Aarhus researcher discovers how to “remotely control” a gene

The technique is effective and non-aggressive.

And, not least, it enables the study of DNA from a completely new angle. We can now study a single gene while it is working – without relying on destructive types of genetic engineering.

‘This means that we can study the natural function of individual genes in cells, for instance when researching disease,’ says Associate Professor Rasmus O Bak from the Department of Biomedicine at Aarhus University (AU).

Bak headed the team of researchers from AU and the Medical University of Graz, Austria, that designed the new technique.

The discovery, which was funded by the Lundbeck Foundation, was recently published in the scientific journal Genome Research.

The technique is essentially based on mRNA, the technology also behind the new COVID-19 vaccines.

Truncated genetic scissors

The method described by the Danish-Austrian research group in their scientific article in Genome Research is basically a further development of the CRISPR gene editing technique, which can be used for genetic engineering of animals, plants and bacteria alike.

CRISPR is also referred to as genetic scissors because the technology can be used to destroy a single gene in an organism’s DNA – or to insert copies of a gene into the DNA. Both procedures can be used by researchers for studying specific processes within the DNA, leading, for instance, to the design of novel drugs.

These genetic scissors can be described as a microscopic tool platform, consisting of a “sat nav” able to navigate to the exact gene the researchers wish to manipulate and of the scissors themselves.

In reality, the “sat nav” is a tiny molecule able to direct the scissors, and the scissors are a protein able to cut into the DNA.

The technology is extremely clever, and since the turn of the millennium, CRISPR has increasingly provided opportunities for using genetic engineering to develop anything from novel medicines to “custom-designed” vegetables.

‘But, in some ways, CRISPR is also rather impractical, and this is what we’re trying to improve,’ Bak explains.

‘When you use the CRISPR technology for genetic engineering in the lab – either to destroy a gene or to insert copies of a gene – you introduce a permanent modification in the cells you’re working with. And this is where our version of CRISPR differs from the rest – because it still has the “sat nav” but has no scissors. Instead of the scissors, we hook three molecules onto our microscopic tool platform, and once we’ve deposited the molecules on the gene to be examined, they make the gene work overtime. It’s as if they speed up the gene’s natural activity, and while the gene is working flat out, we can study it.’

And if Bak and his colleagues want to switch off the activity in a gene, they can also use the new technique to do this:

‘We’ve developed another molecule that acts like an off switch, and our microscopic tool platform can also transport this molecule to a gene we want to study. This allows us to study a gene when it’s doing nothing at all – and that could also be relevant. Regardless of whether we choose to speed up a gene or switch it off, the artificial level of activity we introduce lasts for a few days. This gives us good time to work, and the genes we’ve studied then return to their natural levels.’

Potential for treating disease

Now that we can “remotely control” genes in cell cultures, how long before we can use the technique to “remotely control” genes in patients?

According to Bak, this is not imminent but will most likely be attempted in time:

‘In the studies on which the article in Genome Research is based, we demonstrate that our version of CRISPR can also be used to influence cell development. We succeeded in manipulating blood stem cells using our tool platform. These stem cells develop naturally into a variety of blood cell types – and, to a certain extent, we could actually control this development so that we ended up with a majority of one specific type of blood cell.’

The control mechanism the researchers were able to demonstrate points towards cell therapies aimed at influencing – remotely controlling – a patient’s genes. For instance, by giving the patient “sat nav”-controlled molecules to cause specific genes to initiate production of a substance the patient lacks.

‘It’s quite logical to think along these lines, but we have a lot of tests ahead of us before we reach this stage,’ says Rasmus O Bak.

Lundbeck Foundation Fellow

Rasmus O Bak heads a research group at the Department of Biomedicine, Aarhus University. He was appointed a Lundbeck Foundation Fellow in 2017.

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