Host: Nick Petrić Howe
Welcome back to the Nature Podcast, this week how to build a virus proof cell…
Host: Shamini Bundell
…and designing mini-MRI scanners for places that often don't have access to them. I'm Shamini Bundell.
Host: Nick Petrić Howe
And I’m Nick Petrić Howe
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Host: Nick Petrić Howe
First up on the show, the researchers looking to build a virus proof cell. In biology, there are some things that are pretty universal, like DNA. This coded set of instructions inside cells gets translated into RNA, and from this, proteins are made. This process is pretty fundamental to how cells work, and pretty much everything uses the same code, which is based on the order of the bases A, T, C and G and how they appear in the DNA. Organized into groups of threes known as codons, these instruct which amino acids ultimately get added to the growing chain that becomes a protein. But, over the past few years, researchers have been tinkering with this universal code to give organisms new properties and abilities. One such novel property that's been a goal of the field is to prevent viral infection. The idea behind this is that if the universal code is changed enough, then viruses won't be able to speak the same language as the cells they're trying to infect, as Akos Nyerges, a cell tinkerer from Harvard Medical School explains.
Interviewee: Akos Nyerges
If everything speaks the same language, then you can communicate with everyone, but if you change this language, then you can achieve a situation where you don't have this cross communication anymore, and because viruses exploit the universality of the genetic code to manufacture their own proteins and themselves, if you change the genetic code, you can practically prevent viral infections by preventing them from synthesizing their own proteins.
Host: Nick Petrić Howe
Once a virus infects a cell, it hijacks the cell's own machinery to make more viruses, but changing the universal code makes that difficult for the invading virus. The way researchers change the universal code to make life difficult for the virus is by slimming down the universal code. You see, some amino acids can actually be encoded by multiple DNA codons. A cell can live quite happily with some of these extra codon combinations removed, and it also allows researchers to remove associated parts of the cellular machinery involved in protein production, known as transfer RNAs or tRNAs. But while a streamline cell can carry on without these transfer RNAs, it puts a spanner in the works for viruses that would want to co-op these tRNAs to make their own proteins. This technique has been shown to be effective to prevent viral infections. In the past, Akos and his colleagues have shown that if they modify the genome of E. coli or remove these tRNAs, many viruses cannot infect them, but some viruses still have a way around this by bringing their own.
Interviewee: Akos Nyerges
Viruses very frequently contain on their genome transfer RNAs, and they just simply can bring these transfer RNAs to translate their own codons.
Host: Nick Petrić Howe
But this week in Nature, Akos and his colleagues have developed a new method that outfoxes even these viruses by using their own transfer RNAs against them. The team took some of these tRNAs and tweaked them, so they inserted the wrong amino acid into viral proteins.
Interviewee: Akos Nyerges
What we did is to express in the cells the transfer RNA that recognizes the serine codons, but inserts leucine, and there's a trick, so you already have something in the cells that as soon as the virus enters, even if they bring their own tRNAs, these newly synthesized tRNAs can't compete with what's already in the cell. So, they insert leucine while the virus means serine in certain protein positions or amino acid positions, and as a consequence, you don't have functional proteins.
Host: Nick Petrić Howe
Putting the wrong amino acids in means that proteins don't work, and the virus can't multiply, and whilst this ensures that the viruses only make useless proteins, the modified E. coli is unaffected. Its streamlined genetic code won't use these particular tRNAs, making the cell effectively immune to viruses. But, you may wonder if that gives these bacteria a particular advantage over other cells, if they were to find their way out of the lab would the outcompetes their non-modified brethren that can be infected and killed? Well, the team thought of this and made it so that the modified bacteria only grew when fed a chemical not found in nature, effectively making it so that the modified cells could only grow what the team wanted them to. So, what uses are there for a virus proof cell? Well, one thing is to prevent the unwanted wandering of genetic material from engineered bacteria into the wild. Viruses are one way that DNA can be shared between bacterial species.
Interviewee: Akos Nyerges
You can prevent this from escaping or prevent this from functional escaping to other organisms, it will escape but it means gibberish.
Host: Nick Petrić Howe
As the genetic code in the E. coli has been changed so much, if a virus manages to transfer some DNA, it won't make sense to other bacteria, lessening the chances of any genes leaking out into the wild. Another way that this system could be useful is to prevent infections in biotechnology labs that use living cells to produce useful compounds, something that has happened in the past. The eventual goal of the team would be to use a similar technique in different organisms other than E. coli. However, larger, more complex genomes may be more challenging to do this technique with. Only a handful of such heavily modified organisms exists so far, and as the complexity of the organisms increase, so too do the challenges. For Akos, he thinks that this work has implications for other projects that are using streamline genomes, as they won't necessarily be safe from viruses, because those pesky tRNA containing viruses that he found, may be more widespread than previously thought.
Interviewee: Akos Nyerges
We also discovered that mammalian viruses contain these tRNAs, so these tRNA containing viruses while many people might think that this is a bacterial related phenomenon, it's not. It is a general thing that viruses contain tRNAs other recoding projects should keep this in mind.
Host: Nick Petrić Howe
That was Akos Nyerges from Harvard Medical School in the US. For more on that story, be sure to check out the show notes for a link to the paper and an associated News and Views article.
Host: Shamini Bundell
Coming up, we'll be hearing from a researcher who's developing a low-cost mini-MRI scanner for use in low- and middle-income countries. Right now though, it's time for the Research Highlights with Dan Fox.
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Dan Fox
One of the largest wetlands complexes in the world is poised to potentially triple its methane emissions, according to new research. The Prairie Pothole region of North America spans 820,000 square kilometers from the US Midwest to Western Canada. Researchers analyzed nearly 19,000 measurements of methane emissions from wetlands in the region collected over 13 years and used them, along with other environmental data, to model methane emissions at both the local and landscape levels. Methane is a potent greenhouse gas and wetland emissions are sensitive to temperature. The team's results suggest that emissions from the region are likely to double or triple this century under moderate or severe levels of global warming. The authors say the international efforts to limit methane levels in the atmosphere should take into account rising emissions from wetlands. Sniff out that research in Science Advances.
When it comes to communicating with their hive mates, honeybees often bust-a-move, but to really get their dance moves down, they need a few lessons from their elders. Honeybee workers communicate the location of food by crawling in figure eights and waggling their abdomens. These waggle dances contain info on distance and direction of a resource via the time it takes to complete the dance and the orientation of the dancer’s body, respectively. Young worker bees spend a few days watching older workers make moves before trying to dance themselves. To test the purpose of this observation time, researchers prevented bees from watching older workers dance and compared them with workers that could observe their elders. The team found the bees that hadn't had a chance to watch waggles took longer than usual to finish a dance, meaning that they overestimated the distance that companions needed to travel. These lessonless bees also made more mistakes in communicating direction and performing figure eights. You don't need a waggle dance to find that research, it's in Science.
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Host: Shamini Bundell
50 years ago this week, Nature published a landmark paper by Paul Lauterbur outlining the basis of magnetic resonance imaging, or MRI. In the subsequent decades, MRI has become a standard imaging technique in clinical care. But although millions of scans are carried out every year, some people living in low- and middle-income countries have severely limited access to this technology. Researchers are now looking to address this by designing new types of smaller MRI scanners that, although not as powerful as their room sized counterparts, are much more affordable and can be used in rural settings or small clinics. One of these researchers is Johnes Obungoloch from Mbarara University of Science and Technology in Uganda. Johnes has worked on developing a mini-MRI scanner that could be used to identify a serious brain condition in young children. He's co-written a comment article for this week's Nature, outlining the project and laying out the challenges to be overcome for scanners like this to become more widespread in clinical care. Reporter Benjamin Thompson phoned him up, and Jonas laid out some of the reasons why, right now, MRI isn't available to everyone.
Interviewee: Johnes Obungoloch
MRI basically is a standard care in many developed countries, but that is not really true in the rest of the world. So, over the 50 years that the MRI has been in existence, a large part of the world still does not use it in any meaningful way, and that includes the place where I am. The major reason is the cost of the device, the device is still very expensive to buy, to maintain, to install, and even to operate, so that is one of the major reasons, but of course, the other is also the technical expertise that is needed to sustain these systems is huge, and many developing countries do not have this expertise.
Reporter: Benjamin Thompson
And in your comment you and your co-author suggest one of the things needed to address this is to rethink, to redesign MRI systems that are more suitable for different settings, maybe rural settings or in small clinics, and you yourself have experience working to develop a smaller MRI, working with collaborators to build one, and in your case, it's to help diagnose a serious brain condition that can affect children called hydrocephalus. Maybe you can explain a little bit about what that is.
Interviewee: Johnes Obungoloch
So, hydrocephalus is we could say in layman's terms water in the brain, so the head grows big and also gives a lot of pressure on the brain and actually damages the brain. This condition affects over 180,000 children every year in sub-Saharan Africa, and the cause is not yet very clear, but the burden is high, and Uganda basically sees a lot of these children because there is a center that treats them and that’s the center that we are working with.
Reporter: Benjamin Thompson
And this is where your scanner comes in, then it's a small MRI scanner, designed with your collaborators and made specifically to scan the heads of children, and rather than being you know, a huge machine that someone's whole body slides into this is a small unit that sits over the head and you say it can be wheeled through a hospital or a clinic. What are some of the challenges involved in shrinking down a full-size scanner into something like this?
Interviewee: Johnes Obungoloch
So, the regular scanner has electromagnets, so these are coils that are wound, and you pass a current through them and it generates a magnetic field within the center of the coil. But for you to generate a high magnetic field, you need very high currents. So then, of course, you know when your current flows through a wire, it heats up, so you need them to cool using helium, so these impose very high restrictions. So, our system therefore does not use electromagnets, we use permanent magnets that about two and a half centimeters in dimension that you arrange in a certain pattern to give you the required magnetic field. Our system runs on very little power, probably less than 300 watts, so that is less than a flat iron.
Reporter: Benjamin Thompson
And you're planning, as I understand, to test this machine in the clinic against another working miniaturized system that is available and against CT scans which are currently used to diagnose hydrocephalus. But it's early days for the field of mini-MRIs, low-field MRIs, as you describe them, that have much lower magnetic field strength, much lower Tesla values than existing machines. But in your comment, you're looking very much to the future and some of the key challenges that need to be addressed to further develop them and promote their use, and one of the things you talk about is the need to ultimately improve their resolution for example.
Interviewee: Johnes Obungoloch
So currently, because we generate very little magnetic field 50 millitesla that is 0.05, that's compared to 1.5 tesla for instance, so with a very small magnetic field, we also generate very small signals. So, with those small signals, the resolution is not that high, but we think that the artificial intelligence technology and machine learning is reaching a level where we can be able to work with very small signals to create very clear images, so that is one of the needs that we need to focus on.
Reporter: Benjamin Thompson
And what's interesting as well, is that you talk about the need to improve the buy in for these small systems from clinicians that you don't want them to be seen as, you know, cheap alternatives, or inferior alternatives rather than being a tool for a specific job.
Interviewee: Johnes Obungoloch
Exactly, so many of our senior radiologists and neuroscientists have trained in countries such as the US, Europe, Canada and the rest, so they know what the best system look like. So, when you show them an image from a low-field scanner, like ours, they might not appreciate it so much. That's why we need to work with them and make them understand that we are not bringing this technology as an alternative to the high-field MRI, but we are bringing it as a technology that can function in the absence of the high-field MRI. Our rural areas, our rural hospitals will never see a giant MRI in the near future, probably in hundreds of years to come. So, we want to make it clear to our medical colleagues, that this is a technology that actually works, is not just cheap and inferior, but something that can actually work to save lives, other than having nothing.
Reporter: Benjamin Thompson
And thinking about costs then, could you maybe give me a sense of how much your system could cost compared to a large-scale MRI scanner, for example?
Interviewee: Johnes Obungoloch
So, a typical MRI system is somewhere between one and three million US dollars to buy, install, and have it operational. Our system at the moment is about 50,000 US dollars. Of course, we are not counting the man hours yet, the funds that are used to compensate people that are building and doing this. So, we think that between 70 to 80,000 US dollars will be the cost of our system.
Reporter: Benjamin Thompson
And finally then, if smaller MRI systems like the one you're working on, do become more widely available, what sort of difference do you think they might make in Uganda, for example, but then maybe even more broadly, as well?
Interviewee: Johnes Obungoloch
The standard for brain imaging, at the moment, is sort of like a CT, but the CT is equally expensive, they're only in the cities. So, the rural areas do not have access, so when we have systems that are plug and play, like the ones we are trying to make, the lack of access will be a thing of the past, if I would say.
Host: Shamini Bundell
That was Johnes Obungoloch, from Mbarara University of Science and Technology in Uganda, you can find a link to his Comment in the show notes.
Host: Nick Petrić Howe
Finally on the show, it's time for the briefing chat, where we talk about some of the stories that have been highlighted in the Nature Briefing. Shamini, what have you found for us to discuss this week?
Host: Shamini Bundell
Right, I've got a story that everyone here at Nature is very excited about. I've been reading Nature news article about it, and it was also reported in various other outlets, and this is an exciting announcement from the field of gene editing. Some researchers in Japan have created what we can sort of colloquially describe as mice with two dads, which basically, mice babies created from entirely male cells.
Host: Nick Petrić Howe
Oh, wow, I mean, like, that's incredible if it works, and I think I've heard this before, this is something that scientists have been trying to do for a while, right?
Host: Shamini Bundell
Yeah, this has been something that several groups have been sort of working towards. In 2018, there was some research using embryonic stem cells made from either sperm or eggs to generate, again, sort of mice infants from either two mothers, which was quite successful, or two fathers, which they did manage to get pups, but they didn't survive very long, and the team behind this new work have also been sort of working towards this, some of the steps along the way. They've previously published work on how to mature cells into eggs in a lab dish, and how to reconstruct, basically the environment of mouse ovaries. So, you can actually grow eggs and produce healthy offspring. But there was still a big way to go before what they've currently done making a mouse from entirely male cells.
Host: Nick Petrić Howe
Well, I guess the key question is how they actually managed to do it, you've sort of laid out some of the challenges and where other teams have tried this before. So, what is the key thing that they found to make this work?
Host: Shamini Bundell
I find this technique that they've developed here, quite sort of, surprisingly simple, almost, although I'm sure it wasn't when they were, when they were developing it and putting it into practice. But what they do is they, they're starting off with cells from an adult male mouse, and they kind of induce these into pluripotent stem cells, cells that will just sort of keep replicating and not sort of specialize. And where they want to get to is an egg, which is not something that would usually come about from a male cell at all. So, male cells in mice, like in humans are XY, they have an X chromosome and a Y chromosome, the first step was to get rid of the Y chromosome, and the way they actually did this, is they basically just cloned the cells multiple times, so you know, these are replicating stem cells, and they cloned them until a proportion of them just sort of spontaneously lost the Y chromosome. So, you know, cell replication isn't perfect, mistakes happen, and they basically made use of this and plucked out those cells in which the Y chromosome accidentally kind of got left behind in its replication.
Host: Nick Petrić Howe
That’s super cool, sort of just relying on, I guess, cells mistakes in order to make this work.
Host: Shamini Bundell
Yeah, that was the really surprising thing about this work for me, and it's quite a small sort of percentage that have lost a Y chromosome. The next step is then to get two X chromosomes, and again, the clever thing here is, instead of trying to insert an X chromosome from somewhere else, or you know, somehow build one from scratch, they waited. They cloned the cells, again, they let the cells reproduce until there was another mistake, and the remaining X chromosome, the sort of from this cell that is now just one X duplicated itself. They did actually help it in this step, so they added a sort of compound called rever, reverseen, reversine? Which promotes errors basically causes more errors, and then in that way, they got the cells which had two X chromosomes, they are chromosomally female, starting from a single XY male.
Host: Nick Petrić Howe
So, you've got all these cells that have all the right chromosomes to be female, but that does not a baby mouse make. So how do you get from this to a baby mouse?
Host: Shamini Bundell
Well, as I mentioned, they had previously done work on basically inducing cells to become eggs, like to mature into eggs, so, they sort of turned these cells into oocytes. They then did a sort of extra level of checking where they looked at the gene expression of their sort of artificially created oocytes with, with natural ones, to check that those are the same, and then fertilized the eggs with sperm, and another interesting thing that they found was that it did not work if they tried to fertilize the egg with sperm from the same male as the original stem cells had been taken, it had to be another male. But in that case, it was successful, they made mouse pups, and those pups grew up and were fertile and also able to have offspring.
Host: Nick Petrić Howe
You said before the some of the work before they didn't have the best survival, but these ones seem to be surviving really well, and everything's okay?
Host: Shamini Bundell
Well, it's not the greatest survival rate, so they got 630 embryos, that they tried to transfer into a mouse uterus, only seven of those developed into pups, but the ones that did, did seem to grow normally and be fertile, which is, previously the pups hadn't lived more than a few days in the previous technique from 2018.
Host: Nick Petrić Howe
So, this sounds like a huge step forward for the field, but what could this be useful? And is the aim to do it in humans one day?
Host: Shamini Bundell
Yeah, the researchers have said that they are looking at sort of future human implications for this kind of work. One situation in which this kind of thing could be really useful is in people with chromosomal abnormalities, so for example, some people have Turner Syndrome, which means they only have one X chromosome, like not XX or XY, which is a problem for fertility. But of course, it's also the first step in their technique is making these sort of single X chromosome cells, so you can see how that could then lead to potentially being able to make eggs. And obviously, this has sort of implications for if you're two men and you want to have genetic offspring that sort of related to both of you. This kind of work could be useful. Now, I'm gonna give away all the caveats now, and I'm gonna say this is in the future, you know, there's lots of issues. So, one thing that was mentioned in this article, something to look at is the epigenetics of the cells to sort of check that the epigenetics are preserved properly. Epigenetics, you know, it's not just about what genes you have on your X chromosomes, it's about making sure that the right genes are switched on and off at the right time. So that's one thing. Another issue is that according to one researcher, it's really key that this process happens quite quickly so that you're not culturing the cells for too long. You're not sort of, cloning them, allowing them to reproduce and reproduce for a long time, because that allows potentially genetic and epigenetic abnormalities to accumulate over that time. And it might be that with human cells, you actually need longer than you do with mouse cells, so that could be a bit of a problem. And then, of course, at the moment, there's the low sort of success rate of the embryos, it is, as always, a long way off, but it is absolutely a huge step.
Host: Nick Petrić Howe
No, certainly sounds like it. And yeah, we'll be sure to keep an eye on this in the future. For my story this week, I've been reading about a claim of room-temperature superconductivity, and I've been reading about this in Quantum magazine, and it's actually based on a paper in Nature,
Host: Shamini Bundell
Right, so, superconductivity usually needs very, very cold temperatures, is that right?
Host: Nick Petrić Howe
That's right. So super conductivity is basically where you have zero resistance for electric, so you're not losing anything to the environment, and it can be used for all sorts of things like high-speed rail, or better power lines and that sort of thing. But the problem with using it in reality is like you say, it needs to be super cold. And that's because matter and electrons act sort of weirdly at lower temperatures, and so for the past 100 years or so researchers have been trying to see if they can bump up the temperature where this weird stuff starts to happen, and we get all these sort of cool properties.
Host: Shamini Bundell
When we're saying it needs to be super cold, you know, this is this is well below freezing, like what kind of temperatures are we talking about here?
Host: Nick Petrić Howe
Well, in the past it’s only been done at around 160 Kelvin, which is about minus 110 degrees Celsius, so pretty cold, colder than Antarctica has ever gotten, as far as we know. So yeah, it's, it's quite cold. But there have been researchers have been trying to bump up that temperature, there was a claim that we covered on the podcast two years ago, but that was since retracted, and this is the same group again, who have made a claim that they have achieved it at 21 degrees centigrade. So, pretty much room temperature, and not too high pressure as well, because the way they claim to doing it previously was with very high pressures, and this was with one giga pascal, which is quite a lot of pressure, but not so much for doing this.
Host: Shamini Bundell
Wow. So, I imagine that with their previous work being retracted and this being such a sort of dramatic leap in terms of what people have achieved, and that people are looking at this quite, quite closely.
Host: Nick Petrić Howe
Yeah, the reaction from the community has been quite mixed. So, there are some people who are really excited, because this work shows all of the hallmarks of what we would expect if it really was a superconductor. But others have brought up the fact that there are these previous results that have been retracted, and there are also other allegations about this lab as well, in terms of research misconduct. So, there are questions to be had for sure, because of the previous retraction, the group have tried to do things a bit differently this time. So, they have given all of the raw data with the paper, and also there were independent scientists invited to some of their experiments to sort of verify what was going on, and they've also vigorously denied the sort of allegations have been made against them.
Host: Shamini Bundell
And what kind of experiments are these? And you know, what have they done, where so many people have tried?
Host: Nick Petrić Howe
So, the way this particular one works is they're using something called a hydride, which is a material which has a lot of hydrogen in it. And what they did with it, is they use something called, I don't know if I'm pronouncing this right, but they use something called loo-ter-tium, lutetium, and they bathed it in 99% hydrogen, 1% nitrogen, and baked it at 200 degrees C, which sounds like a baking recipe. So, they baked it like that, and then after they baked it, they compressed it two gigapascals, so quite a lot of pressure, and once they've done it for a while, at this pressure, they then sort of slowly let the pressure off to see where the superconductivity remains, and that seems to be the way they've done it this time, and these hydrides are materials that have been used by other groups for various other kinds of higher-temperature superconductors.
Host: Shamini Bundell
So, is the idea that this sort of baking recipe with these very specific ingredients results in a kind of material which has this property of being a superconductor at certain temperatures and pressures?
Host: Nick Petrić Howe
Yeah, that's exactly it, and the idea is that one day, we can find the right sort of mixture of things and ways to make it, the right baking recipe, as it were, to make one where we don't need these massive amounts of pressure, we don't need really low temperatures, and we can just use it sort of wherever we need to use it.
Host: Shamini Bundell
So, now that this is published, and perhaps some people are still skeptical, I guess, are people trying to see if they can replicate these results themselves?
Host: Nick Petrić Howe
Yeah, that's going to be one of the key things that the field will do and, in a way, this is actually easier than previous results to replicate because the two gigapascals, and then the one gigapascals that it sits at is actually much lower pressures than had been used before, and more achievable by different labs, and the team behind this say they are going to help people to try and replicate it as well. Although the one caveat to that is they've also formed a company and patented the material that they used. So they said, they'll help people to the extent that they can with these sort of intellectual property rights, things that they've got going on as well. So, time will tell if this the thing, some people are very excited, some people are a bit more skeptical. But as one scientist who was interviewed for this article put it, if it turns out to be correct, it's possibly the biggest breakthrough in the history of superconductivity.
Host: Shamini Bundell
Well, this is not going to be the last time we hear about superconductors, on the Nature Podcast, I'm pretty sure about that. And listeners if you want to read a bit more about any of the articles we've been talking about, you can find links to those specific articles in the show notes, and you can also find a place where you can sign up for the Nature Briefing, which is an email newsletter with a carefully curated list of the top science news.
Host: Nick Petrić Howe
That's all for this week. As always, you can keep in touch with us on Twitter, we're @naturepodcast, where you can send us an email to podcast@nature.com I'm Nick Petrić Howe.
Host: Shamini Bundell
And I'm Shamini Bundell. Thanks for listening.