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 been featured

in the Nature Briefing, Nature's Daily Email Roundup of the latest science news.

I'm Nick Bertrichell.

And I'm Sharminy Bundell, and I have a Halloween themed story for you this week, 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?

Yes, so this is a Nature News article.

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, was it from the dead?

Maybe it is, he's de-themed, after all.

But these are bacteria of the genus Micoplasma.

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, and it was about creating what they called the first synthetic

cell.

So what they did was they chemically synthesised the genome, so 1.1 million base pairs,

the full genome of this particular Micoplasma bacterium, so Micoplasma mycoides, and then

they transplanted it into a closely related species, Micoplasma 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 this 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 environments.

So they have like a homologous recombination, for example, just 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 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 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 cells,

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, because they,

yeah, they, so they then incorporate this genome, not synthetic one in this case, but a genome

from the sister species, this is again, still both microplasma 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, and 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 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 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

watched, so that is, that is easier.

So we'll 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 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, 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 20 years of work, because basically, these researchers in 1997 first

cloned a mouse, and ever since then, they've 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've 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...

So that's this limit that you were 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 indefinitely

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.

Yeah, 58th in these particular mice.

Yes, in these particular mice.

So if you clone, clone, clone, clone, clone, clone, 58 times, that's the limit, and 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, difference 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, 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.

Because 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 want it to ensure it's genetic legacy.

A star bulling.

Yes, exactly.

A star bulling.

You can clone it.

And that is done in some places including the US.

I was also thinking of like which people cloning their pets, like apparently you could

just privately, like if you have your favorite pet in 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's interviewed this article said, if you want to preserve animals

in this way, you'll 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.

But 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 the film will work, this is the plot of, do write it 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, in various places.

You can email us with podcastatnature.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 Pertuchel.

And I've been Sharminy Bundel, thanks for listening.

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