Lyme Disease: Ticks, Trends, and Treatment

With Lyme disease on the rise we're exploring the science behind this complex condition...
06 July 2021
Presented by Chris Smith, Eva Higginbotham
Production by Eva Higginbotham.

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This week we’re exploring Lyme disease, looking at the science behind the ticks that carry it, the bacteria that cause it, how we treat it, and why the condition is on the rise in the UK. Plus, in the news, can we mix and match COVID vaccines? We’ve got the results of the latest trial. Also, a new family of beetles discovered fossilised in dinosaur poo, and a pacemaker that dissolves when you’re done with it...

In this episode

Covid vaccine vials

- COVID vaccines: mixing and matching

With rollouts occurring around the world, what are some of the benefits of mixing vaccine doses?

COVID vaccines: mixing and matching

Amid global vaccine rollouts, with nearly 1.2 billion doses currently administered, some countries have recommended a mixed-dose approach where a first prime shot is followed by a booster of a second type.

The measure has been introduced by France and Germany for people who received a first dose of the AstraZeneca vaccine but are in age groups for which that vaccine is no longer recommended in those countries due to rare instances of blood clotting (although the European Medicines Agency (EMA) says the benefits still outweigh the risks).

However, a more widespread policy of mixing different vaccines could also help to ease vaccine supply pressures and may even boost immune response. While the World Health Organisation has said there is currently ‘no adequate data’ on interchangeability, various trials are now assessing this approach.

Here are five things to know about mixing coronavirus vaccines.

Mix-and-match is nothing new - it started with HIV research

Mixing different vaccine types is known as a heterologous prime-boost vaccination. It started in the 1990s as a strategy tested by HIV researchers, according to Dr Pierre Meulien, executive director of the Innovative Medicines Initiative (IMI), an EU and European pharmaceutical industry partnership. ‘Scientifically, this is not anything new,’ he said.

HIV researchers knew that a classical vaccine would not induce the extremely complex immunological mechanisms needed for potential protection from HIV infection. ‘People were trying to understand how you could induce both T and B cell immunity,’ said Dr Meulien, referring to the critical cells in the adaptive immune system. ‘And this was the main driver for that work (mixing vaccines).’

HIV was also the driver for scientists to develop new vaccine platforms to deliver their payload. These platforms include DNA, mRNA, and viral vectors such as the adenovirus, the last two both used in approved Covid-19 vaccines. The raft of new platforms created over the last 30 years is what enabled coronavirus vaccines to be developed so quickly, says Dr Frédéric Martinon an immunologist at the French National Institute of Health and Medical Research (INSERM).

Rodolphe Thiébaut, a professor of public health at France’s University of Bordeaux, says the idea behind mixing vaccines is that ‘you are basically presenting the antigen (the recognisable part of the pathogen) to the immune system in a different way’ which helps the immune system get a better overview of the antigen and tailor its response.

A prime-boost regimen is the only vaccine to ever show efficacy - although not high enough - against HIV infection. In 2012, it was shown to reduce transmission by about 30% in phase 3 human trials. This has led to high expectations around the approach, says Prof. Thiébaut.

Mixing doses can help avoid immunity against a vaccine

Because some vaccines are delivered into the body using a modified virus, it is possible for the immune system to attack the vaccine itself. Mixing the platforms for the booster could reduce the risk of developing immunity against a viral vector vaccine.

When it comes to Covid-19 vaccines, Russia’s Sputnik V, Johnson & Johnson, CanSino Biologics and AstraZeneca’s products use a virus, an adenovirus - it usually causes a common cold - modified to express the coronavirus spike protein that the immune system activates against. It is ‘replication deficient’, so it can’t copy itself in the body once injected and give us a cold, explains Pia Dosenovic, an assistant professor in immunology at Karolinska Institutet in Sweden who researches vaccine development through the project VIVA.

But it’s possible for the immune system to develop a response against the adenovirus platform. This is not dangerous, says Prof. Dosenovic, but it could dampen the vaccine’s effect.

To get around this possible risk, Prof. Dosenovic says Sputnik V uses a different adenovirus in each shot, and AstraZeneca uses one from chimpanzees that our systems have never encountered.

Prof. Dosenovic says getting a third shot - which is possible if vaccines are updated to address variants - with a viral vector vaccine would not be optimal. From this perspective, it makes sense to change platforms to mRNA or one that is protein-based like Novavax.

Mixing vaccines can elicit a stronger/longer-lasting response than a single vaccine regimen

When it comes to viral vector-based vaccines, a mixed-dose approach may not only stop the immune system from inhibiting a vaccine, but also confer stronger and longer-lasting protection.

‘If you give a vector, vector, vector, or you give a vector, vector, protein, then I would expect that you get a stronger antibody response (to the encoded antigen) in the second approach,’ said Prof. Dosenovic. ‘But to know that you would have to do experiments.’

Again, this is because we want to train the immune system to attack the virus causing the disease rather than the one delivering the vaccine. ‘If you mix different types of vaccine, we can imagine that you will increase the (immune) response against the common antigen which is the antigen of interest and not against the vector itself,’ said Dr Martinon.

And there is precedent. The Ebola vaccine developed by Johnson & Johnson is an example of a mixed-dose approach being specifically chosen because the immune response could be long-lasting. The first shot uses the same adenovirus as the AstraZeneca coronavirus vaccine, and the second uses an MVA vector – a modified version of a poxvirus – a type that is also under investigation for future Covid-19 vaccines.

Prof. Thiébaut is coordinator of EBOVAC2, a programme assessing the safety and efficacy of this vaccine. He says they have had a ‘very good response’ with this strategy and predict that the new boost will enable protection to last longer than it would otherwise. ‘At least half of the cells that are producing the antibodies will probably stay at least five years,’ he said.

The safety and effect of mixing coronavirus vaccines must be assessed

While experts don’t consider the approach of mixing vaccines to be dangerous, they say that we don’t have enough data about coronavirus vaccine mixing and that safety should be evaluated as in any new vaccine strategy.

In particular, mixing mRNA vaccines with adenovirus-based vaccines and vice versa has not been done before, says Dr Meulien, as the first instance of mRNA vaccine technology being approved for human use was for Covid-19.

‘I think you really need to start from scratch,’ he said. ‘You have to do dosing regimens and all the usual things that you do in a precautionary way. You will have to do it with these new things because none of them have been tested together before.’

Various trials are underway to test coronavirus vaccine mixing. One anticipated study is that of the Oxford Vaccine Group’s Com-Cov trial - launched after the UK in January approved a mixed-dose approach - to study immune responses and any side effects of combinations of four vaccines: AstraZeneca, Pfizer/BioNTech, Moderna, and Novavax. ‘What I'm hoping is that we won't rule out any combinations,’ chief investigator Professor Matthew Snape told the BBC.

In terms of the research questions that need to be answered, Dr Meulien said: ‘I think the types of immune response that are induced, the longevity of response, and then of course, the safety profile would be the three things that I would say would be very important.’

Spain is planning human trials of the effects of following one dose of the AstraZeneca vaccine with a dose of the Pfizer/BioNTech vaccine. Countries that have already taken decisions to mix vaccines are operating by weighing up risks and benefits, according to Dr Meulien.

‘This is not brand new thinking,’ he said. ‘We have decades of experience in pre-clinical and clinical (work), especially in HIV, using these approaches. So it’s not as if we’re putting populations at risk doing this.’

Mix-and-match could help us fight variants

For Dr Meulien, the main incentive to mix vaccines is to potentially induce a broader immune response. ‘I mean broaden to cover the variants that are now popping up all over the place,’ he said.

But there needs to be a real scientific and regulatory justification to mix, he says.

Dr Martinon says vaccines will be improved for different variants such as those that emerged in the UK, Brazil, South Africa, and most recently in India, which is currently facing a surge in cases and a new coronavirus mutation that is potentially making Sars-CoV-2 more contagious and able to reinfect.

The next generation of vaccines will probably be directed against several coronavirus variants, he says, with different vaccines targeting different variants. Mixing these vaccines would give broad collective immunity and make it harder for variants to circulate or for new ones to emerge, according to Dr Martinon.

Periodic shots will be required, he says, although how much time between them is unknown, the hope is it will be years.

From a public health perspective, Prof. Thiébaut says mixing vaccines could help overcome this pandemic by speeding up the vaccination rollout. Obtaining good evaluations of vaccine combinations that show what works well is key.

‘It's good news in terms of flexibility of every government to be able to use what they can get as soon as possible,’ he said. This flexibility is crucial. ‘The best way to fight these variants is to vaccinate as quickly as possible the largest part of the population on Earth.’

Triamyxa coprolithica, QVARNSTRÖM ET AL.

07:37 - New beetles found in ancient dinosaur poo

Perfectly preserved, 230 million year old beetles have been found inside fossilized dinosaur poo

New beetles found in ancient dinosaur poo
Martin Qvarnström, Uppsala University

A family of previously unknown beetles have been uncovered in the unlikeliest of places: in samples of 230 million year old fossilised dinosaur poo! Scientists from Sweden and Taiwan were using high-energy X-ray beams to probe samples of fossil coprolites to produce high-resolution 3D images of what lay within. What they saw took them quite by surprise, as Sally Le Page heard from lead author Martin Qvanström...

Martin - Complete beetles - a few specimens that were almost complete. It was like you modelled them up in 3D at the screen, and they almost looked back at you from the screen. And this was truly amazing because we didn't expect to find such complete specimens. We could use the complete specimens and the small body parts to actually describe this beetle and describe a new taxonomy. It's a new genus species and even a new family of beetles.

Sally - Who did the poo? What is the animal that we're talking about that's eating all of these insects?

Martin - The problem with fossilised poo is that it's very hard to understand who produced it, right? Because you don't have so many clues at hand, but you have to use all the kinds of clues you have - the contents of them, the size, the morphology, so the shape of the coprolites. And also understand the body fossil records, so the bones from the same site. And the best candidate to produce this coprolite is a really close dinosaur relative, so a cousin to the dinosaurs called Silesaurus opolensis. It was a fairly small, medium sized animal - weighed approximately 15 kilos, 2 - 2.5 metres long, including the tail. It was a relatively small animal and it was lightly pecking insects off the ground, or rooting around in the litter with a little interesting beak that it had. So it was probably eating beetles and other insects in degraded wood or in like a moist environment.

Sally - And how old is the poo, how old are these insects?

Martin - So the poo is 230 million years old, so it's from the Triassic period.

Sally - That's an old poo!

Martin - I agree, I agree! And it's from a very interesting time because it's when we get the first dinosaurs. And when we think about the dinosaurs, we think about like these ecologically dominant animals, right? But for the first 30, 40 million years of evolution it was not like that. Actually in the beginning, they were just minor ecological components of the ecosystem. And the first time dinosaurs are already around in different areas of the world, but they haven't taken over, so to speak, yet. So it's a little bit interesting because diets play a role here in trying to understand what happened, why dinosaurs became so successful. We don't know that yet, so this is a little piece to that puzzle.

Sally - So this is before the T-Rex, the triceratops?

Martin - Way, way before. So if we think about T-Rex, for example, it's like 66, 70 million years ago. So the time gap, the time difference between us and T-Rex is much, much smaller than between T-Rex and the Silesaurus opolensis and the age of the fossilised poo here, it's incredible.

Sally - How did the beetles get inside the poo?

Martin - There are two possibilities here - either they entered the poo when it was already laying on the ground, or they were ingested. And why we think they were ingested is that we have so many of them in the coprolites, and there are various stages of disarticulation. So most are just bits and pieces of, you know, chewed up beetles. And then we have the few exceptions, so it's just really two specimens that are near complete.

Sally - Why can't you just look at insect fossils. Why are you looking inside the poo to find the insects?

Martin - If think about like the most beautifully preserved insect fossils, they're from Amber, and Amber is all nice and good. So it's fossilised tree resin.

Sally - Like that mosquito in Jurassic park.

Martin - Exactly, yeah. So you can look at hundreds of specimens and just under the microscope and see where the nice insects are. The problem with Amber is that it was mainly formed during relatively young geological time. So when it comes to early beetle evolution and early insect evolution, we don't have any insect fossils from Amber to rely on. So this really fills that gap. It's like, Hey, okay, we don't have an Amber, but we can look in, in coprolites, so in fossilised poo, and we find almost the same preservation.

Sally - Are you just going to go around scanning all of the coprolites, all of the poos in museums now?

Martin - That's pretty much what my last 5 years have been all about! With scanning maybe 100 specimens. And we're trying to analyse a lot of coprolites from the same locality, and then try to reconstruct food webs

Sally - I have to ask, does fossil poo smell like poo?

Martin - No, fortunately not. I work with them every day, so that would be really hard for me!

Crystals of sugar

13:35 - Sweeteners influencing gut bacteria behaviour

Sweeteners could be negatively changing the behaviour of your friendly gut bacteria

Sweeteners influencing gut bacteria behaviour
Havi Chichger, Anglia Ruskin University

If you're someone who prefers diet fizzy drinks over their full sugar versions, you'll be used to the taste of artificial sweeteners like aspartame. These compounds provide the same sweet taste with none of the calories or sugar, which can be especially useful if you have diabetes. But might these sweeteners have OTHER impacts on our health? A new study just out suggests they can change the behaviour of bacteria that live in our intestines, turning them from helpful Dr Jekylls into aggressive Mr Hydes. Anglia Ruskin University’s Havi Chichger spoke with Eva Higginbotham...

Havi - So we found with our study that if we take two bacteria, that are most commonly seen in our guts, that are happy, healthy bacteria, they help us metabolise what we eat and break down some of the foods, when we add artificial sweeteners to them, such as saccharin or sucralose, we see the behaviour of these bacteria change and they become more likely to cause damage to us, so more likely to stick to our own gut cells, more likely to invade our gut cells and in some cases more likely to kill our gut cells.

Eva - And what do you think is in the sweetener that's causing the bacteria to change its behaviour all of a sudden?

Havi - Well, we think it's definitely something to do with that ability to sense sweetness or sweet taste. And when we sort of inhibit that ability to taste sweetness, the bacteria don't respond. So there's definitely something in that. And we don't know exactly what it is, we're looking at the mechanism. There's lots of different possibilities because bacteria have lots of different ways they can rapidly change their genetic makeup to respond in different ways.

Eva - So does that mean the bacteria think that the aspartame tastes sweet in the same way that we think the aspartame tastes sweet?

Havi - We think so, and that's what the data indicates. We can't prove what that sweet taste receptor is, there's no documented ability for bacterias taste sweet before our study. So we think they have some kind of sensor and that would make sense because bacteria need to respond to their environment, just like we need to respond to our environment.

Eva - And do we know if it's the sweetener directly changing the behaviour of these bacteria? Or is it that it's having some impact on the local gut cells that would then change the behaviour of the bugs?

Havi - Well, we've shown previously that taking bacteria out of the equation, sweeteners can cause damage to our gut cells. But what we're seeing when we add bacteria to the equation is that we almost have an exacerbation of that. And that more closely mimics what we see in our gut, where we have gut microbiota and our own gut cells usually working in symbiosis.

Eva - And do we know if it would happen with sugar itself or is it something special about the sweetener?

Havi - That's a really good point. So there's lots of work done on things like a low in fat or a low in animal protein diet or a low sugar diet causing a good diversity of gut bacteria. And that's what we want, we want good diversity. The more diverse our microbiome is, usually the more happy and healthy we are. So we do know that sugar decreases the diversity of the gut bacteria, and there have been studies with artificial sweeteners showing the same thing. What we're showing that's a little bit different to that is that it actually takes that good microbiome and turns some of the bacteria into something quite pathogenic, not able to respond to antibiotics, not able to function as we'd want it to.

Eva - Do we know if this would work the same in an actual human body though, as in a dish like you've shown?

Havi - It's a really good point. So we used a human cell model, but actually we took 2 bacteria out of the many millions that we find in our guts. So in fact, it could well be that it's a worse scenario than we're seeing in our dish. It could be that actually there's compensation and over time it's not having such a dramatic effect. And so we really need to look at the whole system to be sure of that.

Eva - And what do you think this means then for people who like their fizzy drinks with their aspartame on the side?

Havi - It's a really boring answer, but I think actually if we think about sweeteners as a compensation for sugar, and we know sugar can be very damaging for our health, the ideal is water I'm afraid. And that's what we looked at, we looked at water versus sweeteners as what you'd expect to see. I think it's just being aware that sweeteners aren't without some effect on us, and we're really starting to understand what those effects are.

Eva - And what if you were someone who, you know, you might have a bit of a diet Coke addiction for a few weeks, but then you go back to the water. Is this change permanent? Or is it something that would come and go as your intake of sweetness goes up and down?

Havi - Well, fortunately there are a lot of studies which show that our gut microbiota can revert back to a sort of healthy environment. So over time, taking sweeteners, taking some of the higher fat out of our diets can help our gut microbiome return to normal. And hopefully that shift can be temporary, but still, as I say, just understanding what that is, how long that takes.

Eva - And is there any way, just speaking for myself here, that we can kind of balance it out. If you have enough salad at lunchtime, does that mean you can have a few diet cokes in the evening?

Havi - Wouldn't that be nice if we could! I think we're better off maybe reducing our overall intake throughout the day, rather than top heavy sweetener loading. I think it's especially worth noting, it's not just drinks. Sweeteners can be found in lots of different parts of our diets, sometimes without us even realising it's there.

 

Logo of a human heart

19:18 - A wireless pacemaker that dissolves

A new temporary pacemaker developed that uses wireless smartphone charging tech...

A wireless pacemaker that dissolves
John Rogers, Northwestern University

A new, dissolving, implantable pacemaker has been developed by scientists in the US. The idea is that, like dissolving stitches, in situations where a permanent pacemaker is not needed, with this device, once its job is done after a couple of months, it disappears without the need for an operation to remove it. It actually works in the same way as traditional pacemakers, which send electrical impulses along fine wires into the heart to control heart rhythm. Power is beamed into the new device from outside, so no batteries are needed. Charlotte Birkmanis had her finger on the pulse and called up the device’s creator, John Rogers, to hear how it works...

John - Well the function is equivalent - the kind of stimulation is functionally identical. The key differences are that it's wireless and it's resorbable. We were able to demonstrate that on actual human hearts, not in human patients, but hearts from organ donors. So we were able to demonstrate that the devices work well in small and large animal model studies; and most importantly that it's applicable to the human cardiac system, which is ultimately the goal in this type of context.

Charlotte - How does it work?

John - The device itself includes several subsystems. One is designed to harvest power wirelessly. Another is designed to take that radio frequency power and smooth it out; that component involves a radio frequency silicon-based diode and a smoothing capacitor. And the third kind of element of the device is set of interconnected traces that terminate in leads that interface to the surface of the heart. Those three components are all integrated into a thin, flexible, lightweight device that gently adheres to the surface of the beating heart.

Charlotte - It doesn't need to be removed - how does it get eliminated from the body?

John - The electronics, the stimulator leads, wireless control interface, and so on are all water-soluble. They react with surrounding biofluids and just dissolve over time, and disappear completely at a molecular level, to biocompatible end products that are just naturally excreted from the body via usual processes of kidney filtration, urination, for example.

Charlotte - What are they actually made from?

John - We use primarily polymer based materials, either biomaterials like silk fibroin... that's a protein that can be extracted from silkworm cocoons as a substrate for building our electronics. Of course, you also need conducting materials; there we choose metals that are naturally occurring in the body, such as iron, magnesium, these types of materials. They're also water-soluble and biocompatible. And then the third class of materials: silicon itself is water soluble. If you use silicon in very, very thin film forms, then it will dissolve completely. When you put those different materials together then you can begin to build wide ranging classes of water-soluble electronics.

Charlotte - Because you don't remove it, how do you control the amount of time that it functions for?

John - Yeah, so the way that we control the operating life is we use a capping layer, a thin layer of a polymer that protects the underlying electronic materials from interaction with surrounding biofluids. And then once that capping layer has dissolved and disappeared, the electronic materials start to dissolve and the performance drifts. So we assume that the device is no longer operating in a stable fashion from that point on.

Charlotte - And what else could you make out of these materials?

John - We have wireless nerve stimulators that can accelerate rates of neuro-regeneration in damaged peripheral nerves. The other thing that you can do is you can build wirelessly programmable drug release vehicles; so these are platforms that contain an array of reservoirs, each one of which is filled with a drug, and we can wirelessly trigger the opening of valves to allow programmed release of those drugs at specific time intervals. Once all of the drugs have been released the platform itself can just naturally resorb and disappear in the body.

Charlotte - Is it ready to be used in human surgery?

John - Not quite yet. Ultimately we hope to use this device with humans, but it's a process and it's a very rigorous process, so the timescale for that is typically a year or two to get the first human tests completed. And we're just starting down that path now.

A blue cgi bacteria

26:01 - Lyme disease bacteria: strains and symptoms

What causes Lyme disease, and how can we identify the strains and symptoms?

Lyme disease bacteria: strains and symptoms
Justin Radolf, University of Connecticut Health Center

Lyme disease is a bacterial infection that causes a range of symptoms, from skin rashes and fevers, to fatigue, joint pains and even neurological problems. And it’s that range of fleeting symptoms, developing over a period of time, that means that Lyme disease can often be overlooked - at least initially.  The condition is also becoming more common, and we’ll hear why later in the programme - but first, we need to find out more about the microbe that causes Lyme disease. Chris Smith spoke to Justin Radolf, a microbiologist from the University of Connecticut…

Justin - Lyme disease is caused by a bacterium in the genus Borrelia. Borrelia are spirochetes - they're elongated, helical, spiral shaped organisms, which is how they get their name. There are approximately 20 species of Lyme disease spirochetes, but only a small number are clearly associated with disease. We don't know what makes some of them more infectious than others, but we know that it ultimately goes back to the genes that they contain. Some species also appear to be able to cause certain forms of disease more often than others. And again, we don't know exactly why that is, but it has to do with the genes.

Chris - And are those different subtypes - are they distributed in different geographies? So if I look in certain countries I will find one particular variant of the Borrelia bacteria that cause Lyme, and if I look in a different geography I might find a different one, and therefore I might see different manifestations of the disease in those places?

Justin - Yes, that actually is correct. So for example in North America there's predominantly one species called Borrelia burgdorferi that far and away causes all the cases. When one looks in Europe, there are several major species that cause different manifestations and they are not distributed equally. One finds some in other countries and some in others, and it's heterogeneous.

Chris - And where in the environment do those organisms hangout?

Justin - They live in wooded areas mostly, though grasslands as well. They live in ticks and in small mammals, often rodents, and they go back and forth between them. That's how they maintain themselves. Humans get infected when they intrude on those cycles. It can happen recreationally. It can happen in terms of where people live; in the northeast United States, for example, a lot of people have their nice houses out in the woods where the cycle is occurring. But we now know it even occurs in urban areas as well.

Chris - So you've got a lifecycle where mice get infected, ticks feed on the mice and they get infected, ticks go on a new mouse and infect that new mouse, and it goes round and round in a circle. So do mice get Lyme disease, then, or are they resistant to it?

Justin - Mice are reservoir hosts, and as a good reservoir host they get infected but they don't get sick. They don't mount an inflammatory response and they don't seem to be able to eliminate the bacterium. So they're persistently infected.

Chris - And how do the bacteria survive in multiple hosts? Because they're going into these mice, and that's arguably a very different environment to then being in the tick, which is a completely different type of animal, and then potentially passing into us as well. So the bacteria have to exist in a whole range of different environments and both make an animal infectious, but also susceptible to being infected, and it's quite complicated. How do they do it?

Justin - Well, actually that is what many of us are studying, because there are regulators of the genes in the bacterium that are turned on and turned off depending on where the bacterium happens to be. If they're in a tick, they actually sense the blood coming in and then they know that it's time for them to move on. And then when they get into the mammal, they actually go through an adaptive process that enables them to survive in the mammal. So it's really quite ingenious what they have evolved to be able to do.

Chris - And when a tick bites a person, just talk us through how the infection is transmitted and then how the infection unfolds in that person.

Justin - Usually it's the nymphal tick that is the stage that feeds on a human. And so that nymph has to have been infected and will have acquired the spirochete in its earlier stage as a larva. So when the nymph eats and the blood starts to come in, the spirochetes sense that; they start to replicate, they start to divide very rapidly, and then they start to actually penetrate the intestine of the tick where they live; and then they go from there into the salivary glands, and they actually penetrate those, and then they are actually able to get into the saliva; and then they hitch a ride into the feeding site, which would be a human, or a mouse - it depends.

Chris - And what happens to the victim - the person who's being bitten?

Justin - Well, initially not much, because what has to happen is the spirochete itself has to establish itself. We know that there are defences that actually try to eliminate the spirochete. The environment in the feeding site also is thought to suppress the immune response in ways that the bacterium can take advantage of. But over the next several days, once they're deposited, that's when they get their foothold, they start to adjust to the new environment. They're also warding off various defences that the host has naturally. And then they start to move on, they start to move laterally. That eventually gives rise to that skin rash called erythema migrans, the bullseye rash. But they also go deep and they start to penetrate blood vessels. That's when they gain access to the bloodstream, and they can disseminate throughout the blood and invade different organ systems: heart, central nervous system, joints, et cetera.

Chris - And produce that range of symptoms, presumably, that Stella was talking about - in a range of different organ systems and at a range of different times.

Justin - Yes. In fact there are components in the bacterium that are actually pretty well known, that the host recognises as foreign. The host then mounts an inflammatory response. That inflammatory response in the tissues can cause symptoms. For example, in certain parts of the heart it can interfere with the conduction system and cause various kinds of heart block; but it also causes systemic symptoms that make people feel muscle aches, tired, headachy, things like that.

Chris - And why is the immune system not able to eliminate the bacteria from the body?

Justin - That's a great question. And we do not fully know the answer. We know that the bacteria actually has its own defences against the host immune system. It has ways of preventing antibodies that the host makes from eliminating it. Part of it may also be because they're very modal. They are much faster moving through tissues in the white blood cells that get into the tissues in response to the presence of the bacterium. And exactly how they can persist in various sites for such long periods of time and not be eliminated is still a very open question.

Deer tick

32:42 - Ticks: Lyme disease and life cycles

From their complex life cycle to their specialised mouth parts, and how to protect yourself from a bite

Ticks: Lyme disease and life cycles
Thomas Mather, The University of Rhode Island

Lyme Disease is transmitted to humans when we’re bitten by ticks. These are small, blood-sucking parasites that are members of the spider family found across the world. Eva Higginbotham has been learning a bit more about them and how they transmit Lyme disease...

Thomas - Most people think of them as rather disgusting and nefarious, sneaky, crafty... and most importantly they can transmit germs that cause disease.

Eva - That's Tom Mather, a self-described tick collector from the University of Rhode Island, describing the critters he has devoted his life to studying: ticks. Ranging from around 1-5 millimetres in size, depending on life stage and species, ticks are parasitic arachnids that feed on the blood of various host animals.

Thomas - Ticks come in four life stages, three that are active and one is the egg stage. Eggs hatch into little, tiny, six-legged larvae. The next stage after a larva is the nymph: so the larvae grab a host, just like all ticks do; they take a blood meal, and they use the blood meal to grow generally about 10 times their size. Which sounds like a lot, but when you start pretty microscopic then 10 times bigger isn't that much bigger. Nymphs do the same thing: they grab a host that increases their weight about a hundred fold, and those nymphs then transform into the adult stage, either a male or a female.

Eva - Although all ticks feed on blood, they have different preferences for which hosts they want to feed on. Some are very picky, and as a result, pose less Lyme disease risk to humans. But some are generalists, like the American blacklegged tick or the UK castor bean or sheep tick. But how do they get onto their hosts in order to feed?

Thomas - Ticks don't jump. They don't have wings, so they can't fly. What they do is wait, low in the leaf litter and the leaf duff where it's a little bit more humid. The adult stage tick will climb up vegetation just a little bit. They want to optimise where they're going to be in case the right host comes by.

Eva - And if a tick makes it onto your skin...

Thomas - Ticks have a fairly sophisticated cutting mechanism. They have a multi-piece mouth part, a little like a Swiss army knife I suppose. First it can cut a hole in your skin, and then it cuts that hole a little bit bigger and bigger, and then it inserts another part of its mouthpart into this hole that has backward pointing barbs. Once a tick finds a host, it doesn't really want to lose it, so it's specialised to hold on. And that's why people notice that it's hard to pull them out sometimes.

Eva - The tick inserts it's mini-saw mouth part deeper and deeper into the skin until it's fully embedded.

Thomas - Some of the earliest things that it does with its saliva - that it secretes into the host - is secrete a cement substance to form this glue-like matrix that helps hold the tick in place with the tissues. It starts secreting more saliva that has this magical property of suppressing the immune system of the host, keeping blood clotting from happening. So it creates a pool of blood that its mouthpart - basically a straw - is sticking into.

Eva - The thing is it's not the blood drinking that's the Lyme disease risk - it's the saliva that's the key. If the tick is infected, the Lyme bacteria is essentially spat out in the saliva of the tick if it's attached long enough. But how does the tick end up picking up the Lyme bacteria in the first place?

Thomas - We know that the larval stage ticks hatch out of eggs don't carry the germs. So they have to pick it up someplace. And so they pick it up from a reservoir host - an animal that's not only infected, but infective as well.

Eva - To be infective, the animal has to be able to pass along the bacteria. Other animals, like the white footed mice in the USA, seem to have evolved to tolerate the bacteria. They don't get sick, but they also don't seem to eradicate the bacteria from their bodies. This is why they are a reservoir. Any tick that then bites that mouse is likely to pick up the Lyme bacteria from them.

Thomas - About one in four nymphal stage ticks in the United States is infected with the Lyme disease germ. That's exceptionally high. When we think about mosquito-borne viruses, for instance, we're talking about rates of infection of one in 1-5 million mosquitoes carrying a virus. So we're talking about a vector here that has a tremendously high infection rate. As incredible as that is, the adult infection rate is almost 50% or even more. You would say, "oh, well then the adult stage ticks are riskier," but they're not - because they're a little bit larger, more easily seen and more easily found and removed before they've been attached long enough to transmit an infectious dose. And so most cases of disease occur just after and during the season of the year, which is May, June, July when the nymphal ticks are active.

Eva - Importantly, though, that 50% infection rate is the average across the States and will vary greatly depending on precise location and the types of animals that live nearby. And the rate is much lower in the UK. But if you've been out and about and realise you've been bitten by a tick, how do you get it out?

Tom - In order to remove a tick safely, there are all kinds of strategies. We want to dispel right away some of the folklore that people have of touching it with a hot object. My favourite and most reliable strategy is to have a pointy tweezer and you don't want to grab the back end of a tick. Think of it as a sack of germs attached to your skin with a straw. So you want to grab it as close to the skin as possible and just pull it out. It may be a little bit challenging because of those backward pointing barbs we talked about, but it will come out. Sometimes the mouth part breaks off depending on your grip and everything. And that's okay because the germs are in the back part of the tick, and as long as you haven't squeezed the back part, you should be fine.

Eva - And of course the best way to prevent catching Lyme disease is to not get bitten in the first place. Tom advises sticking to the middle of hiking trails where you can, tucking your shirt into your trousers and your trousers into your socks, and if you're regularly outside in a higher Lyme area, you could invest in a can of permethrin; an effective tick repellent, which you can use to treat your clothes. That is unless you're Tom.

Tom - Back in my younger days, I actually wanted to teach people the proper way to remove ticks. So I would grow pathogen-free ticks in the laboratory. And before I would go do an outreach activity, I would let one or two attach to myself in an easy spot so I could show people the best way, the safest way to remove ticks from themselves as well.

Eva - I think I'll leave that to the experts.

Close up of a doctor's coat, with a stethoscope and a pocket full of pens

40:31 - Lyme disease diagnosis and treatment

What are the tell-tale signs of Lyme disease, and what can happen if it's not treated?

Lyme disease diagnosis and treatment
John Aucott, Johns Hopkins Lyme Disease Research Center

So if you’re unlucky enough to have been bitten by a tick infected with Lyme Disease, what should you look out for, and how should you be treated? Moreover, what can happen if you miss the initial diagnosis? John Aucot specialises in Lyme Disease at Johns Hopkins School of Medicine...

John - Acute Lyme disease starts at the site of a tick bite. When that bacteria is inoculated into the skin, acute Lyme disease usually begins a week or two later. And that local infection typically causes redness around the side of the tick bite and that redness expands over time as the bacteria multiply with the infection. And then over a period of a week or two causes a round, red skin lesion. And that's where the infection starts, and then if it's not treated initially, that infection has the potential, really in more than half the cases, to enter the bloodstream and spread to other areas of the body and where it spreads to is typically other areas of the skin. So you can get multiple skin lesions from spread. It can spread to the heart and cause inflammation of the heart and especially the electrical system of the heart. And it can spread to the nervous system, the lining around the brain called the meninges and cause meningitis. It's especially prone to go to the cranial nerves, especially this one nerve that causes facial palsy, causes one side of the face to droop, and it can go to the peripheral nerves and to the joints. And so those diverse symptoms in that early what we call 'disseminated' phase as the bacteria spreads to other parts of the body, can cause a diversity of symptoms and make it actually somewhat difficult to diagnose if you don't recognise that initial round, red skin lesion at the side of the tick bite.

Eva - And what is the treatment, if you notice that you've got a rash, what treatment would a doctor give you?

John - So that's the good news is the treatment's pretty straightforward. Treatment of early Lyme disease is with a pill antibiotic. It's typically doxycycline. It's very effective at treating the Borrelia bacteria that causes Lyme disease, especially when administered in that first couple of weeks. And then you take the oral pill antibiotic for several weeks. And that's generally curative.

Eva - So essentially if you take the antibiotic quickly enough, then you're probably not going to have any lasting effects from having had Lyme disease.

John - Odds are that early treatment prevents later manifestations. It's very, very good at preventing later neurologic or joint disease. There is however, an important subset of people that even with early antibiotics still have lingering symptoms, especially symptoms like fatigue and achiness and memory issues. We have a cohort study where we start following people at the very first moment of infection when they have the rash. And we treat the people obviously with a standard of care doxycycline and then follow them over time. And then when you do that prospectively over time, you see it in our states, about 15% of the people clinically still have fatigue and other symptoms, six months after their treatment.

Eva - How do you know if that's you still have Lyme disease or if that's your body being affected by the fact of having had Lyme disease, because there are some things like post viral fatigue, for example, that can last for a long time.

John - That's the holy grail in the research field in Lyme disease; what causes these persistent symptoms? With the onset of COVID actually, we've seen an example of a virus. Now, Lyme disease is a bacteria, but we see in COVID that viruses can cause long lasting symptoms even after the virus is apparently out of the system. So the tough question that remains unresolved is "What is the mechanism of these persistent symptoms after antibiotic treatment of Lyme disease?" And there's a range of hypotheses. There may be lingering bacteria hidden away in the tissues. There may be bacterial products, proteins, or nucleic acid fragments in the tissues that trigger ongoing inflammation, or the bacteria and its products may be gone and the immune system has taken on its own auto-immune activity where the immune system, instead of being our friend, becomes our enemy in a way. And what we've been able to show from our studies is that, using the blood from these patients that go on to develop a persistent illnesses, there are changes in their immune system, in their metabolism. And so those immune markers are potential future tests. For instance, we have one immune marker that's a chemokine. It's a protein that attracts immune cells into tissues, and that chemokine CCL 19 remains elevated after treatment in the people that are destined to go on to have persistent symptoms.

Eva - And what can we do to help people who are suffering from persistent symptoms.

John - So I think this is where we've fallen short is helping our patients with persistent symptoms in Lyme disease. The first reason is it still remains a contested illness. There's many contested illnesses and they're predominantly ones characterised by lots of patients' symptoms and a paucity of objective biologic markers on blood tests or imaging. And so the first way I think we can help the patients is recognising that these are real illnesses, that it's not the patient's fault there's illnesses isn't all in their head. It's not just because they're depressed or anxious. And then the second step is, even without specific proof of the mechanism, offering the patient hope and care. Treat their symptoms. We can help them cope with their symptoms. We can help encourage them to have healthy behaviours. And in the same time also try to treat the illness as best we can with the knowledge that we have at this point. And then finally, I think to give patients hope that we're working on this, that we're trying to do research to understand the mechanisms because understanding the mechanism of the illness is obviously the key to designing future therapies.

Deer tick

Lyme disease in the UK: is it on the rise?
Richard Birtles, University of Salford

Historically, especially in the UK, Lyme disease has been regarded as rare, which is why many may overlook or write-off the initial symptoms. But the condition does appear to be on the rise, or at least it’s being diagnosed more frequently. Richard Birtles, from the University of Salford, has been looking at the possible reasons why…

Richard - It's not a straightforward answer because if you go into a wood, the number of ticks that are present in that wood, what determines that? Then you have to think about, well, what proportion of those ticks are infected and what determines that. For Lyme disease, we have a very complex ecology. So trying to implicate any specific factors as the main cause of increasing tick numbers, increasing cases of Lyme disease is very difficult.

Chris - So you think that the rise has been detected because I was looking at some of the reviews and they suggest really quite dramatic increases in case numbers. Up maybe 300% in a 10 year period, according to some papers that have been published. Do you think that's a real finding, it's not that people like me and you were talking about it, so then other doctors think about it or people think about it, and they take themselves off and get tested.

Richard -
No, I think what you're saying is playing a part as well. We've certainly seen, as you suggest, the number of reported cases rising in England and Wales and in Scotland by five, six fold over the past 20 years or so. And I certainly think awareness in the medical circles, awareness from the public as well, but there is some evidence that tick numbers are on the rise. And certainly the places in the UK where you find ticks is increasing,

Chris - But where are the hot spots? Then you mentioned a couple of places, but where are we tending to see the most Lyme activity?

Richard - When we think historically about Lyme disease, we think about particular places that tend to be wild places, particularly areas that are heavily wooded or heavily grassed, rough pasture, or heathland. So those are the places that historically most cases have been reported. But what we're learning more about now is that we are seeing Lyme disease spread around the country more, and we're seeing urban cases of Lyme disease. So we think that there's a risk of being bitten by ticks in parks, for example, parks in the middle of London are known to support quite high tick numbers and similarly parts of central England where we're seeing a change of land use. So we're seeing a reversion to more woodland, aforestation, replanting of trees, less intensive farming seems to be bringing Lyme disease into those parts of the UK as well. Perhaps the most important driver of this is that these kinds of habitats are fantastic for deer. And we know that deer are fantastic vehicles for ticks. I, for example, have spent a very pleasurable afternoon checking for ticks on a headless legless roe deer in Kildow. And when we got to about 15,000, we gave up and went to the pub. So they carry huge numbers of ticks. And we know that in the UK, the deer population has exploded really. We've got more deer in the UK now than we have in the past thousand years or so. And the numbers are thought to have doubled really in the past 20 or 25 years. So you've got these articulated trucks, the supertankers carrying ticks around the UK. It's not surprising that the distribution of ticks in the UK is increasing and therefore where we're acquiring Lyme disease is changing.

Chris - How does this fit into the life cycle that we were hearing about that Justin was talking about, and also Tom was talking about earlier in the program, when you've got small ticks and big ticks, small animals and big animals, the big animals, presumably are the deer. How does the relationship work?

Richard - Well, it's very complicated because deer are not reservoirs for Borrelia, which is amazing. They carry these huge numbers of texts, but they cannot transmit infection to the ticks. The infection is reservoirs in, as Justin said, I think, in small mammals, so voles and mice and shrews, and also in birds in foraging birds, and also game birds, pheasants, but also thrushes and blackbirds and things like that. So we've got this tension really between a higher abundance of deer, meaning an awful lot of ticks, but maybe not so many of those ticks infected because they're all feeding on deer, which can't transmit the infection to the ticks. So there's a very complex arrangement in that cycle that we need to explore more and understand more. If we are going to somehow be able to manipulate it, to reduce the risk of us acquiring Lyme disease.

Chris - I know what you mean about deer because I took until I was about in my forties before I even saw one properly in the wild. And now if I don't see one, when I'm driving around in the country lanes every day when I'm out and about something weird is happening. I mean, there must be enormous numbers of them. Does that mean then that we, if we've got a plague of deer, we really need to be eating more venison. And I mean the nicest possible way.

Richard - Well, yes, there's a lot of talk. We're concerned about deer from the perspective of Lyme disease, but also we're worried about things like road traffic accidents and crop destruction and destruction of commercial woodland that we know deer are party to. So there's a big discussion going on now about how we weather for the sake of Lyme disease. We look at trying to control and reduce deer numbers, but also for all of these other possible implications.

Chris - Just one final point, which is that in Australia, they've had a plague of mice or parts of the Eastern seaboard of the country. And this is attributed to various factors, including ideal warm conditions, rainfall, surging vegetation. What about climate change? We haven't discussed that yet. Do we foresee that that could also drive a widening of the range of the very small mammals that we heard about from Justin and Tom who can support the Lyme bacteria and therefore widen its geography across countries like the UK?

Richard - Well, I think in truth, the distribution of the small mammals that are important is fairly ubiquitous in the UK already and is driven really by habitat and land use. And we know that the tick that transmits Lyme disease in the UK, in Europe, you can find it right up to the Arctic Circle. So it's unlikely that new parts of the UK are going to be infiltrated by ticks simply as a result of climate change, but there are models, climate change models, looking at the impact of various scenarios of climate change on tick abundance in the UK and Lyme disease risk in UK. And these tend to suggest that first of all, ticks will be active for longer in the year. So there'll be more active in February, for example, and they'll continue to be active well into November and December. So that's a longer period of the year where we can get bitten. And also that the climate change will provoke higher densities of ticks. Ticks really need humidity. So more rainfall is likely to be good for them. So that's what the model suggests. Of course they need to be validated and we need to check for the degree of uncertainty in those, but that's what the models are suggesting.

An image showing the arteries and veins in the lungs.

55:44 - QotW: Do bagpipes help you recover after COVID?

Could playing the bagpipes help your lungs recover after you've had COVID?

QotW: Do bagpipes help you recover after COVID?

Adam Murphy spoke to John Dickinson from the University of Kent and Michael Steiner from the University of Leicester to find out the answer...

Paul - If one is recovering or has recovered from COVID, would playing bagpipes help to expand the lungs and be beneficial or detrimental?

Adam - Bagpipes are something of a love it or hate it instrument. I love them. Although I do prefer a set of Irish Uilleann Pipes more...but you don’t use your lungs with them so we’ll move on. Can the bagpipes help you if COVID’s taken away your puff? John Dickinson is head of the exercise respiratory clinic at the University of Kent, and he says it probably won’t hurt.

John - We know it’s impossible to actually increase the size of your lungs playing wind instruments – even elite athletes don’t get larger lungs from participating in elite sport! However, playing wind instruments can be beneficial for controlling breathing pattern. Many people post COVID are reporting symptoms of breathlessness on exertion and a lot of this may be due to development of a dysfunctional breathing pattern during the time they had and were recovering from COVID. Playing wind instruments encourages an efficient breathing pattern. This may help an individual post COVID adopt a better breathing pattern and reduce symptoms of breathlessness.

Adam - So potentially very helpful, so why aren’t there sets of bagpipes filling every hospital in the world! Well here’s Michael Steiner, Consultant Respiratory Physician at the University of Leicester, who agrees that it probably wouldn’t hurt, and might even help, but...

Michael- This is speculation of course because there haven’t been any trials of bagpipe playing following COVID-19 infection and indeed little evidence on the benefits of playing wind instruments in lung diseases more broadly. There are some trials suggesting that singing might be a useful therapy in reducing breathing problems and improving quality of life for lung disease sufferers.

Adam - and Michael also points out with the bagpipes, there’s one other potential risk to be considered!

Michael - I don’t think playing a musical instrument like the Bagpipes is likely to be harmful although there was a report a few years ago of a patient who became seriously ill with lung inflammation which was linked to regular playing of bagpipes and was termed “Bagpipe Lung”. However, this was thought to be due to a fungus living in the pipes rather than the act of playing itself. On a broader note, listening to and playing music can have a positive effect on mental and physical health and well being for all of us including during recovery from illness. If playing the bagpipes provides pleasure and enjoyment, I would go for it - but make sure you keep your pipes clean!

Adam - But as Colin2B points out on the forum, it might be kinder to your neighbours to do the recommended breathing exercises your doctor gives you than pick up the bagpipes for the first time! Thanks for the question Paul, and that to John and Michael for the answer! Next week, we’ve a mountain to climb, answering Wayne’s question

Wayne - We’ve always learned heat rises, but it’s normally cooler in the mountains. Shouldn’t their higher elevation make it warmer there?

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