The Life Parasitic

After a 7-and-a-half year journey, NASA's Dawn spacecraft is finally in orbit around the asteroid Ceres. Ceres is the largest of the bodies in the asteroid belt out beyond Mars, and scientists hope it will be able to tell us something about how planets like the Earth were formed. Carolin Crawford is from the Institute of Astronomy in Cambridge and helped shed some light on the mission for Chris Smith... 

Carolin - The asteroid belt is this enormous swarm of rocky, icy objects that live out between the orbits of Mars and Jupiter. So, you're talking about just over two to three times farther out from the Sun than Earth lies. They're basically debris. They're left over from the early stages of the formation of the solar system. They're kind of like chunks of a planet that failed to coalesce. There was supposed to be a planet between Mars and Jupiter, but you've got the gravity of Jupiter, kept stirring up all those rocks but they never got their act together. They never formed a planet. And so, they're of interest because they're telling us something about that early solar system.

Chris - So, if we study those rocky bodies, we learn something about the evolutionary history of how planets put themselves together 4.5 billion years ago.

Carolin - The thing about most of the asteroids is they're very small. They go down to tens of meters and there are just a few that are perhaps hundreds of kilometres across. If you have an object that size, it doesn't undergo all the sort of geological processing that the major planets that hasn't had tectonic plate processing, hasn't had all the kind of geochemical activity. So, most of the asteroids remain almost like pristine chunks of that very primitive material that went into the solar system. So, you were just talking about fossils. In a way asteroids are the fossils for our solar system and we look back at those and we can see what the ingredients were to make the planets we have today.

Chris - Ceres is something of an outlier then given that it's about a thousand kilometres across sitting in amongst this debris field.

Carolin - It's an interesting one and you may regard it more as a failed protoplanet. This is why it's interesting because it's got that - it's the bridge between those small pristine asteroids and the major planets, maybe this did get further along in the development and maybe it reached the protoplanet stage before it then failed to continue. Because it's that size, as you say, just under a thousand kilometres across is good enough gravity that it's pulled itself into a sphere, it's undergone some of that geological processing, it's undergone what we call differentiation. It has a core, it has a mantle it has a crust. And so, it's kind of gone somewhere along the way to being a planet but not quite.

Chris - Dawn didn't go straight to Ceres though, did it, because it took in Ceres's smaller sister, Vesta, on the way, a few years ago?

Carolin - That's right. Between 2011 and 2012, it spent a year in orbit around Vesta which is the next largest object in the asteroid belt. That's not big enough to really be a dwarf planet. But it still is a protoplanet. It's only just over 500 kilometres across and it forms an interesting contrast to Ceres. It's slightly closer into the sun than Ceres is. It's a less icy body. It's got a metallic core. One of the things that's fascinating to scientists about this whole mission is to be able to compare two so different protoplanets. Why is one a much more wet object? Ceres has got ice and rock whereas Vesta really doesn't. It's much more metallic and rock. What are the differences between the two planets? How can you count for them being more or less the same part of the solar system, but yet, having had quite different histories?

Chris - I know everyone is saying this week or so has just gone by - that Dawn has arrived at Ceres. But this is only really the beginning isn't it because now, it's got to establish itself in a much lower orbit than it is now in order to do this surface survey it's going to do.

Carolin - Well, we had some fantastic views of Ceres as it was approaching around about sort of mid-February. It effectively overshot the dwarf planet and then it's approached it from the dark side and as you say, it's got to manoeuvre itself into a closer orbit and get around to the sunlit side. So, we're not going to fantastic images probably for a few weeks now until the end of April. It's going to start out in orbit about 4,000 kilometres away and over the next year and a half, work spiralling closer and closer and so, it can then map the surface from down to about a few hundred kilometres away. And get more and more detail about those features that we're beginning to see.

Chris - And just very briefly, what is it actually going to be scrutinising the surface to see or how is it going to examine the surface?

Carolin - Well obviously, they're going to be taking images and spectroscopy of the light reflected from the surface. They'll be looking at the geology of the surface, but there also going to be sensing any variations in the gravitational response of the spacecraft from the dwarf planet as telling us something about the internal structure and help us to kind of dissect what the core is like. And also, whether there are possibilities that it does have a substantial fraction of ice or even possibly water underneath that crust.

Cambridge is currently in the run up the local FameLab final! FameLab is a competition where scientists battle it out to be the best at giving engaging short talks on their favourite areas of research. Paul Clarkson chose to do his three-minute talk on a natural nuclear reactor, as he explains to Ginny Smith... 

Paul - Hi, how are you doing?

Ginny - So, tell me about your work. You're a PhD student. Is that right?

Paul - Yeah, that's correct. I'm currently doing a PhD in the application of face change materials. So, it's to do with nanofabrication, things on the very small scale and taking advantage of what they actually can do, which is change between an amorphous to crystalline state.

Ginny - So, making very tiny materials that can change with temperature and that sort of thing.

Paul - Exactly.

Ginny - What are you going to be talking about in FameLab?

Paul - I'm actually going to be talking about our nuclear fission reactor?

Ginny - What made you choose that?

Paul - I used to be in a past life a nuclear research scientist before my PhD. As soon as you mention the word 'nuclear', it can become quite divisive. So, I like to be able to expel a lot of those belileved demons on it.

Ginny - Well, you've got  me interested. So, you've got a 3-minute talk that you're going to do for us now. I think that's right?

Paul - That's correct.

Ginny - Okay, when you're ready, off you go...

Paul - Who listening has misplaced something? I have, my car keys. They go missing a lot. I accuse my housemates who are trying to sabotage my life and it can be quite annoying especially if you know you have to get somewhere important like KFC before it closes. 

However, in the grand scheme of things, this is pretty trivial. But not everything that goes missing is trivial. 

Imagine you are a French scientist in 1972 in Africa. You're working at the Oklo Uranium Mine and you have just calculated that roughly 200 kilograms of uranium 235 is missing. That's enough to make 6 nuclear bombs. Naturally, this raised a few eyebrows and the scientist tried to think of where it was. But they were never going to find it. The answer was right under their noses literally. 

The uranium no longer existed as it had been burned up. That's right. the scientists were in fact, standing on an ancient natural nuclear fission reactor. But how is this possible? 

Well, 3 key ingredients are needed for a nuclear reactor. One, you need fissionable material. This material is made up of atoms whose nucleus - a fat mass of protons and neutrons - will split into smaller nuclei and release energy when it absorbs neutron. Two, you need neutrons in order to keep the reaction going and three, you need a moderator - something that can help control the rate of the nuclear reaction. It slows down neutrons and allow them to be absorb by the fissionable material. 

And it turns out that 2 billion years ago, Oklo had all of these things. One, it had a large concentration of uranium 235, which is the fissionable material. Two, it had neutrons provided by normal radioactive decay of surrounding rocks. And most importantly, three, it had water. Water is excellent in slowing down neutrons. 

And so with this mix, Oklo was able to sustain nuclear reactions for over 200,000 years with an average power rating of about 100 kilowatts. That's enough to keep a few hundred kettles powered for eons. So, why is this relevant today? Scientists and geologists have been investigating the movement of the fission waste from the Oklo reactor over this time period, one of the key things needed to be understood for a nuclear waste depository. What has been found is that the nuclear waste hasn't travelled more than a few centimetres over 2 billion years. 

That is remarkable. That's without intelligent design or human engineering. Nature has yet again provided a potential solution and it just goes to show that sometimes when you look for something that is missing, you can in fact find something that is far more valuable.

They say there's no such thing as a free lunch, but parasites seem to get away with leeching off their hosts rent-free. Almost every organism on earth has it's own particular parasite, in fact, it's estimated that up to 50% of the earth's species are parasites. But are parasites getting the sweeter deal, or does this lifestyle come with it's own dangers and pitfalls? And how did parasitism first evolve? Mark Viney from the University of Bristol introduced Chris Smith to the "life parasitic"....

Mark - In a broader sense, a parasite is any organism that lives in or on another organism to make its living. So, this would include things like viruses and bacteria. But when we typically talk about parasites, what we really mean are animals that live in or on other organisms to make a living. And these are things like protozoa which are single-celled animals, an example of that is the malaria parasite. But then multicellular animals also live in and on other animals and plants and these are typically worms that for example very commonly live in the guts of other animals or in other locations in their body. Some of them live on the surface of fish for example and on the gills of fish. But the other sort of parasites as well are ectoparasites which are insects and other arthropods. Things like lice, fleas and ticks.

Chris - How long have these sorts of organisms been around in terms of the evolution of life on Earth?

Mark - I think parasites have been around as long as there's been something to parasitize. I think what we have to remember is that every organism is trying to make a living in quite a tough world. What a host or a potential host species is, is a nice patch of juicy resource waiting to be exploited. Of course, parasites have evolved to exploit those resources, those hosts every time they become present. I guess the proof of that is, any animal or plant that you could care to look at in your garden or that you might see on the television on a David Attenborough programme is actually teaming with parasites. Everyone of those animals will have worms in its guts and it'll have protozoa in its blood and will have ectoparasites on its skin, and that's the normal stage of most animals. That's because, that multitude of parasites, is because it's a very ancient history that has evolved to exploit this rare resource.

Chris - Quite a complicated life story too though, isn't it? so, how would something so complicated as the ability to penetrate another organism, stay there, outwit the immune system of that organism and feed off that organism, how would that evolve in the first place and get started?

Mark - That's a very good question and a tricky area I would say. What one imagines is that organisms destined to become endoparasites or parasites that are living inside organisms actually started off in their evolutionary history to becoming a parasite by living in ever closer association with another organism. So for example, if you go and cut up a snail from the garden, you'll very often find some worms living very closely and intimately on those snails, but they're probably not parasites. So, one imagines that these animals, these potential parasites became ever more intimately associated with parasites before then actually becoming dependent on those parasites. But you're absolutely right. parasites have had to evolve a whole range of adaptations to live inside hosts and to cope with all the challenges that brings which is feeding off the host, surviving the immune response that the host is directing towards those parasites. I think the other thing that is interesting to think about with parasites is, there's a patch of resource that parasites have evolved to exploit. But those patches of hosts are quite separated in the environment. So, there's always a distance between two potential host species for the two host individuals for example. The challenge of moving between hosts is something that parasites have to evolve quite a lot of adaptations to achieve and that's the process of infection in fact.

Chris - Is it fair to say then that if parasites have just evolved to exploit a resource, that parasites themselves can catch parasites? Are there parasites that prey on parasites? Do fleas have fleas?

Mark - Absolutely. Well, we can talk about some of the microparasites, things like viruses but any macroparasites such as worms or protozoa for that matter will also have viruses themselves. They're just another resource to be exploited.

Chris - So quite literally, it carries on ad infinitum, as the rhyme goes, doesn't it...?

Mark - Exactly!

You may have heard of parasites influencing host behaviour, but they can go one step further, and even manipulate their bodies. In the mid-1990s there was a flurry of reports from the western USA of frogs being found with severely deformed limbs. Pieter Johnson, from the University Colorado, Boulder, was one of the scientists called upon to investigate, and he spoke to Chris Smith about what had caused this outbreak...

Pieter - One of the main causes turned out to be parasite infection. Essentially, there is this tiny flatworm parasite, no bigger than the period at the end of a sentence that would attack tadpoles while they were developing in ponds. This would lead to severe limb deformities. We would find frogs with 5 or 6 extra limbs, some frogs with no hind limbs at all, others with bizarre webbing. It sort of prevented their limbs from being able to extend. In some parts of the country, we would find 50, 60, or even 100% of the emerging frog showing this severe crippling deformities.

Chris - Why was the parasite doing this to the frogs?

Pieter - Great question! So, this trematoda, this flatworm is called Ribeiroia ondatrae and the main reason it would do this is to reproduce of course. The main reason most organisms do just about anything. It turns out that Ribeiroia has this complex lifecycle. So frogs are only one of the many host that it infects and other animals that it'll infect include freshwater snails that are in ponds. And finally, birds - they get infected once they actually eat the deformed frogs. And so, it turns out that by crippling the frogs, by inhibiting their primary mode of locomotion, you're making them easy prey for the birds. So the birds will swoop down, they'll eat the frogs, they'll get infected by the parasite and it's there that the parasite actually gets to reproduce sexually. And then you have this brilliant system of dispersal because birds fly across the landscape. Essentially, when they defecate, they're dropping out the eggs of the parasite all over the landscape.

Chris - And they then make their way back to the nearest pond and a snail that's in the pond, that will pick them up.

Pieter - That's exactly right.

Chris - How did you, as the scientist involved in investigating these flurries of deformed frogs, actually start piecing all these together to work out what was going on?

Pieter - Mostly by making a lot of mistakes I would say was the best strategy. So, we ruled a lot of things out. I started working on this when I was an undergraduate student. Essentially, what tried to do is combine careful field surveys of where these deformities were occurring, with laboratory examinations of the animals and then finally, experiments. What you find is that if you bring the water in from the ponds where these deformities are occurring, that water doesn't cause deformities in frogs in the lab. If you actually raise the offspring of deformed frogs, those too are not showing any deformity. So, we were zeroing in on something in the environment that was attacking them during early development. 

One of the key observations was that almost all of the ponds where we were seeing this really severe deformities supported this very particularl type of snail. It's called a ramshorn snail. It turns out that that's the key snail that this parasite needs to support its infection. So, once we'd started to make those connections, we actually brought the parasite and the snails into the laboratory and then you can expose tadpoles to even really small numbers of parasites - 3, 4, maybe as many as 10 of these tiny parasite and quickly, you see them attacking the limbs. They show a very specific distribution no matter where you put them on the tadpole that migrate all over the place until they find the limbs. And then they produce these very powerful enzymes that essentially allow them to burn their way into the tadpole's tissue, right where those limbs are trying to grow. Sure enough, if you do this in the laboratory, you get the animals with the extra limbs, with the missing limbs, with the severe skin webbings. You can essentially reproduce all of those same deformities that you see in nature.

Chris - How do you think parasites evolved to do that because it's such a complicated process of being able to target the snail then target the growing limbs of a tadpole, have the right enzymes to do it and then ultimately make your frog get eaten by a bird so that you can complete lifecycle. That's so many steps of evolution. How on Earth did that happen?

Pieter - Yeah, that's a great question. Most of the evidence suggests that if you look at these flatworm parasites that they probably started out as parasite of snails. And then they progressively added a host onto their lifecycle. Some of the reasons to do this are, maybe you end up adding the tadpole first. But it turns out that your frog gets eaten as it happens to many frogs and many tadpoles. Over time, the parasites have basically developed this ability to survive predation. That they are somewhat unkillable by those digestive enzymes produced by something like the bird. And so, this has  one for focusing on being a snail parasite, to being a snail plus frog and then maybe being a snail, frog as well as a bird parasite. 

The advantages are obvious in terms of that extra dispersal ability you have. You can suddenly crisscross the continent and travel thousands of miles inside a bird. And then in terms of the frog component, I think the big challenge faced there is that if your frog lives to ripe-old age and never gets eaten by a bird then the parasite dies with it, without ever getting to reproduce. So, you can imagine how that puts enormous selective pressure on the parasite to find ways, or to have selection operating, to find ways to make sure that frog dies and then it dies the way the parasite needs it to.

Humans have been playing host to parasites for generations, but in modern times our obsession with sterility means that we're living without many of these "old friends". So could there be a downside? Henry McSorley is from the University of Edinburgh explained to Chris Smith why an absence of parasites might be the cause of the increase of modern allergies...

Chris - With Rick is Henry McSorley who is also from the University of Edinburgh. It's fair to say that this sort of cat-and-mouse game between parasites and our immune system has been going on for generations. But in modern times, our obsession with sterility means that we're actually living without many of what we could regard as old friends. So, might there be a downside to this? What do you think, Henry?

Henry - Yeah, absolutely. The evidence for this comes from areas where parasitic infection is still very common. When we look at populations infected with parasites, they tend to have much lower levels of diseases such as allergic asthma, whereas in this country, as you were saying, improvements in hygiene and sanitation have resulted in our really eradicating parasites over the last kind of hundred years or so, and over that same time period, we suffered an epidemic of allergy. So, researchers are calling this the hygiene hypothesis, that we're too clean and this has led to us all being prone to hyperactive immune responses.

Chris - Henry, how could we disentangle the effects of a sterile lifestyle and an obsession with bleach and avoiding bugs like the plague alongside the absence of parasites because might it not be that the exposure to chemicals in our environment that we use to clean our environment are what are causing the allergy and it's nothing to do with the fact that we're now not parasite-laden because, as Mark Viney was saying earlier, actually parasites pretty much are harmful. They're stealing from us.

Henry - Well, that's true. I think all of this kind of correlative work, you know, correlation doesn't imply causation, really has to be tested. And that's really what we're trying to do by being able to control when the parasites infect. Looking at the development of allergy, we can show much more directly that parasites can prevent the development of allergy and maybe be exploited to create new medicines against allergy.

Chris - Indeed. How are people trying to do that?

Henry - Well, what we're doing is trying to move away from using actual parasitic infection. So, there are lots of clinical trials ongoing where people are being infected deliberately with live parasites to try and control diseases such as inflammatory bowel disease or allergic asthma. However, we don't know exactly how these parasites work and what they're actually doing. So, our approach to it is that we think it would be a much better idea to try and find the exact molecules that parasites are using to affect the immune system and the immune pathways that they're acting on. And then we could perhaps develop these parasite molecules as new medicines for these diseases.

Chris - So, you could swallow a pill rather than a worm which sounds a bit more "stomachable", doesn't it?

Henry - Yeah, absolutely.

Chris - Where are we on the way to doing that because it's pretty tricky to try and understand what that particular intestinal worm that is living hooked on the side of your intestine is doing to your immune system at the tiny level that these things are operating at isn't it?

Henry - Yeah, absolutely. So, the approach that we've taken is collecting all of the products that parasites release into the host and which we think contains some molecules which will modulate the host immune response. We collect these molecules and we find that by administering them, we can replicate many of these suppressive effects of the parasitic infection.

Chris - But is the site also important? Because if you have a parasite that has evolved to live latched onto your gut and deliver these things at the right sort of concentration at the right sort of level and in the right sort of way, it might not be just a simple case of, we'll copy those chemicals and then inject them or something. They might not work.

Henry - Absolutely and that's a really good point. And this is what we're finding. It may not be a single molecule. it may be a mixture and it very much actually depend on the dosing, yeah, exactly where you administer it. so, if you're looking at trying to affect colitis, maybe a pill would be a great idea. But if you're trying to affect asthma, then maybe something that you actually inhale straight into the lungs.

Chris - What sorts of disorders are you going for or what sorts of conditions do you think might be amenable to this sort of approach?

Henry - Really any disease where a hyperactive immune response causes problems. So, these are diseases such as allergy which I think is very common in this country, allergic asthma. But also, inflammatory bowel disease and also autoimmunity. There's clinical trials of infection going on in all of these diseases. But as I say, we're trying to create defined medicines to actually treat them.

Chris - And how far have you got?

Henry - We have got from the level of finding that we have whole parasite products, real mixture of stuff which can suppress things like asthma in mouse models. And we've, just in the last year actually, gone down to the level of having a couple of individual proteins which we can produce in a highly purified form in the lab, and these can replicate many of the suppressive effects of parasitic infection. So, these could be perhaps directly developed as drugs and in fact recently, just in the last month, we've shown that these molecules work directly on human cells in the lab in exactly the same way as they do in the mice. So, it seems that there's a very clear pipeline to make these into new medicines and put these into people.

Chris - Sounds wonderful. Congratulations! What about side effects or is there a downside to this?

Henry - Anytime you're talking about suppressing immune responses, there could obviously be side effects which would include increasing your susceptibility to infection or even to tumour surveillance so your immune system can stop you from having tumours progressing. However, what we're talking about in this sense especially in the asthma work is to try and tolerise people against inhaled allergens. These will be things like cat dander or pollen or whatever. So, you could administer these parasite products which are highly tolerogenic with your allergen that you want to tolerise against and hopefully, drive a tolerance state that would last for years and you could essentially cure allergic asthma.