Disease breath tests, and Perseverance papers

Plus, using artificial enzymes to attack COVID, and how low frequency noises make us want to dance
25 November 2022
Presented by James Tytko
Production by James Tytko, Chris Smith.




In the news this week, we hear about the novel approach to diagnosing diseases by looking at the chemical compounds in patients' breath, a new way of attacking viruses without damaging our cells, the potential for life on Mars, successful trials prescribing heat for health conditions, and what low frequncy noises we can't even hear can do for our propensity to dance...



In this episode

A breath full of disease

00:54 - Diagnosing disease using a patient's breath

How the compounds in our breath might hold the key to a more accurate diagnosis

Diagnosing disease using a patient's breath
Dr Michael Wilde, University of Plymouth

A new way to diagnose certain diseases by analysing a patient's exhaled breath has been demonstrated by UK researchers. As he explains to Chris Smith, Plymouth University's Michael Wilde and his colleagues have identified unique combinations of chemicals that are produced in different amounts by different diseases and are released from the lungs alongside the air we breathe out. So if you analyse the composition of that air and measure these chemicals, you can identify the underlying medical problem, even if the patient has more than one thing wrong with them at the time. At the moment it's at the proof of concept stage, but the hope is that the technology could be shrunk to provide a rapid diagnostic system that could screen patients at the hospital doors, or even in their own homes…

Michael - More than one in eight of all emergency admissions to our hospital patients presenting with acute breathlessness and currently the diagnostic markers used to identify the underlying diseases blood tests and radiological procedures such as x-rays. And they have poor discriminatory power in patients with different presentations and also delays in blood sample processing in a triage.

Chris - Because a person could be breathless because they have a chest infection. They could also have heart failure. They could have both.

Michael - Exactly. Despite the same presenting symptom, the underlying causes of acute breathness are highly varied and patients presenting with that symptom will have different disease progressions and treatment options.

Chris - And you think you can improve on what we've already got?

Michael - Yes. So the scope of the study was to develop a new noninvasive method based on breath analysis. And the advantage of a breath test over say a blood test for instance, is not only for those of us who don't like needles because it's non-invasive, it allows for repeated and frequent measurements. So breath is much more readily available than blood and this minimizes the rest of the patient and allows us to monitor those markers or disease a lot quicker.

Chris - How does it work then?

Michael - We know the main constituents of air are carbon dioxide, oxygen, nitrogen, and so most of us would expect exhaled breath to also comprise of slightly altered composition of these main gases. However, it might be surprising to hear that alongside these respiratory gases, our breath also contains hundreds if not thousands of chemicals known as volatile compounds. These volatile compounds are coming from complex chemical reactions happening inside our body. And when we have a disease or a certain condition, this can disturb the levels of these small chemicals in our blood, which then partition to our breath. And so if we can detect these volatile chemicals in breath, we can use them in the non-invasive diagnosis and prognosis of different diseases.

Chris - So different diseases would be represented by a different fingerprint, as it were, of changes in what would be the normal levels of a cluster or constellation of those chemicals?

Michael - Precisely, yes.

Chris - And if you can detect what's changed and by how much, you've got a way of effectively putting your finger on what the diagnosis is, just from sniffing what the person's breath smells like.

Michael - Yeah, precisely.

Chris - Does it work? Is it any good?

Michael - It worked very well. Um, so we were able to identify breath chemicals that differentiate acute cardio exacerbations and the underlying disease subgroups. So we are able to measure and detect about 805 different volatile chemicals across 277 patients. We identified a set of these chemicals that were able to differentiate acute breathlessness, and then within that set of chemicals we also identified smaller subsets, which were able to diagnose acute asthma, chronic obstructive pulmonary disease, known as COPD, community required pneumonia, and acute heart failure.

Chris - How did you find these things in the first place? Because if we envisage an enormous chemical haystack, which is all of the chemicals in the human body, many of which are gonna come out in the breath, how did you find the needles in that haystack that are representative of those different diseases, which are the really sensitive and specific ones that point the finger reliably at the underlying condition each time?

Michael - So that's where I come in as an analytical chemist. To trap the volatile chemicals and breath, we need to pass the breath through a small tube containing a solvent material. So you can think of these tubes as a chemical sponge or a filter. We can send those tubes back to the lab and use an advanced analytical technique called gas chromatography. It's a bit of a mouthful, but most people will have performed chromatography at school. When you place a ink dot on a piece of paper and then run water up for paper, it separates the ink into the different colored pigments. Using this technique, we are able to visualize the separation of hundreds of these volatile chemicals. So we effectively have a molecular lens through which we're able to take a chemical photograph to see the chemicals present in your breath.

Chris - Now obviously you have at your disposal a very good analytical laboratory to do this kind of thing. An A&E department doesn't. So is the idea that having found those needles in the biochemical haystack, you now say, well, we will make small shrunken tests that are just as good on a small scale at finding those particular molecules and that will give us a test?

Michael - Precisely. So in the first instance, we've demonstrated how breath biomarker platforms and how these noninvasive breath tests can be used in an acute care setting. But in the future, now we have an understanding of what these molecules are, what we need to look for, we can start to think about translating these breath signatures, these chemicals onto portable sensors. And then I think most of us could readily envisage in the future a sensor built into a wearable technology or your phone for instance. And you have a constant health status fed back based on the volatile chemicals that you're emitting from your body.

Green coronavirus particles around a strand of DNA.

07:06 - Using 'molecular scissors' to snip COVID

How artificial enzymes can be programmed to attack COVID

Using 'molecular scissors' to snip COVID
Alex Taylor, CITIID

Precision molecular scissors that can operate inside our cells to selectively target and dismantle the genetic material of the COVID-19 virus have been developed by researchers at the University of Cambridge. Dubbed XNAzymes, the scissors are themselves built from short pieces of an artificial genetic material called XNA. This folds itself into specific shapes that can recognise and target for cutting only the genetic sequences of  viruses, rather than any of the healthy genetic material that's meant to be in a cell. And by building sets of these molecular scissors that are effectively multi-bladed, they can be programmed to make cuts in the viral genetic material at several locations; so even if the virus adapts or mutates in one of the cut sites, it will still be disabled by cuts made elsewhere. Alex Taylor, from the Cambridge Institute of Therapeutic Immunology & Infectious Disease, CITIID, is here to explain how they've done this...

Alex - If you imagine the double helix like you sort of get with a short piece of DNA, sort of peeled apart into its two separate strands, one of those strands by itself can fold up into really a variety of different shapes. But in our case, the strings of nucleotides are made from these artificial building blocks. That's what makes them XNAzymes. They're strings of just sort of 35 or so of these. So that makes them about sort of 10 nanometers long. Just to sort of put that in context, it means you could sort of fit about five to ten thousand of these things across the width of a human hair. We know what the sequence of XNA that you need to sort of fold up into an active enzyme, but we actually don't know yet what the sort of catalytic core of these things looks like. But we know they have a sort of catalytic core with a kind of couple of binding arm sequences next to these that recognize the RNA. And in the study, as you say, we sort of took three of these XNAzymes, these molecular scissors and engineered them to sort of fold up into kind of pyramid like structures. So a bit more like a sort of three bladed blender.

James - How do you get them physically into the cells for them to then do their work?

Alex - Well, so for us it's very early days. We are just trying to understand whether and establish whether these things can actually have their kind of catalytic activity inside cells. So at the moment we've just been using this technique called electroporation. So this is where we give cells a little electric shock and that sort of opens up temporary sort of holes in the surface of the cell and allows the XNAzymes in. This isn't really a technique that we could use in a sort of realistic clinical setting. So in the future we want to explore sort of linking XNAzymes to things like the sort of fatty droplets as this is the kind of technology that was used for tthe Pfizer and Moderna RNA vaccines. But actually other researchers have shown that in the case of things like lung cells, it might be possible to sort of just inhale short oligos into the lungs in a fine mist and get them taken up into cells without having to rely on things like lipid nanoparticles.

James - And how effective have they proven to be in what you're trying to achieve with them?

Alex - So far we started off by sort of just in the test tube taking sort of short sections of the viral genome of SARS-2 and sort of linking these to kind of glowing dyes that allows us to kind of track the size of these RNA target molecules. And it was part of the exciting aspect of this technology is that we could rapidly generate a series of the XNAzymes really just within a couple of days of the genome coming out and sort of test whether they worked on these shorter fragments. And once we'd done that, we moved over to using the full RNA genome of the virus extracted from infected cells, tested them sort of with conditions that kind of mimic the inside of the cell. And again, once we saw that it was cutting, I was able to team up with a virology lab in my department who have a sort of safety level three lab and we challenge cells with a live virus. And we found that indeed once the cells have XNAzymes in them, they're able to inhibit the replication of the virus.

James - And just finally, Alex, could this technology be used for other diseases or recurrent infections?

Alex - Absolutely. So at the moment we're really only targeting RNA based viruses. But this includes some of the biggest kinds of emerging threats that we face over the last few decades. So things like Ebola, Zika, influenza, this kind of thing. So we certainly think that we should be able to know we're looking at sort of targeting some of these kinds of viruses. And really RNA viruses are really the big sort of scary group. About 40, 40 to 50% of emerging human infectious diseases are RNA based viruses. So, at the moment that's, that's where we're sort of putting our attention.


12:26 - Perseverance report published

What Perseverance has revealed about the potential for life on Mars...

Perseverance report published
David Rothery, Open University

To Mars, and a treasure trove of information from the Mars rover Perseverance which has just been published. Perseverance landed spectacularly in Mars’ Jezero crater in February of 2021, with the mission of surveying the nearby area for signs of life - or at least signs that life may have once been supported. Images from space showed that the Jezero crater contained what used to be a river delta; so where better to start the hunt for extraterrestrials than a place that was once probably full of water. The rover has been gathering data ever since and, this week, a collection of papers were published documenting the initial findings. Planetary geologist David Rothery from the Open University took Will Tingle through what’s been discovered so far…

David - But there's history of igneous activity there on the floor of the crater. Now a delta flowed across that crater floor and leaves us the delta we see very prominently from the spacecraft images looking down on Jezero crater. But that's not the original delta, that's just an erosional remnant. Most of the delta rocks have been eroded away. And where have they gone? It's a very good question. Some rocks have been flushed out of there as an outflow channel going out of the crater, but maybe a lot's been removed by the wind. The curious thing is, you see the front of this delta, there are some damn big boulders there brought in by torrential floods: metre size boulders potentially. And you can't blow those away in the wind, especially in Mars' very tenuous atmosphere. So there are processes going on that we don't really understand. But what's published this week is the lavas on the floor of the crater were altered by water.

David - So it's clear there was a body of water overlying these lavas and there's been a certain amount of alteration of the original rocks formed by cooling from molten lava being carbon deposited. And then later on some salts precipitated from brine, so water got really salty. So we've got an alteration history, but we haven't yet got samples of the lake bed rocks that might have microbes in them - or not as published. The rover is now at the very bottom of the steep face of a delta in amongst some very fine grain sediments. And that's a chance for finding some fossilised microbes. And I guess there will be caching some specimens for later return to earth from that very site where they are now.

Will - It's good that you mentioned that because it did say that on one of the papers that Perseverance will be collecting up to 38 samples of rock and regular earth (regular being dust that's on top of bedrock.) They plan to be brought back and returned for analysis in earth laboratories. I wonder if you could shed any light on how they plan on bringing these samples back.

David - One plan, given that the Ingenuity helicopter has functioned so well, is to use helicopters to go and collect these little bits of samples and bring them back to a central point from where a future mission can return them. But they're probably going to be using the Perseverance rover as well to bring samples to our collection points. But Perseverance has a big job to do. First, it's going to climb up the front of its delta. It's about a hundred metres high to get it from the bottom of the delta to the top. The top continues to slope upwards. It's got quite a traverse to go through to see the whole sequence of delta morphologies. So we're a long way off yet bringing samples back to work. But it's collecting samples in collection tubes ready to be retrieved when we've figured out quite how we're going to do it.

Will - How optimistic are you that we may find remnants of life, be it alive or in a deep torpor or even just fossilised remnants.

David - There are organic molecules that have been found. That doesn't mean life. Organic is just carbon and hydrogen bonded together with oxygen and so on. So there are some quite complex molecules in amongst the rocks. But we won't find microbes with this mission - unlikely to anyway. But future missions may have a better chance. Mars in the past surely had life. Even if it didn't develop its own life, it could have had life carried from earth. If there was a big impact on earth and a rock gets flung out from earth, it will have some bugs in it. Some of those bugs will survive passage to Mars and can seed Mars. Either life on Earth came from Mars or life on Mars came from Earth. So I'm sure Mars had things living on it in the deep past at the same time Earth had early microbes present, but they're going to be hard to find.

A close up of a thermostat dial

18:48 - Prescribing 'warmth' for the winter

How being cold has a serious effect on new and existing health problems

Prescribing 'warmth' for the winter
Christof Schweining, University of Cambridge

In the past, doctors used to prescribe a hot bath for some disorders, but now in some areas history is almost repeating itself with practitioners writing prescriptions for heating for patients with conditions that get worse in the cold. In an initial trial, the Warm Home Prescription pilot paid to heat the homes of 28 low-income patients to avoid the cost of hospital care if they became more ill. Those running the trial said it achieved such good results they plan to expand it to 1150 homes. So why is heating a wonder drug, and do the figures stack up? Cambridge University physiologist Christof Schweining knows all about how we keep warm and stay cool - he often puts his knowledge into practice as a highly successful marathon runner…

Christof - Well, I wondered exactly the same thing just before I came down to meet you. So I did a quick calculation on my trusty spreadsheet. So I looked up a patient in hospital for a single day, at least in A&E is about 400 pounds. And if you assume that you could target the people who want to have their homes heated appropriately, maybe you could stop 10% of the emissions. And then you imagine that perhaps if you were to get ill and be in an unheated house and get ill, that you would have a stay of perhaps two weeks or three weeks in hospital. Then it's worth, at least over the four months of winter, paying a hundred to maybe two hundred pounds a month off a fuel bill to do that. So I think it actually does make sense. I think it all depends on how well you can target this as a treatment.

Chris - What's the rationale though, for making people warmer in winter and that reducing their risk of disease? What's the link between being cold and getting health problems?

Christof - There are so many links going on here. One of the big links, which isn't talked about often enough, is the effect of, for instance, lying down in bed to stay warm over a prolonged period of time. That's an absolutely massive detraining stimulus. So imagine you've got somebody who is aging and relatively unfit. They've got some underlying disorder as well. If that person detrains as a result of lying down not being exposed to a gravitational field and also not performing exercise, just routine daily exercise, then they really do risk, at the end of a winter period or at least several weeks on into this bedrest, becoming so unfit that they struggle to deal with any kind of exacerbation of an underlying illness.

Chris - So this would be people retreating to bed early because it's warmer in bed than it is in the living room.

Christof - Oh, absolutely. I know I've just bought an electric blanket. Being in bed is a wonderful thing, but it's awfully a dangerous place to be really. Old people are particularly at risk here because the ability to sense your internal temperature reduces and your ability also to control the blood flow to your periphery, really to lock off the blood flow from the periphery to keep it centrally in the well insulated area that declines with age. So you've got old people and ill people who've got low maximal rates of aerobic work. They've got a compromised ability to sense their core temperature and also a compromised ability to restrict the blood flow to maintain the core body temperature. All of this adds together into a scenario where even if you don't have an acute serious illness at the point at which you take to bed, you may well end up at the end of a period in a position where you might need hospital care.

Chris - The rates of things like heart attacks and strokes also shoot up in winter. Can that be explained on the basis of what we know about how the body handles temperature?

Christof - Certainly. So there are some really simple acute effects that are well known. So when you get cold, you peripherally vasoconstrict, so you reduce the blood flow to the periphery. This pushes the blood centrally and as a result of that, you also get a rise in arterial blood pressure as well and somewhat of a thickening of the blood, so a haemo concentration. And all of that places a stress on the heart, which of course can exacerbate any kind of cardiovascular disorders. But there is some disagreement here as to exactly what the drivers are. So there are lots of things that go on when the weather gets cold and you take to bed, you become potentially a little bit depressed, a little bit less likely to exercise, maybe less likely to take care of yourself, to eat appropriately and indeed to drink as well. So all of these things add together to produce cardiovascular stress.

Chris - Do we see then the countries where it is warmer and warmer in winter, that they don't have this surge in winter mortality? Because that's the thing we see, isn't it? Every winter we see this so-called surge in excess mortality. Now some of that will be things like the flu, but many argue it is the cold that is killing people.

Christof - Ah, well this is interesting because you've caught me here on a set of data that I don't have. So I don't know whether the equatorial regions really suffer the same set of problems, but what's certainly true is if you look at different sets of societies, some are certainly much better adapted to cold weather. So if you look at the Scandinavian countries in particular, the infrastructure is such that the cold weather really doesn't present a problem. We are sort of stuck in the middle in that we have winters, which are sometimes quite cold, and so like the leaves on the line, we don't tend to take the necessary set of precautions.

Chris - You preempted where I was going with that, because I was going to say, well, there are many countries where it is much colder in winter than seven degrees today here in Britain, and we are not seeing the sort of surges in mortality that we see here. So it must be all relative then.

Christof - Oh, absolutely. I mean the bus stop is a really wonderful example. If you have a public transportation system aimed at a set of individuals who are more likely to be at risk from cold weather and then you don't have a regular bus service, you risk leaving them sat stationary in cold conditions for a prolonged period of time. And that really then presents a major acute risk. So something as simple as having a regular bus timetable that arrives on time, we just don't think about that. But things like that can be absolutely critical when looking at the risk of cold weather.

Dance Music Venue

25:25 - Low frequency bass boosts boogieing

How sounds we can't even hear might make us move more on the dancefloor...

Low frequency bass boosts boogieing
Dan Cameron, McMaster University

This is an excerpt from a special concert recently performed by Canadian techno duo Orphx. The concert took place at the LiveLab facility at McMaster University in Canada a short while ago. Dan Cameron, post doctoral research fellow at McMaster, uses this music venue with a difference to pull off some pretty unique research. As well as being a neuroscientist, Dan is a keen drummer. He’s interested in the way music makes us want to dance - something of an evolutionary curiosity. The LiveLab hosts genuine concerts and is equipped with microphones and speakers designed to be able to change the acoustics of the concert hall on a whim. They can measure brain activity from the audience members and the performers there using small sensors attached to their heads and also have motion capture technology to measure their movements. I asked what all this tech was teaching us about techno…

Dan - So I've always been interested in rhythm and what types of rhythms make us feel the strong sense of a beat that we can synchronise our movements to. But there's been another component and that's the bass - the low frequencies in music. And we know from anecdotal reports that people who like to go to electronic dance music concerts, they feel immersed in the base. It affects their body, it feels good, it makes them want to dance. And we know from experimental work that there are associations between bass, or low frequencies, and movement and movement timing in particular. But kind of in the same way that with a medical drug you need to test not just if it affects the body or the tissue in the way that you expect, but is there a clinically relevant effect? Does it actually change people's outcomes and lives?

Dan - We didn't know if there was a real world effect. Now, for this study, we were having a concert from the electronic music duo called Orphx. And people were paying to come, they were buying tickets and we thought, "we can do an experiment here as well on bass and movement." So we asked people if they wanted to volunteer for this experiment and all they needed to do was put a really simple headband on their head that had a motion capture sensor on it. And then they went and enjoyed the concert and they danced. And the thing we did to test whether bass affects their dancing is we had these specialised speakers, these very low frequency speakers that play bass frequencies that are really low. Most speakers are not able to play these and they're not generally part of the musical experience. We needed people to be unaware of when we were turning these speakers on and off. When they were on, they were at a pretty subtle level, and we had a couple of pieces of evidence afterwards that really did indicate to us that people couldn't detect when these extra low frequencies were on. What we found was that, by using motion capture, we could track everyone's movements. When the very low frequencies were present, when those speakers were on, people danced about 12% more than when they were off.

James - And what do you attribute that increased dance-ability of the music to, even if it can't be audibly heard?

Dan - So this is speculation because we didn't test these mechanisms, but we have an idea from other work that's out there. And we think that it's not just the auditory system (our hearing) that processes the music and especially these low frequencies, but we think that our tactile system (our sense of touch) and our vestibular system (our inner ear, that part of our body and sensory system that processes our sense of balance and where we are in space.) We know that low frequencies, if they're sufficiently loud, can stimulate the mechanoreceptors on our skin and in our body. So if you've been to a concert and you stand very close to a loud speaker, you can feel it kind of rattling in your chest maybe, or on your skin. That's the sound vibrations. The vibrations in the air are stimulating our sense of touch. And we know that our vestibular system is also important in rhythm perception generally - music perception and our sense of moving in time with music. We can change people's perception by having their vestibular system stimulated at a particular rate. If they bounce along to music, that'll change how they hear that music later. But both of those systems, our sense of touch and our sense of balance, are strongly connected in the brain to our motor system - the parts of the brain that control our ability to move and to control our movements.

James - How did you account for the fact that music naturally has these peaks and troughs - parts of the song that are naturally going to encourage more of an energetic response and parts where listeners are invited to catch their breath, perhaps. How do you know that these parts of the music didn't line up necessarily with when you were using these low frequency bass sounds that people can't actually hear?

Dan - We can't control for that perfectly because this was an ecologically valid, real world experiment. It was a concert; the musicians were performing, people were there enjoying it and dancing. But what we could do is spread out these periods where the speakers were on the extra low frequency. We would turn them on for two and a half minutes, then we would turn them off for two and a half minutes - on for two and a half minutes, off for two and a half minutes.

James - So you saw what you describe as fairly unanimous results across the participants, and you mentioned that there was a 12% increase in movement. Is that, would you argue, pretty significant? Or will we need more of these types of studies to gauge what your numbers really mean?

Dan - That's hard for me to say. We were surprised and pleased at how robust the effect was, how reliable it was overall. But is there a facilitatory effect of the low frequency stimulation that we provided? Does that increase the social cohesion effects as well? Can we see that and how does that change? But yes, absolutely. We want to see the future research that builds from this and connects to this to better understand how this works in the real world.


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