Briefing Chat: ‘Zombie cells’ resurrected with new genes

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1:11Hello 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 Pertruchow. And I'm Sharmini Bundel, 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 take me away, what is a zombie cell? Yeah, so this is a Nature News article, and it's based on a bio-archive paper. And yeah, a zombie cell is basically a cell that they've killed, sort of killed, and then brought back to life.

1:50Thus the zombie. As in from the dead. Maybe it is Easter themed after all. But these are bacteria of the genus Mycoplasma. So these bacteria, 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 going to give you a bit of background here. There's some old news that is still very interesting. It was about 15 years ago, there was a paper which has actually got some of the authors of this paper on as well.

2:25And it was about creating what they called the first synthetic cell. 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 capriculum. 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.

3:10And 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 loads of bacteria have these clever ways of absorbing genes from their environment so they have like a 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 taking up the antibiotic resistance gene and you know the experiment hasn't worked at all, but you've got a completely false positive.

4:10Gotcha, gotcha. So this is a more fail-safe way to test this. Yeah, if you kill them first, probably they can't do that, you hope. So actually, funnily enough, in this particular example, the bacteria used, which is the same as the one that they used 15 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.

4:51So 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 sort of more advanced 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?

5:30Do 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 favourite. 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, what about if you sort of mix and matched 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.

6:05And this paper, again, this is still two species within the same genus that have been swapped. So that is that is easier. So it will still need another step. And there's some talk in this news article as well about CRISPR might be useful as well to make sure that your new genes 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.

6:40but 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 20 years of work, because basically these researchers in 1997 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 16 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 past 20 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 2013 these researchers thought we can do this forever we can do this definitely because they've done it for 25 generations oh 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 58th generation impossible 58th in these particular mice yes in these particular mice so So if you clone, clone, clone, clone, clone, clone, 58 times, that's the limit.

8:51And after then, no clone, no more. And it's just because, you know, cloning, you're 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 58 generations, loads of DNA was going missing.

9:33Parts 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 mutations that were happening. We were actually impacting the whole genetic machinery. So pretty. Yeah. This isn't just a matter of a gene breaking 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 58 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 yes exactly a star bullying you can clone it and that is done in some places including the us I was also thinking of rich people cloning their pets.

11:01Like apparently you could just privately, 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 how much you could do that. And so one of the people who was interviewed in 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 Cooper This all makes sense I feel like this is a sci-fi film That I've seen somewhere I'm not sure what Listeners If you know which 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 naturepodcast In various places You can email us We're podcast at nature.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.

12:04I've been Nick Pertuchel. And I've been Shalmini Bandel. Thanks for listening. Hi, this is Hannah Burner from Giggly Squad. Have you ever put on a bra that makes you feel like a goddess? Prepare to be obsessed with the Dream Angels Wicked Bra from Victoria's Secret, the iconic brand behind the world's most comfortable bras. and I only wear the most comfortable bras. The bestseller features an innovative sling for perfect lift without padding and the fit is chef's kiss. Awaken your inner goddess with new colors and super femme lace embroidery. Find out why this bra has thousands of five-star reviews and counting.

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