story of the next decade. It allows scientists to edit the genome of LIVING organisms quickly, cheaply, and with an incredible rate of accuracy.

This could mean curing diseases, ending world hunger, or even taking the next step in human evolution. The possibilities are endless. But don’t get too excited yet, because CRISPR is still a relatively new technology and there is still a lot of research and refining to be done before in vivo human testing can begin.

Recently though, a new variant of the CRISPR technique called CRIPR-GO (the “GO” stands for “Genome Organization”) was developed that begins to address some of its progenitor’s issues and may hold the key to unlocking a level of the genetic code which has eluded scientists for years.

Let’s get into the SCIENCE!

The lead researcher with a model of the modified Cas9
Source: Stanford.edu

Let's talk CRISPR vs CRISPR-GO… Broadly.

At its most basic level, the CRISPR/Cas9 system takes advantage of a sort of genetic “immune system” many bacteria are equipped with. When isolated, you can feed it samples of DNA or RNA sequences that you want it to target, then when it makes it into a cell, the CRISPR molecule will selectively search out and excise only sequences that match the one you fed it.

This works great at excising unwanted genes, but you can also use this system in conjunction with repair enzymes to INSERT a working, version of that gene, or even something altogether new. Mostly, the reason why CRISPR was and is so revolutionary is because it makes gene editing incredibly cheap and easy.

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What would have taken a team or researchers thousands of dollars and months to accomplish can now be done in an afternoon for about $75. But there are still significant issues to do with the safety of the technique. Though it’s highly accurate, it’s not perfect, and cuts or insertions in the wrong place in a person’s genome vastly increase the likelihood of a person developing cancer.

Moreover, there is the ethical question of whether permanent changes to a person’s genome that affect the germ cells (AKA the cells that would carry the genetic information of your children) should even be legal.

CRISPR-GO takes a first step in addressing some of these issues.

Researchers Crack Genetic Engineering in 3-Dimensional Space
Source: Wikimedia

Developed by researchers at Stanford University, what makes CRISPR-GO unique is that it uses a modified CRISPR protein to reorganize the genome in three dimensions. If CRISPR is like molecular scissors, then CRISPR-GO is like molecular tweezers, grabbing specific bits of the genome and plunking them down in new locations of the nucleus. But it’s more than just physical relocation: displacing genetic elements can change how they function.

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In other words, this sort of technique could be used to optimize rather than repair a person’s genes. Up or down-regulating misbehaving genes, encouraging telomeres (the molecular caps to chromosomes) to grow longer rather than degrade with age, or even guarding against cancer by promoting tumor-suppressor genes.

There is even some research that suggests that these changes can be toggled as heritable or non-heritable based on where they lie within the cell nucleus which could help solve the ethical dilemmas we already discussed.

“But wait,” you might say. “Why the heck would the location of a gene affect its function? It’s still the same code and that’s what matters, right?” Wrong. Well… mostly right, but when it comes to cell biology nothing is ever as simple as we might like. So to answer this question let’s take a quick digression into the idea of EPIGENETICS!

Researchers Crack Genetic Engineering in 3-Dimensional Space
Source: Wikimedia

 Epigen - WHAT - tics?

The hard truth is that sophomore biology teacher you loved actually lied to you when she said that the genetic code determined who a person was. Turns out there is an entirely separate level to gene expression that has nothing to do with the physical “code”. Epigenetics is the study of heritable changes in gene expression (active versus inactive genes) that do not involve changes to the underlying DNA sequence.

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What’s especially interesting is that these changes happen over your lifetime and yet can still be passed to your children- something Mendelian genetics thought was impossible for hundreds of years.

But think back to any identical twins you’ve met. They share the exact same genetic code, but if you look close enough there are always subtle differences that eventually allow you to tell them apart. These are almost always due to epigenetic changes.

This kind of change is a regular and natural occurrence that at it’s most basic level, uses chemical changes in the DNA molecule to alters its physical shape at a particular spot, leaving a gene inaccessible to the enzymes that would read and replicate it, or vice versa makes it easier for them to reach it.

Piggy-backing off of this field of study, this new research adds the idea that the physical location of the gene within a cell nucleus can also affect this kind of secondary expression metric. This was something scientists had long suspected but had no way of proving until now.

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It’s best to think of a cell nucleus like a house with several different “rooms”, and like a normal house each room has a slightly different purpose. Some rooms are for storage, and the genes within don’t get touched often, whereas other areas see more traffic and therefore more reactions.

What makes this approach really special though, is that the change in genetic location is both chemically inducible, and fully reversible. So if a patient were to have adverse reactions to the treatment, it could be quickly undone with little to no side effects.

Researchers Crack Genetic Engineering in 3-Dimensional Space
Source: Wikimedia

 A bright, but possibly far-off future 

I’ll admit, this kind of research is pretty high-level, and on its face may seem a little boring, but the potential it holds is staggering. For instance, telomere degradation is regarded as the singular most important cause of aging, but the scientists showed that by moving telomeres closer to something called the “Cajal Body” they actually grew back, increasing cell viability and halting the aging process. This could be a huge advancement in human longevity.

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CRISPR-GO can also be used to create structures called “Promyelocytic Leukemia bodies” (PLC’s), which are big globs of protein that are known to suppress pro-tumor genes. Unfortunately, most of these pro-tumor genes are necessary for life when they are functioning normally, and it’s only through mutation that they become a problem.

But by positioning cancer-causing genes near these PLC’s one could significantly reduce the rate at which cancers could develop while simultaneously not affecting their normal cellular function. Yes, that means what you think it means… a vaccine for cancer.

Of course, we must end with a word of caution, lest you, dear reader, get too excited. While the evidence shown by CRISPR-GO is exciting, the research is still in a pilot stage, and there’s more work to be done before these findings can be fully confirmed.

Moreover, while there is a lot of potential here and the research has answered a couple of very important questions, it has also opened up about 20 more. In the near future, it will be very important to decipher why these location-based effects take place in specific nuclear compartments, and what the underlying cause is.

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Until then we’ll just have to keep dreaming and hope no one accidentally pulls a Bruce Banner and "Hulks" themselves… That might set back genetic research another decade!

The new research was published in the journal, Cell.

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