Uncovering the secret strategies of a parasitic worm | 91TV
Transcript
- So thank you very much for that, and it really is a true pleasure to be here to talk about worms.
- So, we start this off. It's a real honour to be able to talk in recognition of Antonie van
- Leeuwenhoek. Actually, his birthday would have been yesterday, on the 24th of October in 1632,
- and he was very much the father of microbiology. He was the discoverer of the microscope, and
- here we can see this very early microscope, him working away, held up to the light, and looking at
- this microscope, he managed to uncover this whole world of little animalcules, that he called them,
- and here we can see all the little pictures here that he would draw so beautifully. In 1677,
- for example, we can see that when he reported his discovery of the protozoa,
- 'Creatures so small in my sight that I judged that even 100 of these very wee animals lay
- stretched out one against the other they could not reach the length of a grain of coarse sand.'
- So I'm going to talk about today some of these wee creatures and some of the not so weak creatures,
- but my focus is very much on the neglected tropical diseases and being neglected tropical
- diseases it goes with the name. These are the diseases of poverty, the diseases that hit the
- bottom billion, perpetuating them in the poverty cycle. We can see there's actually a whole range
- of different infectious agents within the NTDs. There's actually even more on this list now with
- Noma coming in. Some are a little bit more well known, such as rabies, and indeed there was a
- past Leeuwenhoek lecture on rabies. Others, such as protozoans that Leeuwenhoek mentioned. One of
- the biggest groups we see is the Helminth NTDs, the worms, and this is what I'm going to focus on
- today. We can see that some of these worms are not so we. So here we can see this beautiful tapeworm,
- this 18 metres out of a 67-year-old Thai man who had a little bit of indigestion. You gave
- him the anti-wormer and this beauty came out. I thought I'd bring some samples to share. So
- here, if anybody wants to pass that around. This is just one tapeworm. So, anybody. We'll have
- tagliatelle later. So this is one tapeworm, the beef tapeworm, and indeed it's actually
- not that bad for you. If you or I got it we might feel a little bit of a windy tummy. We
- might get some of this little exodus of some of these segments at inopportune moments. Indeed,
- the Victorian ladies actually really liked this, and you'd see these adverts. 'Eat,
- eat, eat. Always stay thin. Fat, the enemy that is shortening your life, will be banished by taking
- these sanitised tapeworms.' Now, they don't really work. As I said, they give you a little bit of
- a bad tummy. If you're a child who's obviously malnourished and you've got this in there, they'll
- be competing with this for the key nourishment. Some of the other not so wee worms is Ascaris, and
- these are actually worldwide, again lumbricoides, and again you can see these can be actually a
- little bit more serious. These can be linked with mortality and morbidity. Many of the NTDs,
- why they're neglected in contrast to the big three - the HIV, TB and malaria - is that they tend to
- take a while to kill you and make you sick. These Ascaris, you can see where this little girl,
- you give her the de-wormer and these all come out. It gets really quite exciting when you give these
- deworming because they're supposed to come out with the stool and we give them little pots, but
- if you've got a heavy infection they come out your nose, your ears, your mouth and everything. So
- yes, it makes field work quite exciting at times. What I'm going to focus today's lecture is on
- actually a parasite much smaller and one that Leeuwenhoek might have been really interested in,
- but it wasn't actually discovered, not until 1851 by Theodore Bill Hart, and that's schistosomiasis,
- the schistosomes. I've also brought some to bring along, and here you can see these are tiny little
- schistosomes - if somebody would like to take these - and you can see the male, the paler,
- just visible, and within them you can see from this electron micrograph the female. The name,
- schist, the female, the thinner, darker one, lives within the male and they live, in theory,
- happily ever after together and they're tiny little flukes. You can see them in the mesenteric
- here. The classic, when we think of schistosomes, you think of the three key human schistosomes.
- Schistosoma japonicum, intestinal schistosomiasis you see in Asia and you see this poor little
- boy here with very severe hepatosplenic disease. It starts off with bloody diarrhoea,
- general illness, high levels of anaemia, but if untreated you'll get to this level. Actually,
- japonicum is particularly nasty because each worm lays hundreds of eggs per day, so you
- can get to the severe hepatosplenic disease quite quickly. Just take water and make sure there's no
- worms. Here we can see the other main intestinal Schistosoma here, and this is Schistosoma mansoni,
- which you see across Africa and the Americas, and here this is when you get to this very severe
- stage. You see what we'll see is eggs in a minute. They get trapped and we get this immune reaction,
- then we get this severe pipestem fibrosis, and by this stage you would need surgery,
- portal shunts and to drain the ascites. The other main schistosome you find in
- Africa is the urogenital schistosome, Schistosoma haematobium. Here these children are holding up
- their little pots of their urine, and you talk in some of these communities and they talk about when
- they reach puberty. Adolescence is when their urine turns red, boys and girls. It's actually
- because these parasites are living around the venous plexus and they're causing the damage
- to the bladder. So it will start off with like this. If untreated this is actually a carcinogen
- and you'll develop bladder cancer many years later. Here we can see the portable ultrasound
- of a young child out in Senegal, and you can see these calcifications from the bladder from
- these schistosomes. Now, the schistosomes is an indirectly transmitted parasite involving between
- the mammalian definitive host and a molluscan snail intermediate host, and this is the classic
- life cycle you'll see of Schistosomes anywhere, CDC or the classic life cycle you'll see,
- and you'll see the adult worms here paired away within the mesenteric for the intestinal or the
- venous plexus for the urogenital, and they pass out with the stool or the urine these eggs.
- You can see how you can learn a lot from the microscopy alone from these parasites because they
- have different spines. The haematobium group have these terminal spines, and here we can see the
- mansoni and the japonicum with the spines on the side. So you can get a good idea of what parasite
- you've got. These hatch in the fresh water to the first free-living larval stage, tiny again
- that you can see under the microscope. This is us working in the labs under the microscopes in the
- field. They find their suitable snail host. They get in the snail, you have asexual reproduction,
- and then they'll start shedding the next invasive stage. Again, big picture on here, but they're
- tiny little parasites and they have a few hours non-feeding to find their next definitive host
- to penetrate and complete their life cycle. Now in the past… We saw with the other worms,
- the examples, if you give the drugs the worms come out. With the schistosomes they don't. The drugs
- will kill them but they're still hidden away. So in the past if you wanted to study the genetics
- of these worms, you would hatch out these eggs and passage them through laboratory rodents,
- then kill the rodents to get the adult worms later. So one of the early studies we did, because
- obviously there's a huge welfare, financial and also biological implications of using lab animals
- - they're different from people, we can see a genetic bottleneck - so with Charlotte Gower and
- Jaya Srivastava here, developed these new tools where you can take these directly free-living
- stages in Miracidia and Cercaria, put them onto these Whatman cards, and then from that you can
- extract the DNA and perform the range of genetic and genomic studies to go beyond the microscope
- and find much more about these parasites. If we go back to the schistosomes,
- the other thing of the life cycle, notice we say a mammalian definitive host. It's not
- necessarily a human. In fact, there's lots of different schistosomes, and lots of different
- animals are infected with schistosomes. We have the livestock, the schistosomes
- of livestock. Here we can see this poor sheep here with bovis or curassoni, the sunken eyes,
- and again this introduced cattle there, very, very sick. It's a disease of severe morbidity and,
- particularly in the case of small ruminants, mortality. You also have the rodent schistosomes.
- They've got their own rodent schistosomes here very closely related to the Schistosoma mansoni
- in humans and shared co-evolutionary pasts. Again, with this being a neglected tropical
- disease, we have one drug, a drug we've used for some 70 years now. We didn't even really
- know how it worked until recently. It's a great drug. It's out of patent so it's very cheap,
- or in fact donated by pharma for the use in the field. It doesn't taste very nice. It's
- big and bitter, but it's very safe. You can use it in pregnant women, young children. As I said,
- we have just one drug to treat these humans, and potentially the animals. So the focus of my talk
- today is going to be very much on combining these humans and the animals here, and One Health. There
- are formal definitions of One Health, but I quite like the way it just spells itself out here. One
- Health, humans, environment, animals, living together harmoniously. So where we bring the
- humans and the animals together, and we can see this seismic shift by G7 recognising One Health,
- recognising the critical links between humans' and animals' health and the environment.
- Now of course that was because of COVID, and the potential role in zoonotic and reverse zoonotic
- roles of COVID. We can see this One Health aspect is very much into the NTDs too. Within the last
- few years we've got the new WHO roadmap, the NTD roadmap and companion document. We've got the new
- WHO guidelines and we've also got new focus within the FAO and the WOAH focusing on this interplay
- between the humans and the animals. Then, if we look at the WHO roadmap, we can see what
- is brand-new in this latest roadmap is that for schistosomiasis we have this, additional risks,
- They're aiming for this elimination as a public health problem in all regions by 2030,
- interruption of transmission in selected regions, and that we've got to acknowledge that potential
- zoonotic reservoirs could continue transmission. Also, the assessment of the actions required to
- mitigate against to reach the 2030 targets, that we need to better understand zoonotic
- transmission, and the strategic interventions we need to think about bringing in the veterinary
- public health too. We need to either treat animals or look at prevention,
- treating and keeping animals out of the transmission sites. So how did we get there?
- How was this change in the schistosomiasis world to fully acknowledge the role of animal zoonotic
- transmission? Much of this comes from Asia. The Asian schistosome, Schistosoma japonicum - there's
- also mekongi - have got lessons learned. They have put everything at schistosomes for over 70
- years, the drugs health education, molluscicide, environmental modification, behavioural change,
- and we can see that this once hugely impactful disease across China, really stopping development,
- has been very, very successful, to the point that in the 1950s Mao declared,
- 'We have eradicated schistosomiasis in China.' You had the poems, the songs, 'Farewell to the
- God of Plague.' A little bit premature. Schistosoma japonicum remains endemic in
- seven out of the 12 provinces and is reemerging in some of these areas. The reason, what's accepted,
- is this, is that the Asian schistosomes have been always acknowledged as zoonotic,
- where acknowledged transmission of the parasite between the humans and the animals, with these
- bovines being suspected as the key hosts. So what we did in some early studies - again all the non-
- invasive sampling, spending a lot of time with your hand up animals' bottoms or following the
- poop - you can look across a whole range of the different potential hosts and different habitats,
- and unsurprisingly pretty much where you look the animals were infected. So again, light
- microscopy alone can detect this. We can take the eggs from the stool and see who's infected.
- If we look at the eggs per gram, the number of these eggs within the stool, we have the warnings
- that something's going on with these rodents. They have tiny little poops, but these are packed full
- of schistosome eggs, and these are hatching for potential transmission. These were students here,
- predominantly Chinese students Da-Bing Lu and Tian-Ping Wang. You can then go beyond the
- microscope and do the molecular studies, and here you can see when two points are closely related
- it means they're genetically very closely related. What you can see is that the parasites are sharing
- transmission between the humans and the rodents. We do have dogs too. Dogs are a little bit
- tricky because they like to eat poop, as two pigs, so sometimes eggs are passing through,
- but we see clearly that the transmission is shared between the humans and the rodents.
- Now with the PhD student then, James Rudge took this further. We don't need any of the details of
- the mathematics, but took all this parasitological data from all the range of different hosts,
- definitive hosts and snail hosts, developed novel multi-host mathematical models and to
- develop the magic number that we've seen from COVID, the magic number, R0 of 1, where you know
- if it's above 1 the transmission will maintain. If you get the mathematics of it below 1 you can
- interrupt transmission. So what James can show is that everything China has put at schistosomes, if
- this were a purely human disease, it should be sufficient to interrupt transmission. However,
- in the marshland regions cattle are maintaining transmission for re-infection to humans,
- and in the hilly regions or in areas where they've removed the cattle, rodents
- are responsible for maintaining transmission. These studies were some time ago. Oh no. We'll
- put this one, behaviourally too, to show just how sophisticated these parasites are. So when we talk
- about evolution in action we think of the bacteria that are changing every few hours.
- These worms live quite a long time. They lived on average about seven years. We have cases of people
- not being in Africa or Asia for 40 years still shedding eggs. We can see evolution in action,
- and what we're seeing is that these cercaria that have a few hours to get out their host
- and find their suitable snail, they are shifting towards the more nocturnal and crepuscular times,
- the prime times to find a rodent host to maintain transmission and reinfect humans. So I said that
- was the early study. So what's going on now? China has continued to push everything at
- schistosomiasis and done a super role, and the infections in the humans and the cattle have
- gone down and down and down. However - again, you don't need to see the details here - but
- where we've performed systematic reviews of the literature and also ongoing surveys, we can see
- that while the infection has gone down, continued to go down in the livestock and the humans,
- it's either stayed the same or increasing in the rodents. It's host-shifting to these rodents to
- maintain transmission. So between 2004 to '18, about 3.86 per cent of rodents were found to be
- infected, and most recently in 2019 to 2024, 12.81 per cent of the rodents were found to be infected
- with Schistosoma japonicum, with the highest here in Anhui province, maximum of 27 per cent.
- It gets even more clever when you think that you don't really need to have much of these
- schistosomes circulating for the potential to have bounce-back. What they used to think
- you've seen in the schistosomes there, the females inside the male, the assumption is
- you's need a pair with both gender infection, and while the males can continue living,
- the females will shrivel up and die without their male. What you can see is actually, we've
- done studies here in the rodents and infected them with either single male or single female
- cercaria and then leave them one month, three months, six months, a year and then expose them
- to the opposite gender cercaria. They spring back into life and start shedding schistosomes again,
- so we can see those implications for bounce-back from this sylvatic foci.
- So the implications and the applications. Rodents all over the world are notoriously
- difficult to control, so we have this ongoing challenge for persistence of transmission. China
- is not quite at the point again of declaring farewell to the god of plague, but last year
- they did announce interruption of transmission. They have slightly different terminology to WHO.
- Complete elimination in Anhui province, the region where we just picked up 24 per cent of infected
- rodents. So we're challenging or suggesting that actually, in order to declare, to verify an area
- of interruption of transmission you have to go beyond the humans, the livestock, the snails and
- you have to consider the sylvatic foci. So that was China, an example from China where, as I said,
- it's a known zoonosis. Let's go to Africa. Lessons learned. Schistosoma mansoni we said here,
- and Schistosoma haematobium, not classically acknowledged as zoonoses. Gets even more promising
- when we think of Schistosoma haematobium, which is classed as a uniquely human schistosome. So
- in theory, if we can cover enough treatment, and as long as we don't get drug resistance evolving,
- we should be able to interrupt transmission by just targeting the humans. So Africa started
- the control program somewhat later than Asia, and actually here in 2002/2003 with Alan Fenwick here,
- there was only three of us when we started out the Schistosomiasis Control Initiative,
- working very much with in-country partners to give the praziquantel treatments to the school-aged
- children. The first aim was to actually just simply reduce morbidity, to stop these
- severe pathologies later, and co-treatments with albendazole and mebendazole to treat them for the
- soil-transmitted helminths at the same time. So by 2014, over 100 million praziquantel
- and albendazole/mebendazole treatments were given across sub-Saharan Africa,
- with the praziquantel and actually all the drugs being donated by pharma. SCI has now
- gone independently, and it's now Unlimit Health and continues to do great work across Africa.
- So here what was a progress towards the WHO goals? So these are the first countries where
- we started for mansoni and haematobium. Analysis here with another PhD student, Arminder Deol,
- and with our biostatistician Beatriz Calvo Urbano. We could see that in each of the
- countries infection went down really quickly. As I said, we were aiming at morbidity control,
- but we could have impact on transmission. They went down. However, you can see in East Africa,
- and particularly for the Schistosoma mansoni, levels were staying high, and for the urogenital
- schistosomiasis, the eggs in the urine, West Africa were staying persistently high.
- There's obviously a whole plethora of reasons that you can have continued transmission,
- from the anthropological, whether they're taking the drugs in the first place,
- host and parasite factors, but I'm going to be talking just about the potential interplay
- of humans and animals here at maintaining this transmission. So if we start with Schistosoma
- mansoni, the intestinal schistosomiasis, it's actually a little bit surprising that it's not
- more acknowledged as a zoonosis. We saw in that phylogenetic graph at the beginning how closely
- related it is to the rodent schistosomes, and in fact nearly all the studies on schistosomiasis
- and all the textbooks are all on Schistosoma mansoni because it's so easy to maintain in the
- lab within a rodent host. Indeed, we know across Africa and the Americas that actually rodents
- are infected with Schistosoma mansoni, as are the nonhuman primates, the monkeys and the big apes.
- So in some of these areas, if you go in a pond in some of the areas in Tanzania,
- you're just as likely to have got schistosome from a primate, nonhuman primate, than a human.
- So here, another PhD student, Stefano Catalano, in Senegal here looked at the rodent population
- sympatric to the human populations along the river sites and found that yes, indeed, the rodents
- were infected with schistosomes. As I've said, rodents have their own schistosomes. So again,
- this is where the molecular typing has to come in. This showed that these rodents are infected
- with Schistosoma mansoni. Between 2.1 per cent to 40 per cent of these rodents are infected
- with mansoni, and it's more than simply being infected. When he took this further using, again,
- more sophisticated analysis, we can see that it is the same parasite circulating between the humans,
- the rodents and the snails in these populations. So again pure zoonotic
- transmission going on in these populations. So once again in Africa, like in Asia, we have
- the challenge of the sylvatic host to reach the 2030 targets. So if we go to Schistosoma,
- and we finish on the urogenital schistosomiasis, we're in for a home run. Schistosoma haematobium,
- uniquely human schistosome. Let's just give them the praziquantel and all will be well. As we said,
- we're persistently seeing it in West Africa, maintaining really high in these populations,
- and in populations we knew that they're getting the drug treatments and the
- children are taking the drugs. So back in 2009 with [?Ahmadu Garba 0:25:08.9] here,
- who is our lead in the Niger side, followed some of these children - this was 49 children - and
- gave them the praziquantel, because of course any time when you see treatment failures the
- big worry is we've got drug resistance. As I said, we've got a whole other field
- of research looking on the potential evolution of praziquantel resistance,
- but here what we could see is that the drug was working. These children, the infections were being
- knocked out in these children given praziquantel, but what we were seeing was this very, very rapid
- bounce-back. It gets even more interesting when we think of the timing of these bounce-backs,
- when we look at the points of reinfection. This was urogenital schistosomiasis. They
- had the eggs in the urine. They had the red urine. Schistosoma haematobium takes
- eight weeks from reinfection for this pair to reach maturity and start laying eggs. We were
- seeing bounce-back in these children after six weeks, and it's the intestinal schistosomes that
- reach maturity after six weeks, the Schistosoma mansoni but also these intestinal schistosomes
- of the livestock such as bovis and curassoni. Now, we know that schistosomes, from experimental
- work and from the field-work, that they do pair sometimes with different species. Schistosoma
- haematobium and mansoni will pair. The picture of the mule here is because we're thinking of
- the classic hybrid. They're phylogenetically quite distant, and in general they were going to produce
- ectopic infertile eggs. So you can still get implications for morbidity. Some eggs still
- will be laid, but not for ongoing transmission. Together with Elsa the postdoc here and Ahmadu,
- we can see that in these Niger populations this wasn't haematobium for these children. It was
- haematobium hybridised with these very closely related parasites of livestock, Schistosoma
- curassoni and bovis, and the picture of the baby here is to stress that these were viable hybrids
- for the potential for ongoing transmission. Moreover, with Elsa and Ahmadu again we find cases
- of potential hybrid vigour. Some children in Niger were infected with purely livestock schistosomes,
- hybrids between curassoni and bovis, which on their own don't seem to be able to reach maturity
- and establish but, as a hybrid, they seem to be able to infect these humans for ongoing
- transmission. So this goes against everything we were talking about earlier that you'll see in
- Wikipedia and everything about the schistosomes. They'll pair with their correct species.
- They'll live happily ever after a nice monogamous relationships. In fact, when you go beyond the
- microscopes and bring in molecular biology, it's a complete mixture. Everything is mating with
- everything else, and bidirectionally. We can see this is all within the haematobium group.
- These are samples are just from Niger again. So it brings on the whole concept of species.
- These are urogenital schistosomes of humans hybridising with intestinal schistosomes of
- animals for ongoing transmission, but it is still very focal. So here we then did various
- systematic studies across, in this case Senegal, over time, and we can see here, again with Elsa,
- two sites here. Very, very different. If you go to the north of Senegal, which is an area of very,
- very high anthropogenic change, migration of people coming in, new dams being built,
- good opportunities for ongoing transmission, we see prevalence is extremely high,
- both of the haematobium and of the hybrids. If we go a few hours' drive down southeast to Linguère
- and Barkedji, which is undergoing much less anthropogenic, change levels are a little bit
- lower but still persistently high, still 25 to 50 per cent of both haematobium and the hybrids.
- Likewise you can consistently see the same patterns in the animals.
- In Richard Toll we can see here that it's the cattle responsible for transmission,
- with some 80 per cent of these cattle infected with Schistosoma bovis or the hybrids,
- and in Linguère and Barkedji it's the small ruminants who are being responsible for the
- ongoing transmission with Schistosoma curassoni here, and the hybrids therein. Once again,
- if you look at the rodents, the rodents have got everything. They're a complete biotic hub. They've
- got the mansoni we've talked about, they've got the bovis, and here we see this potential biotic
- hub for the haematobium and bovis hybrids. So the question is, when is this happening?
- Now, I said schistosomes were discovered in 1851 but it's a very, very ancient disease,
- being detected in mummies in 1910 by microscopy alone. You can see in the kidneys of two mummies
- from the 20th dynasty I have demonstrated in microscopic sections a large number of
- calcified eggs of bilharzia in the tubules. Further developments with diagnostics from
- immunology from 2014, when the tools in ancient DNA really progressed well, they have detected
- both haematobium and mansoni in these ancient mummies. I'm not aware they've actually looked
- for the hybrid status in these parasites from the mummies yet, but that will be super-interesting.
- We've seen or suspect from the drawings that they were quite familiar with the morbidity of
- these schistosomes, even in these ancient Egyptian papyruses. So how old is it? Where is it going on?
- Now everybody seems to be working on schistosome hybrids, and wherever you look and wherever in
- Africa, with the development of molecular tools, you're finding schistosome hybrids. Every day
- and every week it seems to be another country. People are looking and finding different hybrids.
- Actually it was in Rhodesia - in Zimbabwe it is now - back in the 1940s from microscopy alone,
- is when people first suspected that hybrids were going on, where they were suspecting a slightly
- different egg structure, somewhat between the two different species. It is again with the
- development of molecular tools that we can now see it really is hybrids, and again in a whole variety
- of manners. When does it go on? We can take it further with the molecular tools and whole-genome
- sequencing, and find out that many - probably the predominant - of these hybrids are ancient,
- not ancient in the terms of Egyptian ancient but in terms of several hundred generations
- and introgression of these parasites. We also know that there is contemporary hybridisation going on
- between the F1, the first three generations. So there is contemporary hybridisation,
- and this again is very, very focal. If we look at again samples from Niger and with
- analysis with again with Elsa and Beatriz, we can see that in one region of Niger here,
- Kakuru, almost everybody is infected with these so-called ancient hybrids, where in another area,
- Tabalak, of ongoing very high transmission it's the schistosomes, pure haematobium - even the
- so-called pure Schistosoma haematobium has even got a little bit of bovis introgression in but
- we'll still say the pure Schistosoma haematobium - and the ancient with the opposite patterns. In
- both populations what you'll find, very rare in comparison, are these recent hybridisations, this
- evidence of contemporary hybridisation going on. So Anna Borlase took this even more complicated
- mathematical model, not simply a multi-species, host species, mathematical model, but a multi-host
- and multi-parasite mathematical model, and showed that even if these hybridisations,
- these contemporary hybridisations, are rare they will be significant to maintain transmission,
- and that we predict to become more important as the elimination efforts occur. So does it
- matter? Does a One Health perspective for schistosomes matter if we have praziquantel
- it works on different species of schistosomes. Does it matter? Well we are in these very changing
- environments for schistosomes. We have the mass drug administration programmes. We have global
- warming. We have big migrations of people and animals across regions. Also differences in the
- fresh water, lots of dams being built - great for the intermediate snail hosts - and also flooding,
- which can move these parasites to new areas. Also, difference in agricultural practices,
- from the expansion of rice paddies here in Africa, putting them in exposure to the sylvatic hosts,
- and also here where many of the children stay with their herds of ruminants, and again,
- prime areas to mix these parasites in the fresh water between the humans and the
- animals. So what we'd predict is indeed under these areas of very high anthropogenic change,
- brings together these increased opportunities for mixed schistosome species, co-infections
- and interactions, which we can predict will impact transmission potential, morbidity and,
- the big worry here for praziquantel, one drug, efficacy. That's potentially what we're seeing.
- As we've seen, the interactions with hybrids are one reason why we're seeing this persistently high
- transmission across regions in Africa, and we've seen in a zoonotic role in China too.
- Schistosomiasis world got all very excited, and we thought we'd get lots more funding - which
- sadly didn't happen - is when Jerome Boissire and his team detected schistosomes in Corsica
- when rich tourists from Germany, from France, were going to Corsica,
- sitting in the lovely Cavu River, and eight weeks later weeing red urine because they were infected
- with schistosomes. They were infected with the hybrid schistosomes, which actually had again…
- The molecular showing had been introduced from Senegal. With global warming we actually have
- suitable hosts for the haematobium group in quite a few places across the world, Spain,
- Portugal, so would we have this potential expense through hybrid vigour of schistosomes spreading
- beyond the tropical and subtropical zones? Also, the implications for morbidity. I said,
- particularly when we talk about the hybrids as they're saying, this is a urogenital schistosome
- of humans with an intestinal schistosome of animals. When you look at that morbidity,
- you see damage to both the bladder and the liver, which has implications for monitoring
- surveillance. In many cases you'll go in and just say, 'There's eggs in the urine.' All you'll be
- looking for is bladder morbidity, but seeing the raise of this issue in hybrid zones we
- have to accommodate the liver morbidity, the intestinal morbidity too. Also, One Health,
- we mustn't forget the animals. This is a horrible disease to animals, particularly to the small
- ruminants, and these animals will die. So we did, with Barbara Haesler here,
- the first cost economic cost-benefit analysis and cost effective analysis with social studies
- to actually measure the impact of schistosomiasis on these animals,
- how much these farmers will lose in terms of their animals dying, reduced meat, reduced milk yield,
- and all again perpetuating the poverty cycle amongst these already impoverished communities,
- and how much they would save if their animals weren't infected or if we treated them. So that
- raises us to our last question. Implications of praziquantel treatment for both human and animal
- schistosomiasis in Africa. Now, if you have large animal reservoirs, that's great at mitigating
- against the evolution of drug resistance because you have this large untreated population,
- this [unclear word 0:38:16.7], and that's probably one of the reasons why resistance has developed
- in China with all these hosts circulating. If you do treat them, and we know we've got
- resistance to all the veterinary anthelmintics, we have that challenge. So some will say, 'Just
- don't treat the animals,' but we've just seen the substantial socioeconomic and welfare costs of
- livestock schistosomiasis, and you also have to acknowledge that these subsistence farmers know
- their animals and they know they're important. So in our social surveys you talk to, for example,
- this butcher. 'It is a disease that causes urine accompanied with blood. Children who bathe in the
- ponds and backwaters are the most affected. If I want praziquantel I say it's for my son, and once
- at home I give it to my sheep.' So this is what we see time and time again. They will get the
- drugs being donated for their children and they're giving them to their livestock, or they're finding
- whatever drugs they can find and treating their livestock at whatever dose they think. They'll
- say, 'Well, you know, as a big man, three tablets, I'll give my cow five, I'll give my sheep one.'
- So that's a challenge for drug resistance, and we've already got the early warning flags.
- We did a drug efficacy study in Senegal with correctly dosed praziquantel which we took out,
- and we see at the specified dose praziquantel is actually working pretty well in the cattle, but
- in the goats and the sheep it's zero efficacy. So these are also the animals which were most likely
- to be treated and mistreated by the praziquantel, by their owners, because it's the small ruminants
- that die of the schistosomes. So the implications. We go on treating the human MDA, but we also have
- surveillance here, these very happy children bringing us their little pots of pee-pee and
- poo-poo for us to do the genetic testing on to see what they've got. We've also got to acknowledge
- the animals, and we've also got to bring in the fact that they are treating the animals,
- so we've got to make sure this is done properly. So one of the biggest things we've had to push is
- to get correct dosage and correct formula drugs into the countries, which we got into Senegal. It
- is not yet broadly across Africa, because before what they had was [?Tenicure 0:38:16.7], which
- was a praziquantel mixed with levamisole. So it was a tapeworm dosage. If they gave them at the
- correct dose to kill the schistosomes it would be a toxic dose of levamisole. So what we've managed
- to help promote is the correct pure praziquantel formula for the proper dosage schistosomes,
- and here developing novel and point-of-care diagnostic tests. Here we have developed with
- Elsa as well with the famous now-famous baton de pee-pee, which is a selfie stick with a pot
- to collect the urine from these large angry cows at a distance to then perform the diagnostics on,
- and then with Martin Walker here developing appropriate measures and techniques for
- targeted test and treat, so we only treat at the herd level of those that are infected.
- Of course, prevention is always better than cure. Wash and vaccination here. When
- I actually went out to perform the drug efficacy trial, I couldn't actually find
- any animals or people really infected in an area that was always very high,
- and that may… Most likely is there was a big water tank being built there, and it wasn't finished so
- the water was free. People were taking the water, they were using it for wash and also very proudly
- showing us that they were taking water to the animals. They weren't taking them into
- the rivers, and we could really see an impact potentially on the health of the humans. Again,
- we have basic pest control management, keeping the build-up of rodents away from humans,
- and we're at a time when we've been using drugs, but the interest is coming back now into vaccines.
- There is developments now for Schistosoma mansoni vaccine in humans. So what we want to promote
- is actually, should we really be pushing now at a vaccine for the livestock? In many ways
- it's easier to get the livestock vaccines than the humans, so should we be pushing to get this
- prevention rather than cure? So to conclude, we can see from the amazing things that we
- can see from the microscopes that Leeuwenhoek has developed and how it does open up this whole other
- world, that we can see implications from these beautiful animalcules and the implications for
- epidemiology disease. We wonder what he would have thought of the electron microscope here,
- and actually to nowadays where you can see these tools, these AI tools,
- and also diagnostics simply from the smartphone in the field and how much it's changed.
- Also, how we bring together we go beyond the microscope and how much more we can see by also
- the developments in the genetics and genomics, and I talked about the role of animals here,
- the One Health shifting from either host shifts to hybridisations to maintain transmission. Actually,
- with genetics and genomics we are seeing these parasites have pretty much every strategy to
- counter everything we're pushing at them. So at the very least we have to stop looking
- at the schistosome in the classic textbook, this very human perspective, human-centric,
- and look at it here in this very much… In Africa as well as Asia, very much from this One Health
- perspective. Here the humans, the animals, sylvatic hosts all maintaining transmission.
- If there's one thing I'd like to take away from this lecture, it's never to underestimate your
- worms. They have every strategy we put against them, and also when we think about medicine
- and veterinary medicine and One Health to go together, are we really sure this is a snake?
- Personally I think it's a worm, and almost certainly a schistosome. So just to finish
- on a more personal note, when I was a little girl, there's two things… As many little girls I begged
- for a pony, as many girls do, and I begged for a microscope. I was never bought a pony,
- but I was bought this beautiful microscope here, and with the lady along the road I spent hours
- looking at the little animalcules. I clearly have not grown out of either, but I never would have
- imagined I could have made a career out of looking at them, and actually to be talking here. So thank
- you so much to all the huge teams. I mentioned some of the key as we go along. Huge international
- teams across the UK, Senegal, Niger and China for this work. The funders which made it all
- possible. You for listening. 91TV and all our One Health study participants. Thank you.
- Well, that was absolutely brilliant. It was extraordinarily clear,
- the extraordinary sex life of the schistosome. So there's lots of
- opportunities for questions. Can you say who you are, and fire away? Roy.
- Roy Anderson, Imperial College. Lovely talk. Really lovely. Could you say a little bit more
- about the vaccines, because we're getting to a crucial stage there where phase one is through,
- or the human one. Phase two has a very heavy cost. Phase three is going to cost a staggering amount
- of money. Would you do all the vaccine development in the actual reservoirs? It's infinitely cheaper.
- Yes. No, absolutely. I mean, it's so exciting we've gone back to that, and as I said they are
- looking very promising. I think one of the things we've touched on here is that the parasites in the
- field, be it mansoni or the animals, are so much more diverse than the lab strains that much of
- these vaccines are being developed. I think, you know, it is easier and probably less expensive.
- Don McManus worked for a number of years - the late Don McManus - on japonicum vaccine,
- but I think this is the time with the lessons learned from this Mansoni vaccine. Can we actually
- go out and start doing these trials in the animal schistosomes too? We have mansoni going on,
- but I think for these livestock schistosomes I think that would be a great way forward.
- It may be a semantic question,
- but do you think these ancient hybrids are actually a different species, effectively?
- Well, I mean, what is a species? That's the beauty here. I mean, the fact is,
- the fact that they're interbreeding, it's like, what is a different species? The fact that even
- when Schistosoma haematobium, which they call is a species, with the molecular you find this
- ancient integrations with the bovis. So I think we can. Phenotypically they're very different,
- but I really don't think it goes beyond this for the schistosomes. Actually,
- this hybridisation, everything's doing. It's not just schistosomes with molecular tools.
- Even some things like the really clonal Leishmania, they're all hybridising. It's
- a really successful strategy. So I think we do have to rethink what is a species.
- To complicate things further, are there viral infections that can transmit from one
- schistosome to another? Schistosomes must have their own infections, Presumably.
- Yes. That's a great question. I know with so many of the other worms as well,
- you can have the Wolbachia which comes in as well, and of course with cholera,
- the classic with being infected by CTX virus, turned it into the killer it is
- now. What have the Schistosomes got? Great question. Next study.
- More genomics. Question at the back.
- Hi, I'm Liz Hollenberg.
- So for the hybridisation, how does this affect the treatment efficacy for schistosomiasis,
- and then what are the implications for future programmes and praziquantel use?
- Yes, absolutely. Again, great question. At the moment, as we've seen it's working. Praziquantel
- is a great drug and it's working equally well on the pure as on the hybrids, but our big next focus
- is… I'll put this down because I'm shaking too much. If the resistance develops in the animals,
- then we get this hybridisation, is this a clear way to get into the human host?
- So I think this is what we really have to be looking at. If there's been a number of years
- of misuse of praziquantel in the animals, we have these two hybridisations together,
- I think that's where the real risks go. We have now very excitingly, after years of not actually
- knowing how praziquantel worked, we have now got the molecular markers for how it works, and
- molecular markers for praziquantel resistance. So this is the time for really detailed surveillance.
- Now I'm somewhat aimlessly holding an iPad. Are there any people in the virtual world who'd
- like to ask any questions? They will mysteriously appear on my screen if there are. In the meantime,
- can I ask a rather ignorant question? What's the role of the snail in all of this?
- Oh, huge. Huge. No, completely. I mean, it's got the two stages and I think also the fact
- we see the differences in Richard Toll with bovis and with curassoni in Linguère,
- the snail is critical. Before, for example, SCI was developed, the main mainstay of
- control in Africa was simply killing the snails. It kills everything else, it's not great, but the
- snail control is essential. When you get to that final stage for the interruption of transmission,
- that's when the molluscicide comes back in. So again, you've got to look at it in the broader
- picture. The snail is essential. Snails are quite interesting. You can have 80 per cent of
- your people infected in Uganda for example, 80 per cent. Trying to find an infected snail
- is near impossible but again, we're having new levels of… The diagnostics are improving so much,
- and the really exciting levels in terms of EDNA, environmental DNA.
- There's lots of schistosomes. Again, it wasn't necessarily specific. It could be
- a bird schistosome. It could be anything, but really exciting developments in EDNA
- for the surveillance which when you get to that last stage is going to be absolutely critical.
- So you can now pick it up in a sort of a lake or something like that.
- You'll pick up environmental DNA even if you can't find the snail.
- Yes. Nastily, what they used to use was sentinel mice, and put these poor little mice out for
- ages to pick it up. The developments in EDNA are really, really promising.
- What makes it a tropical disease? Is it the snails?
- Yes. I mean, again, these are diseases of the poor and the poorer, and it will be the snail.
- So if you look at Schistosoma mansoni and haematobium, you can follow them with the
- slave trade. So when they took the slaves out of Africa to the Americas they came infected with
- both mansoni and haematobium. They didn't have a suitable snail host for haematobium
- in the Americas so it died out, but they had Biomphalaria, suitable snail host, so Mansoni
- established. The reason why we're seeing now these hybrids in places like Corsica - because again,
- there's a blindness - it absolutely relies on the snails and where the snails live,
- and with potential global warming could we see an expanse of the snail populations too?
- Another question.
- Hello. My name is Will. I'm a PhD student, and I used to work
- with Professor Webster so I got a little revision before this talk. I wanted to ask,
- you stated again and again this is a disease of the poor. Especially when thinking about China,
- how much of dealing with this is going to come from an economic solution to this,
- and how much from kind of a medical, genomic… How should the money…
- Excellent question, and if you think of Schistosoma japonicum, comes from Japan.
- Japan doesn't have schistosomes anymore because they've concreted over everything. So there's
- one strategy, just concrete everything. No water. That would be the strategy,
- but it will be with development and water, and you can see like in North Africa and Morocco,
- places like that, just actually going back to the snails again, by having the channels,
- areas with the water flow and sanitation, that's the best way to interrupt it. It's to stop
- the sort of the communities where they've got to go to the water for their washing,
- with the sort of sanitation. It will improve with development. Again, it's a vicious circle
- that it's perpetuating the poverty cycle. If they're so sick, the two have to go hand in hand.
- Question in the middle there.
- Hello, I'm [?Izet 0:53:41.5]. Fantastic talk. We've seen that the microscope,
- mathematical models, everything that is going around is telling
- us more and more about these things. What in your view is the place of the
- latest developed technologies in AI and automated robotics that will enhance and
- speed the diagnosis or identification of this and their varieties? Thank you.
- Of course, this is one area of your expertise. So absolutely that's what we need. So much of these
- diagnostics for the microscopy depends for the intestinal on the Kato-Katz,
- so it's really quite smelly having to deal with this, a big slice of poop and stuff like that,
- and then searching through them. Urogenital's a little bit easier, but it does take time and we're
- losing those skilled microscopic technicians. So this is the future. Can you have this ease of
- access with the mobile phones, with AI technology? Again, I think we've got to go beyond assessing
- these and developing on these lab strains, because as we see in the field they're quite different. So
- again, being able to detect what you've got in the urine, with the stool. If you have a very
- heavy infection as well sometimes you'll get urogenital coming out in the stool,
- mansoni in the urine. Again, these diagnostics are absolutely the way to go. They've got to
- be low-cost so they can be used in the field. The phone is a brilliant technology because
- wherever you go in Africa everybody seems to have about three phones. So
- I think that's definitely a very exciting new and very necessary new technology.
- Another question there. Microphone coming your way, don't worry.
- Thank you. Hi. Alexandra [unclear word 0:55:36.1], biologist. I was wondering
- what's in the kits if you're not looking for the parasitic eggs. How does the kit work? Are
- we looking for specific proteins in the test kit to test the urine or to test the faeces?
- Sorry, which test kit?
- To identify the parasites. Are we still using
- the analysis of the eggs? Finding the eggs. That's what we're still doing.
- In some. A lot of this, I've been focusing on this microscopy and then hatching the DNA is all from
- hatching these larval stages. One of the previous slides here… Oh my goodness. Oh here. So here,
- one of the standard tests is now the POC-CCA for intestinal schistosomiasis. You're not going to
- pick up the soil-transmitted helminths, but it's a little urine dipstick, a bit
- like a pregnancy test, and you'll pick up the antigens. So this is again with Beatriz here
- and the test. We've been working on modifying this to make a livestock-specific POC-CCA,
- so again we don't need to go through that smelly stage, and it's inexpensive, it's rapid,
- and we simply have to do that dipstick. We can tell a lot simply from the dipstick,
- from the urines too. There's past red urine studies where again you're simply putting in
- and you detect for blood in the urine. It's not so simple with teenage girls,
- but again, there's a lot you can test from urine, and there is big developments in the
- POC CAA… Not POC, within the CAA. We don't have a point-of-care test yet,
- but again that will put it right down to the level of a single worm and different
- species beyond just mansoni. So again, huge developments there and that's what's needed.
- Fantastic. Thank you so much.
- Another question in the middle on the other side.
- Please tell me if this is not an appropriate question. Does your what seemed to be beautiful
- grasp and representation of this whole subject affect the approach
- to governmental advice in other epidemic and other situations from a government viewpoint,
- as to how you approach a new COVID, for example?
- I would hope so. I mean, the beauty of this - and again we selected the UKRI for the highest-impact
- study - these studies have changed national and international policy for the schistosomes
- and brought in this One Health. I absolutely agree. Could we take this further, and actually
- what implications are for pandemic potential too, and again the importance. We know that almost all
- pandemics are going to come from the sylvatic, from the bats or the rodents. So again, can we
- bring in this routine surveillance? Yes, it's needed. It's needed for all of them, and actually
- the ideal future would be again to keep teams working together. So actually if you're going
- out and you're studying the bats, you're studying for the rodents, can you test for a whole range of
- these potential… Be it a worm, be it a virus at the same time. So I think hopefully, absolutely.
- Now, I've realised I've been looking at the wrong clock,
- because that one's actually about five minutes slow. So we'll have one
- more question, but then there's the important presentation. So last question in the middle.
- Ellen here from the Royal College. I'm a molecular biologist, as you know. Quick question. Awesome
- talk, first of all. You were talking about hybrid vigour. Where does the fitness selection come? Do
- we know this? Is it in the vertebrate host? Is it in the mollusc, and at which stage?
- I mean, that's a great question, and we don't know for sure. When we did experimental studies before
- we can see there's a trade-off. So if you have the same genotype is very successful in
- the definitive host and very high reproductive output, it has the opposite in the snail host.
- So when you've got indirectly transmitted parasite it's not so simple. Many of the
- laboratory studies will talk about this hybrid vigour, and saying the hybrids are pumping out
- more eggs. We actually haven't found that's the case, and in fact again it's quite complicated,
- that we're not seeing the same pattern. We're seeing hybrid vigour potentially in the expansion
- of host range. More snails can be infected, more definitive hosts can be infected, and potentially
- this geographic, but actually in general in the field populations on average the egg output from
- the hybrids is actually slightly lower than the haematobium-haematobium hybrids in the definitive
- host. We haven't had enough natural infections of snails to work out, are we seeing the same
- as we see in the lab as this inverse trade-off? Again, it shows the beauty of these studies that,
- mathematical models traditionally have looked at one host, assume the same in the host and the
- parasite. When you've got multiple hosts, multiple parasites and indirectly transmitted… Again,
- the beauty of having people like James, Martin and Anna, with really sophisticated
- mathematicians that really need to bring this in to see what's happening in the real world.
- Thank you. That was absolutely fantastic. So let me just remind everyone why you were awarded
- the Leeuwenhoek Award and lecture, for your achievements in advancing control of disease
- in humans and animals caused by parasites in Asia and Africa. We've heard a lecture
- which shows how apposite and appropriate that award is. So many congratulations,
- and I now have the enormous honour of presenting you with the medal and the
- scroll. So, many congratulations. I'm not sure I've got enough hands to shake with.
Join us for the Leeuwenhoek Prize Lecture given by the 2023 winner Professor Joanne P Webster.
Zoonoses, diseases transmitted between animals and humans, pose a critical global health threat. Increased migration, changing agricultural practices and climate, all enhance the spread of infectious agents among humans and animals, facilitating co-infection and genetic exchange, creating new genotypes.
Schistosomiasis is a major Neglected Tropical Disease, with over 250 million people currently infected and untold millions of livestock. Despite over two decades of human mass drug administration, the burden of schistosomiasis remains extremely high in certain regions. Whilst animal hosts are acknowledged as zoonotic reservoirs across Asia, elsewhere any zoonotic component of schistosomiasis transmission and its implications for disease control has, until now, been largely ignored. This is true of both Schistosoma mansoni, but also notably, S. haematobium, which was assumed to be an exclusively human infection – and thus amenable to elimination by targeting treatment of humans alone.
Here Professor Joanne Webster will present some of her and her team’s recent research revealing widespread viable hybridization between schistosome species of humans with those of livestock throughout Africa and beyond and their roles in disease persistence. This work raises profound epidemiological and evolutionary implications regarding the One Health control strategies needed, as well as for pathogen transmission dynamics in general in our rapidly changing world.
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