Artificial DNA: What is XNA?

27 February 2018

Interview with

Vitor Pinero, UCL

Georgia Mills is exploring the weird world of xenobiology – aka strange biology. Making something that follows the general rules of life, but is so completely different from what exists in nature that it can’t integrate, a sort of biological firewall. Vitor Pinero is aiming to this by building a completely new type of DNA.

Vitor - All life on Earth has always depended on DNA and RNA which is very limiting. Our plan has always been to can we change that chemistry, can we create a genetic material that is not DNA, that is not RNA? And, of course, once you have established that can you then bring it into biology, so can you have an informational system outside biology, but that we have to engineer all the bridges?

Georgia - A new type of DNA - the building block of life itself. So how do you go about changing it?

Vitor - The big advance is really coming from the chemists because they are the creative ones. They can come up with how to modify the nucleo base, how to modify the sugar in DNA, or how to even modify the backbone - the phosphate in DNA.

Georgia - When I think of DNA I immediately picture the famous double helix. But each step on that twisted ladder is what’s known as the base and it’s made of three parts, a nucleotide, a sugar, and a phosphate.

Vitor - They have many ideas. Chemically is an interesting area to explore but if you want to go into biology that’s not enough. You need the next step so you need to make sure that that chemistry is not toxic. You need to make sure that that chemistry is not used naturally by the enzymes that would normally replicate DNA. And if those sort of initial statements are sound you can start now moving the biological system to a user. Any modification in any of the chemical parts of DNA, we give it a name of XNA, so Xenobiotic Nucleic Acid.

Georgia - I see. There are these three components of DNA. There’s the base, there’s a sugar, and there’s a phosphate; combined, that’s one building brick of DNA?

Vitor - Yes.

Georgia - And then what you’re doing is taking one of those components and putting in something else - a different kind of chemistry which does a similar job and then hoping that will work the same way as DNA but it’s not made of it?

Vitor - Yeah. Because even small changes in the chemistry result in molecules that don’t have this classic helical form that DNA has, it has a distorted version. Ultimately over the course of six years we’ve managed to show that for multiple of these XNAs you can have a polymerase, this is the enzyme that replicates the DNA, but working with XNAs, so they can synthesise an XNA. I think we now have demonstrated about ten of those. They can take the XNA and bring back that information to DNA, these are all outside the cell in a test tube. But, of course, having demonstrated that, now the next step is can we bring this a step closer to biology.

Georgia - And that would be going in the cell because one of the things DNA does is it is used to build the bits of cell and, eventually, all the way up into an organism. Could XNA be used to build new organisms?

Vitor - To some extent that’s the hope; that’s where one of the applications would emerge from XNA. But, of course, that itself is a big challenge to bring it into a cell because you have to solve how to deliver the chemical precursors into the cell. You have to make sure that the cell can’t use it and any enzyme you engineer can’t use the natural blocks.

Georgia - What are the possible uses of XNA?

Vitor - Some uses don’t need to go into biology, because from the moment you have a chemistry that is resistant to biology itself that opens up a series of applications. For instance, nucleic acids you can evolve them to become natural binders, so they  become single molecules of nucleic acid, short, they can fold upon themselves, and almost work like an antibody, so they have a very tight specific binding to whatever you’ve engineered it to. However, they can be good diagnostics but they don’t usually make good therapeutics so you can’t use them like an antibody drug, primarily because biology has evolved to exclude biology. Our bodies are designed to destroy any DNA that’s outside the cell.

Georgia - So DNA doesn’t make a good drug delivery tool because the body will recognise it and destroy it. But XNA can slip past the defences taking the drug where it needs to go, a kind of pharmaceutical invisibility cloak…

Vitor - That’s in a test tube. If you want to bring XNA into biology you have different applications. You have, of course, the blue sky, the big question: can you make life with a different molecule?

Georgia - How far along is this? Is this something we’ll see in the next 10 years, 20 years, 100 years, what’s the timescale of when you think this might come off?

Vitor - With XNA, I think we’re probably looking the next decade to have a proof of principle, in a cell, an XNA is viable. But once that system is achieved, progress towards an organism would be very fast. In a way, we’re trying to emulate biology, it allows inventor, but once we can invent something then it’s easy to optimise.


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