Dr Phil Holliger, MRC Laboratory of Molecular Biology
Listen Now Download as mp3 from the show Hacking biology - synthetic DNA and experimental evolution
Phil:: Weíre trying to change the type of media, if you want in which one could write it. If you think of the Rosetta stone where you have the same message rendered in three different scripts, itís the same - the message is the same. Itís just the writing thatís different and really, thatís what weíre trying to do, by building different scaffolds on which the letters of the code can be mounted on, if you want.
So we replace the ribofuranose with a whole range of different chemical structure Ė 6-membered rings, 5-membered rings, interlocked rings, and weíve been able to show that these alternative scaffolds retain the ability to display the code in a readable form. So really, that basic function of storing and propagating genetic information is not unique to DNA and RNA, and that is a profound result that tells us a lot about Ė I guess both the chemical basis of life on earth and potentially, elsewhere in the universe.
Kat:: So life for millions of years on this planet has been built on this structure of deoxyribose, DNA, sugars, and RNA, and you're saying that you can make basically, ladders of information based on different sugars. Is there any particular reasons that evolution selected DNA and RNA, and didnít select these other sugars?
Phil:: We obviously have not tested out these other scaffolds to quite the same degree as life has tested out DNA and RNA, but what one could say with some certainty now is that the very basic functions of encoding, storing, and propagating genetic information and not unique to DNA and RNA. And I think the sort of inescapable conclusion is that life chose DNA and RNA, not for fundamental functional reasons, but presumably, you know, for opportunistic reasons. So, they represent, if you want, a frozen accident from the origin of life. RNA at that time was around, did the job and thatís what life got started with. Once youíve made that choice, you know, you stick with it. There's no reason to change.
Kat:: Itís a bit like VHS and Betamax or Blu-ray and HD DVD - people just go with one and that becomes the main one.
Phil:: Yeah, to some degree. Obviously, the current thinking is that life really got started on RNA and as the genomes grew bigger, RNA was slightly too unstable for the job. So, life moved on to DNA for storing information but retained RNA for many of its other functions. So thatís really how far life got and there was never any need to go any further than that, but it could have started potentially on some other backbone.
Kat:: What do you think are some of the applications for these new types of sugar-based codes that you're developing?
Phil:: Thereís a class of single-stranded nucleic drugs made from DNA and RNA called aptamers and really, these have the potential to rival things like antibodies at least in some clinical settings. But I think one of the reasons that really havenít had such success in the clinic so far is that the DNA and RNA are very much degradable and degraded by the body.
So, they generally need to be modified to have a chance to work as therapeutics and that really drives up the cost, lengthens the development process and makes them in some cases also compromises their actual functionality. So, one of the advantages of these new backbones is that they're very, very hardy. I mean, some of the ones weíve worked with, they're essentially Ė can't be degraded in the body and they're also very, very chemically inert, for example, very stable to sort of acidic conditions that you might encounter in the stomach. The hope is that we can build much more resilient therapeutics and potentially, also diagnostics and other structures from these backbones that will have a whole range of utilities.
Kat:: But if these Ė these are basically are life codes and they can't be degraded, they can't be broken down. Are there risks of putting something like that out in the environment?
Phil:: Well, if I said it can't be degraded, I think they can't be degraded within the sort of useful lifespan that you would think of a therapeutic. I think everything would eventually be degraded and excreted by the body, but you know, rather than being degraded within an hour of entering the bloodstream, these, I would expect them to last for days, weeks, possibly months.
Kat:: So not some kind of rogue code thatís going to take over your body.
Phil:: As I've said, there's nothing rogue about it. I mean, itís really, the code has not been changed. It is really just the scaffolding that has been modified.