Briefing Chat: ‘Zombie cells’ resurrected with new genes

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Hello and welcome to the Nature Briefing Podcast. This is the Friday show where we take you through a couple of stories that have been featured in The Nature Briefing, Nature's daily email roundup of the latest science news. I'm Nick Berchichau. And I'm Charmanie Bundell, and I have a oddly Halloween themed story for you this week, actually. It's all about zombie cells.

Yeah, it seems like an odd time of year to talk about it considering it's nearly Easter, but um take me away, what is a zombie cell? Yeah, so this is a nature news article and it's based on a bioarchive paper. And yeah, a zombie cell is basically a cell that they've killed, sort of killed, and then brought back to life. Maybe it is Easter themed, after all. But these are bacteria of the genus Mycoplasma.

How does one bring them back to life and why is that something that scientists would be interested in doing? Yeah, it's the why that is key, because they weren't really interested in bringing them back to life. That is not the point of this study at all. This is all about genetic engineering and

transferring genomes from one species to another. So I'm gonna give you a bit of background here. There's some old news that is still very interesting. It was about fifteen years ago there was a paper which has actually got some of the authors of this paper on as well, and it was about Creating what they call the first synthetic cells.

So what they did was they chemically synthesized the genome, so 1.1 million base pairs, like the full genome of this particular Mycoplasma bacterium, so mycoplasma mycoides. And then they transplanted it into a closely related species, Mycoplasma Capricolum.

So this is now a species with an entirely synthetic genome and they put a little antibiotic resistance gene in there, which basically is the way that you tell whether it's worked or not, because you can't really go in and look. But what you can do is you can grow your cells in the antibiotics and The ones that are fine presumably have this gene in and therefore presumably have the genome successfully. Transplanted.

And so in this case they've gone one step further and done it with a dead bacteria, they've transplanted a synthetic genome into that. Is that what they've done? Yeah, but the reason they wanted to do that is in a lot of cases where you want to be doing this kind of genetic engineering, you know, this is a really interesting topic that has a lot of potential. But, you know, starting out just with the bacteria.

In a lot of cases, when you are trying to test whether you've transferred your genome or not, you know, let's say you use your antibiotic resistance gene as a little marker, it's really hard to be sure that your process has worked. Because if you Loads of bacteria have these clever ways of absorbing genes from their environment. So they have like um homologous recombination, for example, which is one way that they like

take in these genes, which could mean that your bacteria is just Oh, a gene, I'll have that. Taken up the antibiotic resistance gene and ha you know, the experiment hasn't worked at all, but you've got a completely false positive. Gotcha, gotcha. So this is a more fail safe way to test. Yeah, if you kill'em first, probably they can't do that, you hope. So actually, funnily enough, in this particular example, the bacteria used

and which is the same as the one that they used fifteen years ago. And it doesn't actually give false positives because it doesn't have this recombination ability. So this is more of a proof of a methodology that could work in other species. So what they've done in this case is they've basically inactivated the recipient cell's genomes. So these cells can't replicate, they're functionally dead. One of the authors said the cell is destined to die, but we give it life.

Um because they Yeah, they so they then incorporate this genome, not a synthetic one in this case, but a genome from the sister species. This is again still both mycoplasma species. But because the cell was dead you know that it can't have done, even if it could, any sort of homologous recombination or anything like that. So it's a proof of concept that could be adapted to other bacteria that would allow us to do all sorts of

DNA engineering and synthetic DNA work as well than we can do right now. So in the future this could be used for other bacterial species, as you said. So what sort of things are they aiming to do? Do they have any ideas where they might like to take this next? Well being able to use it in other species is kind of the key starting point because obviously everyone knows E. coli the lab favorite and if you can get something like this working in E. coli or some other sort of model organism

then you have this sort of general purpose platform, this base to go off and do your experiments with. One example is given is oh, what about if you sort of mix and match the cellular chassis of different bacteria to see which combinations work and which don't, and that would be interesting from an evolutionary perspective. still at the bacterial level. And this paper, again, this is still two species within the same genus that have been swapped. So that is

That is easier. Um, so it will still need another step. And there's some talk in this news article as well about like CRISPR might be useful as well to make sure that your new jeans that you're adding are definitely being taken up. So it seems like there's a lot of options and a lot more that needs to be done to get these processes working that could then eventually lead to more fascinating discoveries.

Well I've got a very related story this week. It's also about shuttling genomes across and that sort of thing. But it's in bigger animals, it's in mice, and this is all about cloning. Researchers think they found the limit to cloning, at least in mice. Why does cloning have a limit? Well that's a very good question and one that they were trying to find out. So this was an article I was reading in Nature, based on a Nature Communications paper, and also based on twenty years of work.

Because basically, these researchers in nineteen ninety seven first cloned a mouse. And ever since then they have been basically trying to push the boundaries of what is possible with cloning. So cloning works by taking the nucleus from a cell that isn't reproductive normally, so like a skin cell or something, you'll take the nucleus, you'll take all the DNA, all that stuff, and put it into an embryo that's been emptied out of its nucleus.

And they've done this with live mice, they've done this with dead mice, they've done this with dead mice that have been frozen for sixteen years, they've done this with freeze dried cells from mice. And cells in mouse urine. Okay. So they've been doing a lot of cloning, right, for the for the past.

Twenty years, cool. Yeah. Their whole bag is trying to push the limits of what is possible with cloning. And that's where this particular story comes in. So Since they cloned this first mouse, they've been trying to understand how many times you can clone a mouse before things start to go wrong. And so that's this limit that you're talking about? That's this limit I'm talking about. So if you clone a mouse

Then from that cloned mouse, clone another mouse, how many times can you do that before there's some sort of issue? And in twenty thirteen. these researchers thought, we can do this forever. We can do this indefinitely'cause they've done it for twenty five generations. Well you'd think, like, what could possibly go wrong? Well it turns out if we fast forward to today

A lot of things go wrong in the DNA. So it seems that an accumulation of mutations sort of renders this process by the fifty eighth generation impossible. Fifty eighth in these particular mice. Yes, in these particular mice. So if you clone, clone, clone, clone, clone, clone, clone fifty eight times, that's the limit and after then no clone no more. And it's just because, you know, cloning your

copying the DNA exactly. But throughout life, throughout the process, mutations arise and generally when random mutations arise they're more likely to be Bad than good. Yeah, and in this case, they estimate that the mutation rate that they saw in the clones was about three times higher in normal mice. So something was happening in the clones that was you know different and increasing this rate.

of mutation. And it actually got so bad that towards the end of this experiment, when they're approaching this limit of fifty-eight generations, loads of DNA was going missing, parts of it was flipping, parts of it was moving into different chromosomes and eventually they lost the entire X chromosome. And To quote the article here, ultimately this genetic mayhem made it impossible to continue creating new clones. Wow. So it was the the mutations that were happening were actually impacting

the whole genetic machinery. So pretty, yeah. This isn't just a a matter of a gene breaking and and being unable to survive. This is Everything breaking down. Genetic mayhem. Genetic mayhem is the name of the game and yeah, ultimately they just weren't viable anymore. But it's possible that some organisms have found a way around this. You may remember that a couple of weeks ago we spoke about a fish, Benjamin Thompson, our colleague.

Spoke about a fish that was able to reproduce asexually without accumulating all these bad mutations. So there may be ways to circumvent it, but at least in this study they found that the limit was fifty eight generations.

And this could have implications. for animal breeding. So you may not know this, but in some places in the world, if you have like a prized animal, say a prized bull that had particularly good you know, it was really good at being a bull. Like you really wanted to ensure its genetic legacy. They start bulling. Yes, exactly. A star bullying. You can clone it and that is done in some places, including the US. I was also thinking of um like rich people cloning their pets.

Like apparently you could just privately like if you have your favourite pet and it passes away, you can clone it and have Another one. But perhaps there is a limit to d how much you could do that. And so one of the people who was interviewed this article said if you want to preserve animals in this way

It would maybe be advisable to store a large number of cells from the original animal to then clone rather than cloning the clone, if that makes sense. Don't clone the clones. Don't clone the clone. I feel like this is a sci-fi film that I've seen somewhere. Um I'm not sure what. Listeners, if you know which the film or book this is the plot of, do write in and let us know. I think that is all we have time for this week.

But you can reach out to us with your thoughts and comments in the gap before you hear us again. You can find us on social media, we're at nature podcast. and various places you can email us with podcast at nature dot com. And if you've enjoyed these stories, we'll put links to them in the show notes and a link of where you can sign up to the nature briefing. If you want more like them directly to your inbox I've been Nick Perchichel and I've been Shamani Bundel. Thanks for listening.

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