Urban microbiomes, and crushed cancers
This month, what happens to the microbiomes of wild animals when they share cities with humans, how being crushed in a cancer makes metastatic cells more malign, a genetic tool to uncover when populations merged back in history, how mating affects the moth sense of smell, and why Africa offers a wealth of research opportunities for the neuroscience community...
In this episode
00:39 - Urban Wildlife Shares Human Microbiome
Urban Wildlife Shares Human Microbiome
Andy Moeller, Cornell University
When people live together, inevitably they share things, and that also goes for the microbes - dubbed the microbiome - that live on them and in them. But what happens when people and animals share the same space? Do they trade bugs too? As he explains to Chris Smith, that’s what Cornell’s Andy Moeller has been trying to find out…
Andy - One of the major ways we're impacting wildlife is through urbanisation, the spread of cities over the landscape. And we set out to answer this question of whether urbanisation and close contact with humans is actually leading to the spread of microbes from humans into wildlife.
Chris - Usually when this happens and there's a jump from wild animals into humans, the outcomes are not good. And one product of that is things like monkeypox, which is causing a headache around the world at the moment, and COVID possibly. So are we talking about pathological spread: us giving animals things that make them unwell, or are we talking about a more innocuous thing where I happen to coexist with an animal and some of the bugs that live on me and in me become incorporated into the microbiome of that animal too?
Andy - That is the key question, I think. Anytime, a microbe from one host transmits into another host species where these are two lineages, the microbe and the new host, that have never interacted before many times you can have very negative effects on the new recipient host. We don't know, in this case, if the bacteria that we find shared between humans and cities and wildlife in cities are deleterious or harmful for the wildlife, but there are reasons to at least speculate that receiving a microbe from a distantly-related host could end up being bad for the recipient.
Chris - How did you study it then?
Andy - What we did is we went out and sampled faecal samples. So we took faeces from wildlife, living in multiple different populations and multiple parts of the world living either in cities or in rural areas, more natural areas. And we simply asked, did the wildlife living in cities share more microbes with humans than the wildlife living in rural areas. And we found, over and over again, this increased sharing between urban wildlife and humans compared to the levels of sharing that we observed between rural wildlife and humans. And so the inference from that was that wildlife seemed to have actually acquired some of these human microbes.
Chris - Is it the interaction and proximity to humans, or is it that for instance, I eat a chicken and that does something to my microbiome; I Chuck the chicken bone in the bin and along comes "Mr. Fox". He raids my bin and eats the chicken bone, and the chicken has the same impact on his microbiome as it did on mine. Do we know whether that is the, the process or is it that I leave some of my microbiome on my chicken, "Mr. Fox" comes along and he picks up my microbiome directly?
Andy - That's a great point. So we can't definitively distinguish between those two alternative explanations. So I should back up, I've sort of been favouring the transmission explanation, but it is possible that there's parallel selective pressures. For example, like you mentioned, due to diet or some other shared environmental factor that leads to the same bacteria being selected for in both wildlife and humans and cities. I think that explanation, although possible, is less likely. It's a little more complicated, less simple of an explanation than there's this sort of cloud of human-derived microbes that's floating around us everywhere we go - our trash and so on, our waste - and that the wildlife in cities are likely just picking up microbes from time to time from humans.
Chris - Is there any evidence that it might be impacting the health of those animals? Because researchers in Australia did a similar sort of study looking at seagulls in the last few years. And they were concerned to see that seagulls, probably playing around in sewage outfalls, were picking up antibiotic-resistant forms of microbes - human forms - but they weren't necessarily becoming unwell in the process, they were just acting as vectors and they were spreading these things around. Do we have any insights, or what does that instinct tell us, these acquisitions or human microbiome makeups might be doing to these animals?
Andy - Yes. So our study finds this very significant pattern of increased sharing of microbes and urban settings, but we don't investigate or, or have any data to speak to the health effects on the wildlife of having microbes that are also found in humans. It is important to note, however that some of the microbes that we see in the urban wildlife that are missing from their rural counterparts belong to bacterial groups known to cause disease in humans. For example, very close relatives of Clostridium difficile. We see close relatives of that bug showing up in some of the wildlife.
Chris - So while there, there may not be direct or visible obvious health impacts on these recipient animals, it may almost end up with us parking some of our pathogens among that community, which may then in some way, continue to evolve or amplify, but ultimately might find their way back into us again?
Andy - Exactly right. It is a possibility. If multiple species of mammal and other vertebrates are able to harbour these lineages of bacterial pathogens, you're completely right, it could actually help maintain genetic diversity in that pathogen and potentially allow it to evolve in ways that it wouldn't have been able to evolve if it didn't have those reservoirs and wildlife.
Chris - Has anyone done the equivalent experiment in humans though, and you compare urban dwellers versus rural dwellers, do you also see sort of sharing - more sharing - of an urban microbiome in the people, and might that have an impact as well?
Andy - We do actually, if, when we just look at the humans, for instance, living in urban settings, their microbiomes tend to be more self-similar than humans from rural populations. So we see kind of this parallelism in convergence, in, in urban settings, among humans and also among humans and, and wildlife species
Chris - And turning it around then how do we know that what we are calling a human microbiome associated with urban living has gone into an animal. Could it not be that the animals give it to the human city-dwellers?
Andy - Right? So in that case, we can show that the microbes underlying this increased similarity between wildlife and human microbiomes and cities are also found in rural humans, but they're not found in rural wildlife. And so that observation tells us that these are more likely human-specific microbes or human-derived microbes than microbes that were already present in the wildlife before they moved into cities.
07:35 - Genetics reveals when populations mixed
Genetics reveals when populations mixed
Manjusha Chintalapati, University of California, Berkeley
When we’re trying to piece back together the events of thousands of years ago that lead up to giant leaps like the inception of farming, or the colonisation of a continent, we rely heavily on the archaeology for clues. But thanks to a technique developed by Manjusha Chintalapati and her colleagues genetics can also be brought to bear and enable us to see very accurately when, back in history, so called “admixture” - the merging of one population into another - occurred. It can give us new insights into when postulated migrations, crucial to the evolution of the human race and practices like agriculture, did, or as it turns out, did not happen…
Manjusa - When you have two populations, which admix then the offspring has one chromosome from each parent and these chromosomes get shuffled when the offspring gives rise to the next generation. So basically the chromosomes fragments get shuffle every generation. So you can actually use the combination as like a molecular clock: based on the length of the DNA fragments you inherited from each of the parent, you can ask, when did the admixture occur? Because, if the fragments are a bit longer, then admixture could have occurred, you know, few generations ago, or if the fragments are much shorter then the admixture was many generations ago.
Chris - Very elegant idea. So I presume though, this is dependent on knowing some sequences, which are exclusive to each of the populations, so you can tell what's been added? Because, if they're the same, you wouldn't have any kind of footsteps to follow, would you. So how do you know what is unique to each of the populations that have merged?
Manjusa - You do need information of both the parent populations. Basically, the genome you want to date admixture in, and also the information of the populations you think that admixed genome has information from. Let's say you have an example of African Americans. You do need information of source populations, which are the European populations and also like the African populations. And then you can ask, when did these source populations admix?
Chris - And are you considering the entire genetic code when you do this? Or do you just look for individual little bits and you, you follow those little bits as almost like markers?
Manjusa - We actually follow the entire genome. So basically we process the entire genome of an admixed individual and ask, where are these blocks of DNA coming from? Let's say, European or African. And then we ask how long are these fragments? And just based on a estimate of how long these fragments are, we can actually go back and estimate, because this actually follows theoretically an exponential distribution, we can fit an exponential distribution to the segment length, and then find out when the admixture actually occurred.
Chris - Does it not matter where these bits are on the chromosome in terms of how likely they are to get diluted and recombined and that kind of thing? Does your method take that into account?
Manjusa - Yes. That's a very good question. It matters because there are recombination hotspots and cold spots in every genome. So, some of the fragments can get much shorter just because there could be more recombinations, meaning there's more DNA breakage there every generation. So we do use a recombination map. We actually have information where this recombination occurs and we do account for that.
Chris - This is brilliant! But I I'm frightened almost to ask, does it really work? And how do you know it works? Have we got a gold standard against which we can run this, so we can say, well, we, we know when this genuinely happened. Now we're going to ask what does your genome tool return, and do the two agree?
Manjusa - Yeah, there are examples where, you know, some of the history is documented, right? So you can use them as positive controls, but a much more better way of evaluating your method is always simulations. We actually simulated admixture between European and African ancestries. Let's say hundred generations. When we apply our method, we can date back 99 generations with three standard error, let's say. And this is true when we changed the proportion of admixture; when we change the time of admixture; when we changed the sample size of the population. So we tested a method for several scenarios and it works robustly in many scenarios.
Chris - It's almost like the genetic equivalent of carbon dating, isn't it, in the sense that, you know, you have a half life and the radioactivity is falling by a predictable amount each time. But it gets less accurate, the farther back you go, because the graph flattens out. Now does your method fall prey to the same thing where you've got a sweet spot, but once you start to get to a long, long, long time, the noise becomes more pronounced than the actual signal. So what are those ranges?
Manjusa - Yeah, that's a very good question. You read my mind! When the fragments get very, very short, it's very hard to date back the time, just because there isn't any information, right? The resolution of our method is actually up to 300 generations. So if you approximate the generation time to be around 28 years, on average in humans, that is around 5,000 years. But the novelty in our method is that because it can work with many degraded data, we can apply to ancient samples - let's say which lived 5,000 years ago - and the admixture in that sample could have occurred 5,000 years ago, so now we have ability to look at admixture events, which occurred let's say 10,000 years ago. That's the exciting part of our method.
Chris - Mm. I mean, it hasn't escaped my notice that this is mapping on beautifully to the times when ancient peoples were doing really interesting things and moving around a lot, embracing new ways of living, farming, agriculture and so on. Are you already probing some of those important questions around when people did things historically?
Manjusa - Yes, exactly. Just to give you a background, all present day, Europeans can be modeled as a mixture of three populations, which are the hunter gatherers, which come from the Mesolithic time period, Anatolian farmers from neolithic time period, and pastoralists from Steppe: from Bronze Age. So we could actually date back the time of formation for farmers and Steppe pastoralists using dates.
Chris - We have vague ideas based on a range of measures for when those different things and those different populations and different groups arose. Do our current predictions - based on those proxy measures - do they agree with your method? Have we got it right? Or have you found, with this, that in fact there are some gaps?
Manjusa - We know that agriculture in Anatolia actually dates back to a time of around 8,000 BCE, right? There's been a debate in the field saying that the agriculture in Anatolia reached there probably because of the movement of Iranian farmers, which was originally where agriculture comes from. But using our method, we could actually date back the gene flow of Iranian farmers in Anatolia to around 10,000 BC. That is way before what is documented, suggesting that probably it was just not the moment of the people themselves, but probably the techniques got diffused over time. So it was, it could have been, you know, the, probably the hunter gatherers locally transitioned to agriculture subsistence. So, using our method, we could actually give a precise timing of a mixture between two groups, which could shed some light on like how farming actually reached Anatolia.
14:54 - Squashed cancer turns tough
Squashed cancer turns tough
Gabriel Ichim, University of Lyon
Scientists have made a remarkable observation about the behaviour of cancer cells. When they spread - or metastasise - inevitably they become much more robust, and less vulnerable to chemotherapy or the assault of the immune system. Many had speculated that this is just a product of the cancer equivalent of survival of the fittest, but, as he explains to Chris Smith, Gabriel Ichim, who’s at the University of Lyon, has found that fighting their way out of the tightly pressured environment of a tumour, and squeezing their way into the bloodstream, does something to the DNA of these cells, endowing them with their more resilient profile…
Gabriel - Cancer is very dangerous when it spreads through the body, and at this stage it is basically incurable. These cancer cells are resistant to cell death, but we don't know why the spread of cancer through the body is very stressful. From a point of view of mechanics, for the cells to spread, they really have to squeeze through tight places. Sometimes they are so stressed, they will explode. So putting these two points together, we wonder whether when they embark on this voyage, this stressful condition actually is responsible for this resistance to cell death.
Chris - You don't think it's just a survival of the fittest thing that some cells, which are a bit more robust and resilient and resistant to cell death are ones that are best equipped to handle the stress of breaking away from the parent tumour and going to a new part of the body.
Gabriel - That was actually the main question raised by the reviewers. And we did a series of experiments that is not a selection of a pre-existing population, as you said, that are resistant to death, but actually is something that is induced by this mechanical stress.
Chris - So this is effectively what doesn't kill you, makes you stronger. It really is true with these cancer cells that the physical pressures applied to them to get to a new part of the body changes their behaviour.
Gabriel - Exactly. There's another thing, it is not the strongest or the most intelligent who will survive, but those who can best manage a change. And so it's how you better adapt to the stress that will determine how fit you are to spread through the body.
Chris - So we'll come in a minute to actually what they're doing, but what is it that actually induces the change in the cells, or how do they detect that they're being stressed and how does that alter their behaviour to give them these additional abilities?
Gabriel - My opinion is that the nucleus is the limiting factor. Sometimes it explodes. So the DNA is getting released. Sometimes there are DNA damages and this mechanical stress therefore can be also metagenic. So when you stress the nucleus, this will be perpetuated to the next generation of cells. So, in my opinion, it starts with the stress on the nuclear level.
Chris - When we started talking, you pointed out that cells that do this metastasis appear to become much more resistant to, to dying. So therefore, whatever the process is that changes them. It changes them in that way. So how have you unpicked what is happening to the cells to make them more resistant? And how do you link that to this idea that it is the stress and perhaps doing things to the nucleus of the cell that makes them change their behaviour like that.
Gabriel - First of all, I'll have to tell you how we created these stressful conditions. We basically put lead weight on the cells. We created the compression that is found in tumours. We also use a membrane with very tiny pores; diameter is three micron. To give you an idea of the diameter of a nucleus, it's around 10 micron. And we found that only the constriction lead to increased survival of cancer cells. We wonder, okay, maybe how the genetic information that is translated change. And for this we've done RNA sequencing and these cells modified their message. They are telling us more about how they move, how they resist immuno-surveillance.
Chris - Given that you've now disclosed this, can we use this in a therapeutic way? Are there ways to exploit this phenomenon, perhaps the detectors or whatever the processes are that make the cells behave in this way? We can pre-empt that this is gonna happen and block the ability of the cells to respond in this way so that we have a new way to block metastasis, but also to target cancers.
Gabriel - Yes, our study was very descriptive. We simply describe these mechanisms. We left the door open for another researcher and maybe, they will take these findings further and find, as you said, better therapies to target these new mechanisms that we described. So we kind of opened a Pandora's box of ideas. Since mechanical stress is bronchogenic, we can consider a strategy to soften the tumours. There'll be no mechanical stress and like this, they will not have this survival too. There are ways to soften, to make tumours less hard, and then the last point, this mechanical stress cells become invisible to our own immune cells. So there may be ways to remove this invisibility cloth and enhance the killing by the immune cells. But this is something that, we didn't yet investigate. And then hopefully, there will be other researchers that will take the study further.
20:20 - Mated moths smell different plants
Mated moths smell different plants
Sonja Bisch-Knaden, Max-Planck-Institute for Chemical Ecology, Jena
Confronted with a mixture of scents, some coming from plants you can feed from or lay eggs on, and others from plants that are just a distraction, how do insects like moths track down and tell apart the sources of the useful from unhelpful odours? It turns out that they can discriminate very precisely between them, and their sensitivity also changes depending upon whether they've mated or not. Speaking with Chris Smith, Sonja Bisch-Knaden is at the Max-Planck-Institute for Chemical Ecology in Jena, Germany…
Sonja - I wanted to know how moths can, just by using their sense of smell, find important plants that, for example, provide nectar, for feeding, and plants that are suitable as host plants for their offspring. This is especially interesting in the case of moths as most moths are specialised on specific plants. And if these plants are rare in the habitat, this means they have to find these resources against a huge variety of odours that are emitted from other plants that are not relevant for the moths.
Chris - But moths do have an exquisitely sensitive sense of smell, don't they? I mean, I remember one friend of mine pointing out to me that moths can pick up the smell of another moth at less than parts per billion concentrations. So why should it be a challenge for them to find the plants they're after?
Sonja - The challenge is that these plants that they want to find release a complex mixture of odours, but plants that are not important release also mixes of odours. And the components in these mixtures might be very similar, just differ in the ratio or the concentration. So they have to somehow differentiate or distinguish important plants from the unimportant ones. We know that they find the plant, but we don't know exactly how!
Chris - How did you then pursue it to work out how they were doing it?
Sonja - So we went to the natural habitat of one of these moths and there we were at the field station of the University of Tucson, and there is a lot known already about the moth species that live there and also about the plants. So that means we could go there and we were sure that this is the correct habitat, and there are all the plants there that the moth needs. And then we did collect the orders that are released by the plants in the field. And we did this with the plants that are important for our moths, but also we sampled from other species that were around trees or from grass flowering plants in the vicinity of the important plants.
Chris - So you end up basically with a smell snapshot of what the environment that these moths are operating in is like. How do you then work out how they respond to those different odorants that are in those samples?
Sonja - Yeah. We used these samples as stimuli in physiological experiments, and we wanted to know what the antennas - or the nose - of the moths can detect. And then, in a second step, we wanted to know how these odour mixtures from each of the plants is processed in the brain of the moth.
Chris - How on earth do you do that?
Sonja - For what the moth can detect? We have a GC - that's a gas chromatograph - that separates a complex mixture into single components. A stimulus is then going to the antenna and each time the antenna can detect one of these stimuli, we see this as an electrical amplitude. So then we know this chemical is detected by the antenna.
Chris - And what about the response in the insect's brain? How does it then interpret that constellation of signals coming in?
Sonja - We focused on the first processing centre, the antennal lobe. This is equivalent to the human olfactory bulb. It consists of 60 or 70 subunits. And each of these is targeted by one specific receptor type. And as each of the subunits has a different range of odours that it detects, in the end if our moth, for example, has 70 of these subunits, the moth can detect much more than 70 odours by this kind of combinatorial coding.
Chris - And do you see then that the insect has a unique brain response for the plants that are high value for the insect and lower for the plants that are just contributing to the, the sort of "smell scape" that's going on in the environment?
Sonja - Yeah. In we did another kind of experiment. We did also test virgin and mated females, as we thought, looking for a host plant, where the eggs can be laid and the larvae develop, is more important for the mated female. And there we thought, maybe that we find a difference. And what we saw in the virgin female, especially the flower odours were very much represented, but plants that are host plants were activating only one of these subunits and very weakly.
Chris - So you've got quite an interesting set of findings there then, which is sort of multi-dimensional, isn't it in the sense that a) they can detect the plants that are high value that are gonna be good hosts that, or that are gonna be a good food source, but that depends on whether they are looking for a host plant on which to lay eggs, or not. And so it sort of switches in response to, to their mated state as well?
Sonja - Yes, in the mated female, we expected that the host plant, so the important plant for egg-laying will be represented in a more, in a increased way in somehow maybe more subunits or higher activation, but this was not the case. It was exactly the same, but the activation of the background plants almost vanished. So the moths didn't smell this background plants anymore. Only the floral odours that are important for feeding, and also the host plants for their own larvae. But at the moment, we don't know exactly how the mating influences the olfactory system. So we don't know the mechanism.
26:50 - Why Africa Holds Huge Neuroscience Potential
Why Africa Holds Huge Neuroscience Potential
Kirsty Donald, University of Cape Town
"Working in Africa provides neuroscientists with opportunities that are not available in other continents. Populations in this region exhibit the greatest genetic diversity; they live in ecosystems with diverse flora and fauna; and they face unique stresses to brain health, including child brain health and development," as UCT neuroscientist Kirsty Donald writes. This, as she explains to Chris Smith, is a unique chance to develop ways to benefit the continent and also the field…
Kirsty - Neuroscience in Africa feels like it is an area of massive potential. The African region is one of the last remaining areas in the world where there is a young and relatively growing population. So what we are trying to communicate is the importance for us of optimising institutions and scientists, to be able to answer questions which are important for our region, but also to be able to contribute to the global questions in the area of neurological and mental health and neuroscience.
Chris - Those are the opportunities then. How do we capitalise on them? What's it going take to realise the opportunities and make the most of them while this window is open?
Kirsty - One of the things which is really encouraging about our area is that people coming from resource limited settings have a lot of resilience and resourcefulness with respect to how to use equipment, how to solve problems. You know, if you don't have a ready, made answer, you try and address it yourself. And so that mindset of resilience and resourcefulness is a huge opportunity to harness. A number of elements have been put forward by the community as things which we can use to build this community. One is a model of having hubs of expertise and systems of understanding the spread of expertise across the region. Ironically, COVID has facilitated this level of communication because of the more widespread use of virtual methods of communication. So, for example, having a database where you know, where all the MRI machines are in the country or in the region, where are they, who has access to them? Are they available for research or just for clinical use? Is there a possibility of adding more resources so that one can expand the community of people using a particular methodology? The other area, which is critical is mentorship for students coming through the system to develop critical thinking and scientific citizenship, being able to communicate your science, clearly being able to develop independence in your thinking, giving people experience of not only good mentorship, but being able to mentor themselves while in a mentoring process. There are a number of things which are easy to do. They don't necessarily cost money, but can really help move the field forward.
Chris - What's it going take to implement them though? So you've given me the opportunities. You've told me what your aspirations are and why they matter. Now, what about the practicalities? What's it going take to join up Africa? It's a big continent, lots of countries there. This is a huge job that you've just outlined. Yeah, huge potential huge job though. What's needed?
Kirsty - So what's needed are champions. The neuroscience institution, Cape Town aims at leading in this area at bringing not only different people in, from across the continent to be able to facilitate this emphasis on regional growth, rather than just local growth, but there are other virtual networks which are also driving this. So, for example, there's a network called CAMERA (The Consortium for Advancement of MRI Education and Research in Africa), led by scientists in Uganda. It's driving to run workshops in MRI work and get people speaking to each other across the continent so that they can ask questions and utilise equipment that is available to be able to answer relevant questions to the region.
Chris - So this is almost like a call to arms on your part. It's a call to action: community needed! We need to build the network. This is what we have in mind. Call us, let's start a conversation.
Kirsty - It is absolutely! It's call us, or expect our call. <Laughs>