Even a ‘minimal cell’ can grow stronger, thanks to evolution

Benjamin Thompson

Welcome back to the Nature Podcast. This week, exploring evolution in a minimal cell...

Shamini Bundell

...and hints of galaxy-wide gravitational waves. I'm Shamini Bundell...

Benjamin Thompson

...and I'm Benjamin Thompson.

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Benjamin Thompson

Back in 2016, a team of researchers published a paper in the journal Science describing an organism designed to have an extremely small genome, containing just 493 genes. In simple terms, the team behind the work developed it by modifying a strain of the bacterial species, Mycoplasma mycoides, which already has a pretty small number of genes. The team went through its genome and deleted any genes that weren't essential to life. In total, they removed about 50% of the strain's genes, ultimately resulting in what's known as a 'minimal cell' with a bare-bones genome for sustaining life. This work had an impact on Jay Lennon from Indiana University in the US.

Jay Lennon

Yeah, so the story, I went to a meeting two years after that paper was published, and I heard the lead author give a talk on this. And I was blown away by the approach, the questions, the analogies of trying to understand something from its simplest basis. But I had a question immediately that arose from that. And that is, if you create an organism that can reproduce, but then you allow it to experience the force of evolution, the inevitable occurrence of mutations and damage that's going to arise. How does it contend with that? Is a stripped down, streamline organism going to be constrained and how it responds to the forces of evolution?

Benjamin Thompson

And this is a question that Jay and his colleagues have been trying to answer in a paper they've got out in Nature this week. They wanted to know how this stripped-back minimal cell might fare compared to the non-minimal strain it was derived from, and what this might reveal about the process of natural selection itself. To see what they found, I gave Jay a call. And he explained why the minimal cell's genome could stymie at scope for evolution.

Jay Lennon

So the way you can think about this is that there's basically no degrees of freedom, you know, every single gene in the genome of the minimal self is essential for life. Yeah, mutations can't be avoided, especially in the minimal cell where we've deleted some of the non-essential genes that can repair mutations and damage that's going to arise. But one hypothesis is that this organism is just not going to be able to contend with the inevitable mutations that are going to hit one of those essential genes.

Benjamin Thompson

And so there's this potential lack of wiggle room then, but to find out what's going on, you first looked at whether mutations, so changes in the DNA sequence, were happening and what sort of level. So the mutation rates between the minimal cell and the non-minimal cell it was derived from, what did that show?

Jay Lennon

Yeah, so the reason why we did this is that the mutations are sort of the raw material by which natural selection can operate on. And so it was important for us to know how mutations were entering these two different populations, and there was a really high mutation rate, but it didn't differ. The effects of the synthetic streamlining actually didn't modify the rates of mutation or demonstrably the types of mutations that were arising. And the question is, how would a minimal cell with no degrees of freedom deal with that, and a prediction might be is that those populations perhaps, could die, they might go extinct. Or there may be ways for the cell to adapt.

Benjamin Thompson

So you showed them that mutations can happen in this minimal genome. But the fact they are happening is one thing, what's happening to the bacterium itself is another thing, right? And so you've looked at evolution in action, then of the minimal and non-minimal cells. And that can be quite difficult to do in more complex organisms, because you have to wait for each subsequent generation to happen. In this case, you've got through 2,000 generations of these bacteria. How long did that take? And how did you go about it?

Jay Lennon

Yeah, so we would take what we call the ancestor, so the zero-generation lines, and we would put them into fairly-rich media that would promote growth, and those populations would undergo many duplications and they reach high population sizes. These are conditions under which there's competition, giving conditions for adaptation. We would take a small fraction of those cells and transfer them into a new flask with rich media and repeat this process where there's a transfer every other day. So we were able to track these populations in the minimal cell and the non-minimal cell for 2,000 generations, which equated to about 300 days in the laboratory. And so I think if you put that into human terms, it's something like 40,000 years of human evolution.

Benjamin Thompson

So you got these 2,000 generations, then what happened to the minimal cell during this time then? What did generation 2,000 look like compared to generation zero?

Jay Lennon

Yeah, so the first thing that we were able to observe from this experiment was comparing the ancestors, prior to any evolution of these strains. So the initial effects of genome reduction were quite large, they made these cells sick. So we measured something, which is known as 'fitness', which can be measured either as the growth rate or the competitive ability of the strains. And the effects of genome minimization, made the cell 50% less fit. So it had a really strong negative effect on that population. So then, fast forward 2,000 generations, and when we measured the fitness of that organism at the end of the experiment, and we asked, basically 'how sick is it now?' And we found that it recovered all of those fitness costs over the 2,000 generations. So its fitness was equivalent to the original, non-minimized genome. So the ability for this organism to readapt from the effects of genome minimization were complete and occurred pretty quickly.

Benjamin Thompson

You've got this result then and shown that the minimal cell can regain its fitness to an extent, I think you say in your paper that it doesn't necessarily overcome its small size, it remains quite weedy compared to its cousin. But of course, the non-minimal cell evolved and became fitter during the 2,000 generations as well. And you peered into the genomes of these two cell types, as the experiment went on to find out what was going on. What did you find in terms of how they were adapting?

Jay Lennon

Yeah, I think one thing that was interesting is that when we compared the rates of adaptation for the minimal cell and the non-minimal cell, they were pretty comparable. So they both kind of adapted at the same rates, despite the fact that the minimal cell had 50% of its genome stripped away. So that was curious, because those rates were comparable, we thought, well, maybe they're adapting via the same mechanisms, maybe there's certain mutations that have arisen that are beneficial. Maybe despite the differences in genomes, maybe there's a similar path to improvement in growth. And what we found actually was that was not the case. So even though these strains evolved at comparable rates, they did so via distinct genetic ways. The non-minimal cell had its own path to improving its fitness, and the minimal cell evolved via mutations and other types of genes that were distinct.

Benjamin Thompson

Seeing these results, then, I mean, you had this question, 'can the minimal cell do it', right? Can it can it adapt? Showing that it did was it a surprise to you? How did you feel about it when you saw that it was doing its thing and recovering itself?

Jay Lennon

Yeah, I think there were some surprises there, because I thought that the ability of this organism to adapt to its environment would somehow be hampered. And what we found is evidence to suggest that that's not the case at all, and that in some cases, this minimal cell actually evolved faster than the non minimal.

Benjamin Thompson

I mean, I'm tempted to quote, Jeff Goldblum's character in Jurassic Park, which is 'life finds a way'.

Jay Lennon

Yeah.

Benjamin Thompson

I mean, there's this hypothesis, that this was so streamlined, that evolution couldn't occur. But you've shown that really isn't the case.

Jay Lennon

That's right. And I think that's interesting from a basic evolutionary perspective. And it also has implications for thinking about how we should be developing organisms for synthetic biology. You know, the whole field is about trying to take parts and put them together so that we can in some cases, manufacture products in sustainable ways. The question might be, are there certain rules or principles that we should be thinking about in terms of how we construct those organisms and how they may behave? We can create cells, and be very specific about them. And we know what those basic elements are going to be. But the forces of evolution, these are all processes that simply can't be avoided.

Benjamin Thompson

That was Jay Lennon from Indiana University. To read his paper. Look out for a link in the show notes.

Shamini Bundell

Coming up, what hints of galaxy-wide gravitational waves could mean for our understanding of the cosmos. Right now, it's the Research Highlights with Dan Fox.

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Dan Fox

Have you ever found yourself using high-pitched baby talk when talking to kids? Well, now it seems that dolphin mothers do it as well. Adult humans often alter their voices in funny ways when talking to young children. This way of speaking, called child-directed communication is found across many human cultures and is thought to help parents and other adults teach children how to speak. Scientists have noticed that a handful of other animals also change their sounds when communicating with their young. To see whether bottlenose dolphins do so, researchers recorded the whistles of 19 dolphin mothers that were caught and released over several decades, either with or without their calves. The recordings revealed that dolphins produced whistles with higher pitches when caught alongside their calves, suggesting that they were using a dolphin form of child-directed communication. Given the similarities to high-pitched human baby talk, this way of whistling might also help dolphins to teach their young how to communicate. You can find that research in Proceedings of the National Academy of Sciences of the United States of America.

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Dan Fox

Microplastics have been found everywhere from Arctic snow to common table salt. Now, researchers have found that these tiny specks are released in huge quantities when certain types of plastic are microwaved. As plastic degrades, it creates fragments that are invisible to the naked eye. Researchers measured the levels of these fragments that were released from two types of vessel commonly used to prepare and store food for infants: a reusable polyethylene-based food pouch and polypropylene-based plastic containers. Both types of container were found to release micro- and nano-scale plastic fragments when heated in a microwave for three minutes. One container studied released more than 4 million microplastics and 1 billion nanoplastics per square centimeter of plastic container. Even storing the containers in conditions that mimicked refrigeration led to the release of microplastics and nanoplastics, though not as much as microwaving. The findings mean that an infant weighing 10 kilograms will consume up to 1.4 micrograms of micro- and nanoplastics per week if drinking water that had been microwave using such a container. You can read that research in full in Environmental Science and Technology.

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Shamini Bundell

Gravitational waves were first detected in 2015, when two black holes collided, sending ripples in space-time across the universe. That momentous discovery was made using interferometers at the LIGO facilities in the US, which picked up the subtle changes in the path of lasers as the gravitational waves washed over Earth. Last week though, after decades of searching, four separate research collaborations found hints of a wholly different kind of gravitational wave whose origins are unknown. These waves are monstrous in size and couldn't have been picked up with LIGO. So spotting them required a very different detector. Nature's resident gravitational wave superfan, Davide Castelvecchi has been writing about this discovery and reporter Nick Petrić Howe caught up with him.

Nick Petrić Howe

Davide, hi, how's it going?

Davide Castelvecchi

Hi, Nick. Very well. How are you?

Nick Petrić Howe

I'm good. Thank you. So last week, there was a new result announced for gravitational waves. So Davide, can you tell me what this result was?

Davide Castelvecchi

So I would go as far as saying that gravitational waves have been rediscovered. We have discovered gravitational waves that are from an entirely different origin and in an entirely different part of the spectrum, meaning at much longer wavelengths. And with an entirely different technique, that when you think about it, kind of boggles the mind.

Nick Petrić Howe

While I'm preparing for my mind to be boggled, then. In the past, we've used interferometers to detect gravitational waves. So how does this new detection method differ from that?

Davide Castelvecchi

It's similar at the very basic conceptual level because gravitational waves stretch and compress space as they pass through. In this case, though, they're not using lasers inside these arms of the interferometers, as LIGO did, they are using the entire galaxy as a detector by seeing how the passage of gravitational waves affects the distance between us, the Earth, and other stars that act as beacons. There are maybe tens or hundreds of light years away.

Nick Petrić Howe

And these stars that act as beacons, like how are we able to use them to figure out that you know, space has been shifted by the gravitational wave?

Davide Castelvecchi

So the idea is that the astronomers are tracking very special stars, which are called pulsars, and they rotate some of them at vertiginous speeds. So the particular stars that these projects have been following rotate at up to hundreds of times per second. And some of these stars, they also spew out radio waves. And as the star rotates, this beam also rotates with it. And so if you're lucky enough, you can detect a little blip every time the star rotates on its axis, and specifically what these projects are doing, they're following the ones that rotate faster, which are extremely reliable cosmic clocks. And by monitoring them year-after -year, and decade-after-decade, if you start seeing variations, you might infer that maybe the space that separates us from the star is being affected by something. And that something could be gravitational waves.

Nick Petrić Howe

But as I understand it that this hasn't quite been confirmed yet, could this be something else?

Davide Castelvecchi

The evidence that was presented last week is not yet at the level of statistical significance that would make people say, you know, we have the smoking gun, we've done it, we've nailed it. But at least for the first time, something that researchers have actually seen at least some level of statistical significance. And it's comforting to see that it's not only one collaboration, its four independent collaborations, they are seeing this similar signature in their data.

Nick Petrić Howe

And so is the idea then that all these groups' data will be combined to get a better picture of what's going on here.

Davide Castelvecchi

Yeah, so the papers that were released last week, each of these four collaborations published its own results, but at least some of their data now is being pooled into one common set of data that together should be able to increase the statistical power of the findings, hopefully by next year.

Nick Petrić Howe

And so in the past, these detections of gravitational waves have been because of things like black holes colliding. Do we know what the origin of these very big wavelength gravitational-waves that are potentially detected in these results, where they're coming from?

Davide Castelvecchi

The short answer is no. Because in the case of LIGO, what LIGO saw was a very specific kind of signature that is produced by two objects that are in the final stages of spiralling into each other and merging. In the case of the discovery announced last week, they're not seeing individual pairs of objects merging. So what they're seeing using these pulsars is the Earth moving as a result of gravitational waves, but in a chaotic way, it's not a nice waveform that you can say, comes from one particular merger. So even if you are sure that you're seeing gravitational waves, this doesn't tell you what is producing the gravitational waves. So that's why I said the short answer is no. On the other hand, there are some very plausible theories and also some maybe less plausible or more speculative theoretical models for what could be generating these waves.

Nick Petrić Howe

And so what do you think is the most likely cause of these gravitational waves?

Davide Castelvecchi

From what researchers tell me kind of the standard explanation or prediction is we know that galaxies merge over their history, and we know that most galaxies harbour a very large black hole in their hearts. And when two galaxies merge, each of them carrying a black hole, the two black holes kind of sink slowly towards the centre of the newly formed larger galaxies. And at some point, they might start orbiting close enough that they emit strong enough gravitational waves that you can detect them. So because you have billions of galaxies, many, many of them have pairs of supermassive black holes in them, some of those must be emitting a lot of gravitational waves and the combined hum from all these pairs of supermassive black holes in the entire observable universe together gives you the signal.

Nick Petrić Howe

What does this mean for our sort of understanding of how the universe is then?

Davide Castelvecchi

If it's confirmed, and if it does turn out to be from pairs of black holes, it validates decades of theoretical work on how galaxies can merge and what happens to the black holes inside of them. And can they get close enough to get to the point where they emit gravitational waves and then eventually merge themselves. This last bit was not at all obvious, because the astrophysicist say that it's quite easy to predict that the two black holes will end up orbiting each other, but they will end up orbiting each other at a distance of light years. But to get to the point where they make gravitational waves and then they start spiralling into each other and then they merge. That's not enough. They need to get you know, hundreds or thousands of times closer, and that is a lot harder to explain theoretically, but apparently you know, if the signal does come from black holes, it means that it does happen.

Shamini Bundell

That was Davide Castelvecchi. For more on that story, check out the show notes for some links.

Benjamin Thompson

Finally on the show, it's time for the Briefing Chat, where we discuss a couple of articles that have been featured in the Nature Briefing. And Shamini I think I'll go first this week. And this is a story that I read about in Nature. Now, a couple of weeks ago, I chatted with Nick about efforts to vaccinate koalas against chlamydia. And this is another story in a similar vein about vaccinating an iconic Australian animal. But in this case, it's about vaccinating the Tasmanian devil against the deadly contagious cancer.

Shamini Bundell

Right. So we have definitely discussed before that there's a particular cancer that these Tasmanian Devils get, and it's really harming their population, right?

Benjamin Thompson

That's absolutely right. And it's called devil facial tumour disease, okay. And it's killed up to 80% of Tasmanian devils since it first emerged in Tasmania, which is the large island southeast of mainland Australia, of course, about three decades ago. And there have been some worries that this could ultimately lead to this animal's extinction.

Shamini Bundell

And this is something that's being somehow transmitted between the animals, right?

Benjamin Thompson

That's absolutely right. So this is a transmissible cancer. And from what I've read, these are super rare in nature, only a few examples of this happening in different animals. And in this case, the devil facial tumour disease and the Tasmanian devil disease is transferred by biting, okay, and it leaves these enormous tumors on the animal's head, and they usually die in a few months. And this is quite an insidious disease, because the cancer cells, they don't produce many of the molecules on their surface that kind of act as a flag to the immune system. So they can kind of slip in unannounced if you see what I mean. And so this new vaccine that's just starting to be tested is targeting one of the two forms of this disease.

Shamini Bundell

So how have the researchers gone about developing a vaccine that will target this cancer?

Benjamin Thompson

Well, it seems like they've taken inspiration from some of the COVID-19 vaccines that were developed, okay, so this vaccine uses a modified adinovirus, and this virus has been modified so it can't cause disease, but it makes the animal cells produce proteins associated with the tumor cells, but not with healthy cells. And ultimately, the aim is to make these tumor cells more visible to the immune system that can then go in and attack.

Shamini Bundell

And what kind of stage are we at with this vaccine at the moment?

Benjamin Thompson

Well still quite early, it has to be said. So on June the 14th, Australia's Office of the Gene Technology Regulator issued a license to the team behind the work to test the vaccine against this one type of the cancer. And it's been tested on 22 healthy, captive Tasmanian devils, okay. Now this is the first phase of that this is just seeing whether it's safe, and whether it elicits an immune response. And ultimately, only animals that are free of disease and have no remnants of this vaccine left in them can be released back into the wild. So just that first step, but I think the researchers behind it have high hopes. But there have been some knockbacks in the past, because another vaccine was developed. But in 2017, a study found that it only ellicited a strong immune response to prevent cancer in one in five vaccinated animals. But I think it did show that the immune system can get better at identifying this disease, which I think has given hope to the researchers behind this new vaccine.

Shamini Bundell

And how're they actually able to test this one? How do you give a Tasmanian devil vaccine?

Benjamin Thompson

Well, that's a great question. And it's one of these sorts of hurdles that needs to be overcome as they move along. So at the moment, the vaccine is delivered by injection and in an oral liquid during this early trial. But of course, that's ultimately not scalable to a wide, wild population. So the researchers need to come up with a plan. And yet again, they're taking inspiration from a different vaccine, in this case, a rabies vaccine that's delivered to animals in Europe and the US via edible bait. So it could be that if the vaccine is approved, that they go down this road in the future, and this might be a more practical approach. And apparently, they're designing an AI-driven bait dispenser that will just deliver the vaccine to the Tasmanian devils and not other animals in the vicinity.

Shamini Bundell

Wow, this story has everything.

Benjamin Thompson

Yeah, there's a lot going on here. But fingers crossed, of course, that it does show some efficacy. And I think if it is safe and effective, the researchers want to ultimately develop it further so it targets both sorts of cancer, this type one and the type two. And someone quoted in this article says that even if it only partially shields these animals from the disease, it could buy some more time for them to breed which could ultimately boost dwindling populations. And it's such an interesting one because these transmissible cancers, as I say, are so rare, and I've read about examples in in clams and in dogs, but to have two versions in one animal is spectacularly unfortunate. But only time will tell whether this vaccine is something that can help these animals out.

Shamini Bundell

Well I'm sure we'll be chatting more about Tasmanian devils again, I'll be looking out for updates to that and hopefully some progress on that horrible disease. I've got a slightly cheerier story for you now actually a bit of a mystery. Some things that scientists don't know, which I always find very fun. And this is actually about a new species of plant a kind of palm. And I had been reading about this in an article in The Guardian and it's been published in the Journal of the International Palm Society and in Plants, People, Planet about this new species that was discovered in Borneo.

Benjamin Thompson

Right, I've got a few palms on the patio here. So I'm guessing this one is maybe a little bit more interesting than them.

Shamini Bundell

It is, I was fascinated by the story, because it's an area I didn't know about at all. So this is a species that has been known about for a while, depending on who you ask, which I'll get back to it a bit, but has only now been sort of officially described as a new species. And the weird thing about it is that this species, both flowers and fruits underground, and my favorite thing about this is from the top of The Guardian article, it says, Kew botanists admit they have no idea how its flowers are pollinated.

Benjamin Thompson

Yeah, because flowers are those things that poke up and insects and sometimes other animals can come across and move the pollen from plants planted pollinate other flowers, right?

Shamini Bundell

Usually, yeah, they come along, they pollinate them, those flowers then turn into fruit. And actually sort of in looking into this, it turns out that there are other species that either flower or fruit underground, although not usually both. And there was one species that I sort of thought, 'oh', when I read this, 'of course', a plant that we often eat that flowers above ground, but then that moves underground to fruit. It's peanuts, a member of the legume family, the pea family.

Benjamin Thompson

Oh, yeah of course.

Shamini Bundell

Not actually a nut, that's your bonus fun fact for today. But yes, it's really rare for a species to both flower and fruit underground. And even then, in some of the examples, their flowers might be sort of just slightly underground, but covered by a little bit of leaf litter. Whereas in this case, this sort of completely overlooked, by scientists anyway, palm species has these flowers that are completely underground, and then these bright red fruits, and they do know what happens to the fruits because they've seen bearded pigs eating them. So the idea is that the bearded pigs are probably, you know, moving around the seeds. And in fact, one of the researchers, and Indonesian researcher noticed it because the soil had been sort of dug up by boars. And then and then they saw the flowers and fruit, and said, "it was as if the boars guided me to find this palm."

Benjamin Thompson

Okay, so that's how the fruits are spread, but say pollination is still a mystery.

Shamini Bundell

Yeah, absolutely. And they haven't been able to sort of sit and watch and spend a lot of time waiting for a pollinator to come along. They found some sort of small insects around the flowers, but it's unclear. Most palms are pollinated by insects, but usually, being underground, you would have thought that would be a barrier to pollination. So you know, perhaps there is some particular kind of creature that sort of specialized in pollinating these say they don't know yet.

Benjamin Thompson

An earlier on, you implied that, although this species has been newly described to science, it has been known about for a while.

Shamini Bundell

Yeah. So it turns out that lots of local and indigenous people in the parts of the world where this grows, snack on the fruits, while they're out and about, and they're quite tasty. So certainly not a new or surprising discovery to them. But one that sort of seemed to fly under the radar of scientists until relatively recently. And as I said, this is the first time it's been sort of officially described. So there have been some Malaysian and Indonesian botanists, and they've also collaborated with folks at Kew Gardens in order to sort of officially declare this, a new species. But the fact that the indigenous people have known about this, the researchers in the paper, take note of that fact and say, this might be a bit of a wakeup call for scientists to fully embrace indigenous knowledge in the global effort to catalogue all life on Earth.

Benjamin Thompson

Well, a fascinating story, Shamini thank you for bringing that one to the Briefing Chat this week, and listeners for more on the two stories we've chatted about and where you can sign up to the Nature Briefing to get more of them delivered directly to your inbox. Look out for the show notes for some links.

Shamini Bundell

That is all for this week. If you want to get in touch with us. You can reach us on Twitter, we're @naturepodcast, or why not send us an email, we're podcast@nature.com I'm Shamini Bundell...

Benjamin Thompson

...and I'm Benjamin Thompson. Thanks for listening.