How electric acupuncture zaps inflammation in mice

Host: Shamini Bundell

Welcome back to the Nature Podcast. This week, controlling inflammation with electroacupuncture.

Host: Benjamin Thompson

And how antibiotics interact with our gut bacteria. I’m Benjamin Thompson.

Host: Shamini Bundell

And I’m Shamini Bundell.

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Host: Shamini Bundell

First up on this week’s show, reporter Nick Petrić Howe has been finding out about a neuronal basis for electroacupuncture.

Interviewer: Nick Petrić Howe

In your life, you’ve probably experienced a swollen, hot and sometimes painful sensation – that’s inflammation. This is a normal part of the body's response to foreign objects and is key to fighting off things like bacteria. But too much inflammation can be damaging and results in diseases like rheumatoid arthritis or inflammatory bowel disease. And each year, thousands of people die from sepsis, which is characterised by out-of-control inflammation. Now, typically, the body is able to reign in inflammation through the nervous system, as neurosurgeon and inflammation researcher Kevin Tracey explains.

Interviewee: Kevin Tracey

The nervous system can control inflammation directly and indirectly. It can control it indirectly through steroid hormones from the adrenal gland, and these hormones can turn off inflammation. About 20 years ago, we made the rather then surprising discovery that the nervous system can also turn off inflammation directly, where signals arise in the brain and travel down the vagus nerve, through the neck and into the spleen and other organs, where the electrical signals in the vagus nerve are converted to chemical signals, and these chemical signals switch off inflammation in the tissues.

Interviewer: Nick Petrić Howe

The fact that there are these neuronal processes that can modulate inflammation has led many scientists to wonder if there’s a way to harness them. Could we stop inflammation by hijacking some neurons, getting them to fire when we want? Enter electroacupuncture.

Interviewee: Kevin Tracey

Electroacupuncture is essentially delivering electricity through electrodes placed in the body’s tissues at relatively low currents so that bursts of current are applied to the nerve, which causes nerves in the area of the electrode to become stimulated and fire.

Interviewer: Nick Petrić Howe

Now, whilst the evidence supporting conventional acupuncture is controversial, electroacupuncture has been shown in several studies to reduce inflammation in mice if the mouse body is stimulated in just the right way, as neurobiologist Qiufu Ma explains.

Interviewee: Qiufu Ma

Electroacupuncture in the hindlimb region can activate a pathway for the vagal-adrenal pathway, which can reduce inflammation.

Interviewer: Nick Petrić Howe

This appears to work by promoting signals through the nervous system. When the hindlimb is stimulated, signals are sent through the vagal-adrenal pathway to the adrenal gland, which then releases molecules called catecholamines, resulting in less inflammation. But there are still a fair few unknowns here.

Interviewee: Qiufu Ma

But the question is why? Why can acupuncture do this in one body region but cannot do another body region?

Interviewer: Nick Petrić Howe

The reduction of inflammation only seemed to occur when the hindlimb in particular was stimulated. It didn’t happen when the abdominal region was used. So, Quifu has been trying to find out why, and this week in Nature he’s got a paper out that looks at the specific neurons involved in this response.

Interviewee: Qiufu Ma

So, in this paper we make one hypothesis where we say, ‘Okay, there must be some kind of sensory pathway unique for the hindlimb region compared with the abdominal region.’ For example, you have the joint ligaments, you have bone, you have a larger skeletal muscle, which you do not have in the abdominal region. So, we make the hypothesis that some sensory neurons, most likely select to innervate this bone, ligament or limb region, which are not innervated in the tissue in the adnominal region, and that indeed we found the sensory neuron exactly like that.

Interviewer: Nick Petrić Howe

The neurons Qiufu found were ones that had a specific receptor on them – prokineticin receptor 2 or PROKR2. To figure out if these neurons were indeed responsible for the reduced inflammation seen in mice, Qiufu removed them.

Interviewee: Qiufu Ma

We use a genetic tool to remove this neuron. Then we did the acupuncture in mice, and we found that the acupuncture can no longer supress sustained inflammation, and it cannot promote animal survival anymore. It’s a complete loss to this acupuncture effect.

Interviewer: Nick Petrić Howe

Qiufu then wanted to see if this worked in reverse. Using a genetic tool, again he modified the Prokr2 neurons so they could be specifically stimulated by a laser. This laser would only affect the modified neurons and no others. Quifu found that the laser reduced inflammation in the modified mice but not in the control mice. With this new understanding of the specific neurons involved, Qiufu believes that we can now identify which other parts of the body we could stimulate to reduce inflammation, or which points we could combine stimulation of to control the effect. Kevin, who you heard from earlier, also thinks this paper could be a blueprint for future studies to tackle a key knowledge gap.

Interviewee: Kevin Tracey

We know very little about the nature of individual nerve fibres and their function and their connectivity, and so this paper provides a powerful map and is a recipe, if you will, for others to replicate as they address their own specific questions about the function and control of specific cells on specific organs under the control of specific neurons. It’s beautiful.

Interviewer: Nick Petrić Howe

Of course, these studies are in mice, so in the future Qiufu would like to see human studies to work out if this effect can be replicated, and he has some hope for this.

Interviewee: Qiufu Ma

Some basic anatomic organisation should be evolutionary conserved, and deep stimulation has long been used to control a lot of chronic inflammation in acupuncture fields. But exactly how strong, how deep you need to go, you need additional human study.

Host: Shamini Bundell

That was Qiufu Ma of the Dana-Farber Cancer Institute and Harvard Medical School, in the US. You also heard from Kevin Tracey of Feinstein Institute for Medical Research, also in the US. If that research has pricked your interest, be sure to check out the paper and a News and Views article in the show notes.

Host: Benjamin Thompson

Coming up, we’ll be hearing about the complicated interactions between antibiotics and our gut bacteria. Right now, though, it’s time for the Research Highlights, read by Dan Fox.

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Dan Fox

In his attempts to summon spirits, sixteenth-century English astrologer John Dee, a confidant of Queen Elizabeth I, gazed into a mirror made of polished stone. Now, researchers have confirmed that Dee’s mirror has Aztec origins. Mirrors made of the glassy volcanic rock obsidian were made by Indigenous people in Mexico and taken to Europe during Elizabeth’s reign, but the exact origin of Dee’s mirror has been a mystery until now. A team of researchers used a technique called X-ray fluorescence to identify trace elements in the mirror’s mineral structure, and then compared its profile with geological samples from Mexico. The analysis revealed that the stone of Dee’s mirror matched obsidian found near Pachuca, a city in central Mexico. Obsidian mirrors were connected with the Aztec god of sorcery and were used in religious activities, and authors say this symbolic value might have made them appealing to European colonizers and motivated John Dee to acquire his mirror. Reflect on that research in full in Antiquity.

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Dan Fox

Decades-old spy satellite images have shed light on the ecological devastation caused by a Soviet plutonium-making facility in the Southern Urals. The Mayak Chemical Combine produced weapons-grade plutonium for the Soviet military. Western spy satellites kept a close eye on the top-secret facility, and Soviet dissidents carried reports of a large explosion, abandoned villages and dying forests. But the scope of devastation linked to the facility ― which is still operating ― has been unclear. Now, a researcher in Poland has studied declassified images and Secret Service records from the 60s and 70s, revealing demolished villages across hundreds of kilometres of contaminated land and steam rising from a lake that should have been frozen, suggesting heat exchangers for making plutonium had been installed there. The research suggests that the declassified records indicate that US intelligence services were well aware of radioactive contamination in the region, but that officials in the United States did not disclose the intelligence, for fear that it might undermine public confidence in the safety of the US nuclear programme. Read that research in full in the Cambridge Archaeological Journal.

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Interviewer: Benjamin Thompson

Antibiotics are designed to target disease-causing bacteria in the body. But unfortunately, many of them are pretty indiscriminate about the bacteria that they act on, which can wreak havoc with the communities of so-called commensal bacteria that live in our guts. Doctors know that disturbing these communities can cause all kinds of problems, like increasing the risk of Clostridium difficile infections, a huge problem in hospitals and healthcare settings. But exactly how different antibiotics interact with different gut bacteria isn’t very well understood. I spoke to Nassos Typas from the European Molecular Biology Laboratory in Heidelberg, Germany, who is part of a team that is trying to get to the bottom of the problem, and they’ve got a Nature paper out about it this week. I asked him why this work has been so difficult.

Interviewee: Nassos Typas

I think part of the difficulty is because of the diversity of those communities. There are so many different bacterial species growing in them. Most of them, until a few years ago, we didn’t work with them, so people wouldn’t care about it, so there were no means also to do the experiments. I think the second reason is that the majority of them can only grow anaerobically and so where no oxygen is around, and some of those assays, when you want to do them at larger scale, it’s much more difficult to do them under control environments.

Interviewer: Benjamin Thompson

And so, if it’s quite difficult to model what’s going on, how have you gone about it then?

Interviewee: Nassos Typas

I think what has changed in the recent years is that people have been able to cultivate a lot of those species and one can go directly and apply some of the more automated experimental platforms, so one can measure many of those species, how do they interact with many of those antibiotics. And I think the second reason to do it is because we now realise that it might matter. I mean, of course, antibiotics, still what they do is tremendous. They can target pathogens and you can do that very easily so you don’t die from infectious diseases, and the collateral damage is something secondary so people have always neglected that second part.

Interviewer: Benjamin Thompson

And so, you really wanted to get an idea of what sort of damage antibiotics might be doing to the gut microorganisms. How did you go about doing that and how many antibiotics did you look at?

Interviewee: Nassos Typas

We looked, initially, at over a hundred different antibiotics, and then we had a more refined picture for a smaller set of them, but we tried to cover all the different major classes that were there. And then we tested in the order of 30 different bacterial species, and we just measured the growth and we can see how well they can grow with the antibiotics and with different concentrations of antibiotics. And then we found out basically a concentration which is the minimum concentration that inhibits that microbe.

Interviewer: Benjamin Thompson

And so, you’ve tested this sort of suite of antibiotics against bacteria then that live in the gut, and in some of the cases it seems like the antibiotics really worked in kind of the opposite way to what’s been described in the textbooks.

Interviewee: Nassos Typas

So, what is going on is that antibiotics, traditionally, from the very beginning, have been divided in two different modes of action, and one is that antibiotics inhibit the growth of the microbe, but then some of them do also on top kill the microbe, so even if you remove the antibiotic, the microbe cannot grow anymore. And bacteriostatic are the ones that just inhibit microbes and bacteriocidal are the ones that actually kill also the microbes. And we noticed that some of the bacteriostatic microbes were inhibiting the growth of all the microbes we would see on the screen. But what we knew from data from patients is that some of them actually change a lot the composition of the microbiome when patients get it. And what we reasoned is that if they stop the growth of everybody, then they shouldn’t change so much the composition because the moment you stop the antibiotic, the community should resume growth and you should have the same communities. And then we thought, alright, maybe we should revisit. I would say to our big surprise, what we saw is that a lot of the textbook bacteriostatic antibiotics, they actually kill some of the commensal species and they kill them also with very fast kinetics. And I think in retrospect that might explain also why we have community composition changes because you target every microbe, but some of them you kill, some of then you just inhibit, so when you remove the antibiotic and you stop taking the antibiotic, the ones killed cannot grow again, but the ones that have been inhibited can resume growth and the community takes a different composition.

Interviewer: Benjamin Thompson

And so, to try and prevent this collateral damage to particular gut bacteria species then you looked at ways to modulate how some of these antibiotics worked, by combining them with other non-antibiotic drugs. Why did you try that?

Interviewee: Nassos Typas

There is evidence that if you combine two drugs, the outcome that they have is quite species-specific, so if they interact and they interact synergistically – so one helps the other – or antagonistically – one makes the other work less or masks the effect of the other – this outcome is quite specific to the species you’re testing. So, we reasoned that we can take a second compound and try to mask the effect of the antibiotic on gut commensal but still retain its activity on pathogens. So, we did a large screen to try identify those compounds, which we called them antidotes. We found those. They worked in vitro. And when we had that combination of the antidote and the antibiotic, we had now an antibiotic that wouldn’t inhibit the gut microbes but would still work against pathogens, not all gut microbes but some of the gut microbes and the prevalent and abundant ones.

Interviewer: Benjamin Thompson

But, of course, when we’re talking about the guts, we’re talking about hundreds if not thousands of species living together, and you’ve tested whether an antidote could protect against antibiotic collateral damage in communities derived from human stool samples. What did you see there?

Interviewee: Nassos Typas

The biggest surprise for us is that when we took communities that actually exist, and those communities were from 9 different individuals, containing very diverse microbiomes, different strains, different species, we didn’t know if the antibiotic would work and whether the antidote would also mask the effect on the antibiotic. And this was a surprise that actually the effects transpired also independent of the strains that the individuals carried, and I think that was the key experiment to show that this is beyond the individual, single species experiment.

Interviewer: Benjamin Thompson

And you also showed some in vivo results, suggesting that this works in mice that have simple gut microbiomes. So, a series of experiments then that maybe give an idea of what’s going on inside our guts when we take antibiotics, and ways to mitigate some of the negative effects. What do you think this work has done and where do you think it needs to go?

Interviewee: Nassos Typas

I hope it will raise awareness about the effects of antibiotics that happen on commensal species that we can extrapolate from knowledge we have on selected pathogens. A lot of times what people do because there’s not enough data is that they lump all antibiotics together, so different classes, combinations of antibiotics, and we see that antibiotics act very differently, so I think this is also a flag that we should be careful and study antibiotics separately because they have very different effects on the gut microbiome. And when they start understanding what is the collateral damage and which antibiotics cause what collateral damage, there might be ways to prevent it.

Interviewer: Benjamin Thompson

That was Nassos Typas from the European Molecular Biology Laboratory. To read more about the work, look out for a link in the show notes.

Host: Shamini Bundell

Finally on the show, it’s time for the Briefing chat, where we discuss a couple of recent articles that have been highlighted in the Nature Briefing, so, Ben, what have you found for us to discuss this week?

Host: Benjamin Thompson

Well, Shamini, a bit of a sad one from me this week, and it’s something that I read in The New York Times, and that it’s that over 20 species in the US should be declared as being extinct.

Host: Shamini Bundell

Oh, man, and is this all just in the last few years that suddenly they’ve all gone extinct?

Host: Benjamin Thompson

Well, actually, Shamini, what’s interesting about this is that many of these species are likely to have gone extinct or at least very close to being so quite a long time ago, certainly before the US Endangered Species Act was passed in 1973. But up until now, only 11 species previously listed under this act have been classified as extinct, so to have more than 20 added in one go is a very sad state of affairs.

Host: Shamini Bundell

Oh, so is this one of those ones where it’s quite hard to prove conclusively the absence of something. It’s quite hard to prove that something is in fact extinct.

Host: Benjamin Thompson

Well, yes, I mean, it’s not something that’s taken lightly, declaring something extinct, and scientists often search for decades to make sure that they’re absolutely convinced. Now, about half of the species in this group were already considered extinct by the International Union for the Conservation of Nature, which looks at things globally. But in the US, the Fish and Wildlife Service have been a bit slower to kind of get to this point, mainly because they’ve got a bit of a backlog, and according to this article, they tend to prioritise protection for species that maybe need it rather than removing protection from the list for those that don’t, and very sadly, in this case. But that’s not exactly it though. So, a 60-day public comment period has just started, and if people have got any pertinent information then they can certainly share it but after that, the US Fish and Wildlife Service will make their final ruling on the state of these species

Host: Shamini Bundell

And are there any sort of particular species that you think people will be hoping are still hanging on somewhere in some sort of distant area?

Host: Benjamin Thompson

Yeah, I mean, one of the species that has caused a bit of controversy for whether it’s still about or not is the ivory-billed woodpecker, which was the largest US woodpecker, and the last confirmed sighting of that was in 1944. But there were some potential sightings in 2004, and a paper came out saying that these birds were still alive, but then other people were saying that this was a different woodpecker, but officials have been unable to find it so the conclusion seems to be that it is extinct.

Host: Shamini Bundell

And it’s sad isn’t it, when you still have the glimmer of hope that there’s a breeding pair of this rare species somewhere, but it sounds like for these 20 now, this is the end of their story. And what’s been happening in the US that’s kind of caused these various different species to be driven to extinction?

Host: Benjamin Thompson

Well, sadly, it’s the story around much of the world. A lot of this has come down to us, Shamini, habitat destruction. A lot of these species were on the islands of Hawaii and Guam, and island populations are particularly at risk to things like introduced species of pigs and rats which can destroy habitat and eat birds and bats. And on Hawaii, for example, I didn’t know that mosquitoes didn’t exist until the 1800s, and these can kill birds by infecting them with avian malaria. But of course then you throw in climate change, so birds that maybe lived in colder parts, mosquitoes couldn’t get to them, but of course as these areas have warmed up, the mosquito population has expanded and potentially threatened other bird species as well. So, really, not a great state of affairs. But for some of these, like the freshwater mussels, not enough was known enough about them to say for sure why they disappeared. Obviously, they have a very complex life cycle and if any part of that was disrupted, the ultimate effects could be that sadly they only exist in the history books now.

Host: Shamini Bundell

Well, yeah, that’s a pretty sad story, so I am going to try and cheer you up with my contribution to the Briefing chat this week. I’ve got a story about something that has been discovered instead of lost, maybe. It’s maybe a planet.

Host: Benjamin Thompson

Right, okay. So, where is this maybe planet? I’m guessing it’s quite a long way away.

Host: Shamini Bundell

Yes, I mean, exoplanets are often difficult to find and spot and determine whether they’re there or not, and this one is certainly no exception to that, but it is particularly interesting because, if it exists, which a new paper says it does and this is another New York Times article, it would be the first planet found to be orbiting three stars.

Host: Benjamin Thompson

Wow, is that unusual? I guess, having watched Star Wars, Tatooine has got two suns, so I guess that’s got two stars. Is three the magic number?

Host: Shamini Bundell

Well, multiple star systems are very common, so systems with two stars, three stars, even more than that, and some of these stars have planets. So, for example, if you think about Alpha Centauri, our nearest star, is actually a trinary star system, and an exoplanet has been discovered circling Proxima Centauri, but it’s only actually orbiting one of the stars, and we have found planets orbiting two stars before, but this is the first time that it would be a planet that is orbiting all three in a system.

Host: Benjamin Thompson

So, I guess, with exoplanets orbiting different stars, Shamini, it’s actually pretty difficult to spot them in many cases. Why do researchers think that there’s something in this system that is orbiting these three stars?

Host: Shamini Bundell

Yeah, so this is not a situation where they pointed their telescopes and have seen a little black circle, and that’s partly why this is controversial. So, this particular system, GW Orionis, it’s a star system in the constellation of Orion, and these three stars are surrounded by this huge disk of dust and gas, which is quite common in sort of young star systems that are forming planets. But this disk of dust is actually sort of split into two, so there’s a sort of inner ring and then at a weird angle there’s an outer ring with this big gap in between, and it’s the gap that everyone’s been looking at. And it has been proposed that this gap could either be formed by a planet that’s sucking material into it and causing this gap, or it could not be a planet at all, it could be to do with the gravitational effects of the stars themselves that are causing this gap.

Host: Benjamin Thompson

And so, what needs to be done then to come up with a definitive answer, do you think?

Host: Shamini Bundell

Well, this new paper says, hey, look, we have found strong evidence that there’s a planet there, it would be a gas giant maybe the size of Jupiter, and they say that the alternative theory, their models actually disprove that. However, not everyone is convinced yet and, interestingly, there might be some more data coming on this soon. Observations from the ALMA telescope and the Very Large Telescope in Chile could end the debate once and for all, potentially in the next few months.

Host: Benjamin Thompson

Well, Shamini, thought experiment time, what do you think a sunrise or a sunset would look like on this potential new exoplanet – kind of strange, I would imagine?

Host: Shamini Bundell

Well, actually, the way the system works – and there’s actually a very cool animation if you go to this article which will be in the show notes – is that the two inner stars are actually quite close together, spinning around each other in sort of tight circles, and then there’s the third star in sort of big circles around the outside. So, apparently, if you were somehow on this gas giant, you would probably only see the two stars because the two inner ones would just look like one because of the distancing because they’re so close together. But even more exciting thought experiment – if a planet can form in this kind of weird situation, which, like I said, it would be the first time that they’d shown it could, if they find it for sure, then why not star systems with four, five, six stars? And then, yeah, I don’t know what a sunset would like from one those planets.

Host: Benjamin Thompson

Well, let’s keep an eye out for those. But for the time being, let’s call it for today’s Briefing chat and, as you say, there’ll be links to both of those stories in the show notes. And listeners, if you’d like more stories like this but delivered directly to your inbox, then why not sign up for the Nature Briefing, and we’ll put a link of where to do so, and it is free, in the show notes as well.

Host: Shamini Bundell

Well, that’s all we’ve got time for this week. But don’t forget, if you want to get in touch with us, you can. We’re on Twitter – @NaturePodcast – or you can send us an email to podcast@nature.com. I’m Shamini Bundell.

Host: Benjamin Thompson

And I’m Benjamin Thompson. Thanks for listening.