eLife Episode 51: Transmissible Tumours and LSD Receptors
The wildlife impact of urban sprawl, how climate change will affect the distribution of mosquito-borne outbreaks, Devil Facial Tumour Disease 2, how LSD works in the brain and gender bias in peer review all go under the microscope in this latest episode of the eLife Podcast.
In this episode
00:36 - The Urban Jungle
The Urban Jungle
Arielle Parsons, North Carolina State University
One prediction is that by about mid-Century, over three-quarters of the human population - that’s destined to reach 10 billion by then - will live in a city. And cities themselves will of course need to grow to accommodate this burgeoning populace. Where they’ll expand into will inevitably be the habitats of wild animals - with what effect? Speaking with Chris Smith, Arielle Parsons has been trying to answer this question in the US...
Arielle - The idea is that these cities are out of ecological balance: that humans have taken away too much of the natural habitat and too much of kind of the natural systems and so they're not really functioning to the same level as we would expect of wild ecosystems. And so we wanted to look at that in terms of the mammal communities and compare two cities in the United States - Raleigh North Carolina and Washington D.C. - to nearby wild areas and see if we could see any differences in terms of diversity - so the number of animals present - and then the relative abundance - so kind of the population sizes or some estimate of the population sizes of each species.
Chris - Sounds like a very tall order! How did you do it?
Arielle - It is indeed a tall order! And so we had to cover these really large areas in both cities to get kind of an idea of these communities in the very suburban areas, all the way out to the more wild areas. And so to do that we used citizen scientists to run camera traps - devices that we can put out in the forest, or in a yard - and when an animal walks by it senses the body heat and the movement and it automatically takes a series of pictures. Without these volunteer citizen scientists we simply couldn't have covered the areas that were necessary for this study.
Chris - Where were they deploying their cameras?
Arielle - So we asked them to deploy them in different areas around these cities that were based on housing density so areas of highest housing density, or what we call suburban areas. And then, as we step down in housing density, we get to these wild areas. Citizen scientists then put those cameras in yards and also in forested areas - both small forest fragments less than a square kilometre, and large forest fragments.
Chris - And how do you log all the data?
Arielle - We use a software called eMammal: a network that helps camera trappers organise their data; and that software allows our volunteers to go through all the pictures that they collect and identify the species in them. Then they upload the data to us so that we can look at it and make sure that they've correctly identified species. There are some some tricky ones here.
Chris - Why?
Arielle - Why are they tricky?
Chris - Yeah!
Arielle - Yeah. So we have two fox species: we have the red fox. Then we've also have the grey fox, and they're of similar size and, especially at night, these cameras - they're black and white - it's an infrared flash - so we can't see whether the coat is red or black. And so there are some characteristics, especially of the tail, that make it easy to distinguish. But our volunteers sometimes have trouble...
Chris - Assuming that your volunteers were diligent and they weren't too easily confused, what did you find?
Arielle - So we found, rather surprisingly, that the diversity - so the number of species that we were getting on our cameras - was not significantly different between the suburban areas and the wild areas. And, in fact, in Raleigh the diversity was significantly higher in the suburban areas compared to the wild areas. We did have some exceptions: for example, we only found beaver in the suburban areas and we never actually detected it in the wild areas; and we never got bears in the suburban areas!
Chris - I guess that's a bit of a relief in some respects isn't it!?
Arielle - I think it is at the same time we know that bears actually can do quite well in suburban areas. The tricky thing is making sure they stay wild. So especially not letting them get into trashcans and allowing them to maintain their distance even if they're living close to us.
Chris - Does one take away from this then that, contrary to the prevailing view that these urban environments are really bad for wildlife, in fact the opposite is true?
Arielle - Yeah, I think in terms of these mammals - and it is important to say that these mammals that we were sampling with our cameras are mammals that are chipmunk-sized and up, so there are a number of mammal species that this wouldn't apply to - but certainly in these two cities it seems as if this idea of ecological function being different between suburban and wild areas, at least as it applies to the mammalian community, is maybe not the case but there have been a number of studies on other taxa showing that urban areas and suburban areas do have quite drastic negative effects and so we want to be very cautious about extending this, you know, to other taxa in other cities even.
Chris - So what about other cities? Because, obviously, you've looked at just two; you looked at a lot of animals in a big area admittedly, but it is just two zones isn't it? So what would happen do you think if you went elsewhere, both in the US and maybe even further worldwide.
Arielle - Yeah. And that's something that we're very very interested in doing. We're really interested in looking at cities that have an impact apex predator. In the east, in these cities, of course there were once mountain lions and wolves - they are here no longer. But there are cities in the United States where the foxes the raccoons et cetera still persist in the presence of an apex predator like a mountain lion or a wolf. And we would expect then perhaps the dynamics to be a little bit different. And then the other thing, kind of thinking about cities around the world, of course cities in different parts of the world - and Europe for example - tend to be more concentrated less sprawling. The separation between urban and suburban and wild tends to be very stark. Whereas here there's quite a lot of sprawl. And so we would then expect it to be more difficult for animals to go in those small concentrated European cities from the wild straight into the suburban areas. But it's something that we're very interested in and looking into further, and we actually have some partners in Germany right now that are just beginning a replication of this study.
06:49 - Climate Change and Disease Spread
Climate Change and Disease Spread
Marta Shocket, Stanford University
Now speaking of urban dwelling, most of the world’s big cities are sited in places where the conditions are ideal for human habitation. And, often, our ancestors chose those locations for their settlements to avoid diseases: for instance, they avoided swamps so they wouldn’t be plagued by mosquitoes. But, with climate change, in the future some of these urban venues may become much more propitious for mosquitoes and the diseases they vector than they are at the moment. So is there a way to tell which ones? As she explains to Chris Smith, Marta Shocket hit upon the idea of using Australia as a giant petri dish to find out: the country’s so big that it exhibits a broad temperature range across the continent, and the use of a single healthcare system means there’s excellent data on at least one mosquito-borne disease: Ross River virus. So she’s been able to model accurately how temperature affects mosquito behaviour and disease transmission...
Marta - My lab was really interested in trying to figure out how temperature affects the spread of infectious diseases and specifically infectious diseases that are spread by mosquitoes. We know that climate change is going to be changing the temperatures that we observe and not just what those temperatures are but when they occur in the year. And we know that temperature has a really big impact on the way that mosquito bodies work.
Chris - So basically what you're saying is if climate change changes the temperature, the temperature changes the behaviour of potential vectors like mosquitoes, and that means that the dynamics of how diseases may spread will be secondarily affected?
Marta - Yes exactly. And it's not even just behaviour in the way that we typically think about it like where they go in and how far they fly, but every aspect of how their body functions: how long they live, how many eggs they lay, how quickly they turn from eggs into adults, how good their body is at transmitting the virus - because the disease has to get from their stomach to their salivary glands and so that process depends really sensitively on temperature.
Chris - So given that, how can you make predictions about what impacts climate change is likely to have on things like emerging infectious diseases and the distribution of the diseases we already do have?
Marta - One way that you can do that is by building a model. And so, by model we basically just mean an equation that lets us turn body functions - things like lifespan, egg production, how good you are at transmitting the disease - into an overall prediction for disease spread. And so we can take lab experiment data where people actually take mosquitoes and put them in incubators at different temperatures and measure how all of those processes are affected by temperature, and then we can come up with an overall equation for how we think temperature affects the spread of disease.
Chris - That tells you what your model thinks is going to happen, but how do you validate it?
Marta - So that's a great question. So in order to test this model we basically need to take human cases for different diseases and say "how much do these current cases of diseases match what we would predict based just on the model?"
Chirs - So what disease did you actually look at?
Marta - So for this study we were looking at a disease called Ross River virus. It's the most common mosquito-borne disease in Australia. The reason why we were so interested in Ross River virus is that Australia is basically perfect to study how temperature affects mosquito-borne disease because Australia is a huge continent that stretches from very tropical areas in the north to much cooler areas in the south. But throughout that entire range there is a single case reporting system. So we have a really good dataset for both the human cases, weather data and, in some cases, even mosquito data. We can use all of those pieces to try and test our model that was based just on data from lab experiments.
Chris - Right. So, because you've got this broad range of different temperatures across the continent, and you can see how in the present situation that temperature and the seasonal data alters the behaviour of the mosquitoes, you can then use that to say "well, if climate change causes areas to become warmer or colder accordingly, we would anticipate that we'll see what currently happens in that geography happening in this new geography, and therefore this is what the likely outcomes will be"...?
Marta - Exactly. And actually one of our main conclusions is that we expect to see different impacts of temperature increases in the different regions. So it turns out that there's a best temperature for the spread of mosquito-borne diseases, and it tends to be kind of a middle-intermediate temperature. So areas that are already really warm, and maybe like right at the best temperature, when they get warmer we'll actually see that disease transmission will probably decrease, because it will become too warm. Unfortunately, most people in Australia currently live in the southern parts of the country, which is right now below that best temperature. And so, in general, we probably will expect to see more cases of Ross River virus due to climate change...
12:35 - Devil Facial Tumour Disease 2
Devil Facial Tumour Disease 2
Hannah Siddle, University of Southhampton
In recent years we’ve realised that some cancers can spread - not just around the body but - between individuals. And a very striking example of this is Devil Facial Tumour Disease that’s wiping out the Tasmanian Devil. We think that when these animals fight, cancerous tissue from one can be injected into another by a bite. There it takes root and grows, using an immune trick to prevent it being “rejected” by its new host. Recently, scientists discovered new form of Devil Facial Tumour Disease - DFT2 - distinct from the first one. This hasn’t evolved to hide from the immune system yet, but it if evolves to do that, it could be curtains for the species. Speaking with Chris Smith, Hannah Siddle is studying these diseases at the University of Southampton…
Hannah - Not many people know that some cancers can become transmissible. And what we've been interested in is two transmissible tumours that have occurred in the Tasmanian Devil, which is a marsupial species endemic to the island of Tasmania. And in the mid 1990s a really nasty transmissible tumour emerged called Devil Facial Tumour 1, or DFT-1 and it's had a really negative impact on the population. So, in some areas, 90 per cent of the Devils have actually died. But our most recent work is actually on a more recently emerged contagious cancer in the Tasmanian devil. So this is a species where lightning has kind of struck twice if you like!
Chris - How does the cancer spread from one Tasmanian devil to another?
Hannah - We think that this is actually occurs by biting. Now, this new transmissible tumour DFT-2, which emerged only quite recently, also looks a lot like DFT-1. And actually if you looked at these two tumours, even though they're completely different diseases, they look really similar. So they still cause these huge tumours around the faces of the animals. So with DFT-2, we haven't shown this experimentally but we think that they're also passed by biting.
Chris - It was a number of years ago that Anne-Marie Pearse put some cells from the first of these types of tumours under a microscope and she showed that they had to be clonal: it was exactly the same genetics in each of them. So how did this second type of tumour emerge and how do you know that that's history repeating itself, or as you put it, lightning striking twice?
Hannah - Yeah that's a really good question because actually I mean what you'd kind of assume is that this new tumor would be somehow related to the first tumour, right? That would that would feel more obvious I think, because of how rare these are. But actually, when people first discovered this second tumour and it looked exactly the same, they found that it expressed some proteins on the cell surface of the tumour cells that were different to DFT-1. And then, looking a little bit deeper at the genetics, they found that actually the karyotype or the chromosomes of this new tumor were really different to DFT-1, the first tumour, and then going even deeper and looking at some of the specific genetic markers they were different as well, and they were also different to the host animals. So, from this it's really clear that this new tumour actually emerged in a completely independent animal - so a completely different animal - that came from a different part of Tasmania and lived much more recently.
Chris - One of the first things that you published on this was the discovery as to why, when you put foreign tissue from one of these animals into another animal, the immune system doesn't recognise it and get rid of it. Why is that?
Hannah - Yeah. So initially when we were looking at this disease in Tasmanian devils, there was... we thought that it was just because they had low genetic diversity, and that's why we could have these cells grafting if you like as a graft between them because we know in humans and mice that you can't just take skin cells skin or a kidney and transplant it to someone else it just doesn't work. The immune system sees it and it rejects it. And what we were able to show with the first tumour is that the tumour cells have down-regulated or lost really important molecules from the cell surface which are called MHC Class 1 molecules; and the tumour has cleverly lost these to make it invisible to a certain subset of immune cells are called T cells. And so that's how DFT-1 really probably became so dangerous and managed to kill so many devils.
Chris - It flies under the immune radar?
Hannah - Yes that's right. Yes.
Chris - Does the second type that you're now describing pull the same stunt?
Hannah - Yes. So that's... that's what we were asking the question in this paper. And as so often happens in science you start out answering one question and actually you end up answering something different. But we did manage to answer that first question and to our surprise, the second tumour DFT-2 still expressed MHC Class 1. So how is it possibly moving between individuals? And I don't think in this paper that with being able to conclude this 100 per cent. But what we've proposed based on our results is that actually the tumour and the host animals that are within that population actually share a lot of their MHC Class 1 molecules. So in the human population you have so much - what we call - diversity, genetic diversity in these molecules that you can't do transplants. But we think that perhaps this tumour has kind of stayed at the moment within its like favourite animals that have very similar MHC molecules to what it has.
Chris - it's sort of showing us how DFT-1 could have evolved in the first place it could have started out a bit like this and then evolved to have this this down-regulation of the immune response. This one is now doing the same thing?
Hannah - Yes. And if that's right we're really concerned about how quickly the new tumour could spread, because if the fact that it has expressed MHC Class 1 has kind of held it back or kept it in it in a constrained population, if it loses MHC Class 1 presumably those constraints are off and it could really spread and transmit much more easily. And from what we know at the moment it seems as if it is just as aggressive - in terms of killing the animals - as DFT-1. And unfortunately though we have far fewer devils; they have less genetic diversity than they did 20 years ago before they got in any of these diseases. So we have a much more vulnerable species.
Chris - And looking on the bright side, does what you've discovered shed any light on how we might better stop this thing?
Hannah - Hmm. Yeah that's kind of the million dollar question isn't it? And I wish I had a better answer to that. One thing that my lab is working on is trying to design better vaccine strategies against this. And you know that is a pretty tall order, but we have had some success against DFT-1 that still needs more work but that does look as if it's promising. And I think, at the moment though, it's really getting a better understanding of these tumours because if you think about it if we didn't even know that these tumours were losing MHC Class 1 we might be quite complacent that this tumour was just going to stay confined to these animals. So really understanding - and I think that's a general lesson isn't it - the more we understand about how diseases and pathogens work then you know the more chance we have of being able to come up with ways of preventing them spreading further...
20:07 - The brain on LSD
The brain on LSD
Katrin Preller, University of Zurich
April the 19th, 1943, is a special day for some and commemorated as “bicycle day” - it’s the day that Albert Hoffman, a chemist working in the Sandoz pharmaceutical laboratories in Basel, took a dose of the LSD - lysergic acid diethylamide - that he’d developed in his laboratory. As he rode his bike home after swallowing the chemical, strange experiences began to unfold. Since then we’ve learned more about how this chemical affects the brain and now, thanks to a recent study by Katrin Preller at the University of Zurich - appropriately enough also Hoffman’s own alma mater, we know which chemical receptors seem to be responsible for many of the effects of LSD in the human brain. She tells Chris Smith what they've found...
Katrin - We had healthy participants in the MRI scanner and they underwent three drug conditions. The first condition is just a placebo condition. The second condition was participants received 100 microgram of LSD; and the third condition was a condition where participants received ketanserin, which blocks a very specific receptor in the brain which is called the serotonin 5HT2a receptor. And after that we gave them the LSD to find out which effects that LSD induces are dependent on this particular receptor.
Chris - And who were the participants? What can you tell us about them in terms of what you knew about them when they embarked on the study?
Katrin - Participants were 20 to 40 years old. They were all healthy. Most of them were students or interested people.
Chris - And had any of them used LSD recreationally, or did you not ask that?
Katrin - Oh yes, we did ask them; about half of them didn't have any prior experience. The other half did have prior experience but none of them were regular users of psychedelics or any other substances.
Chris - What sorts of experiences did the participants say they got when they took the drug?
Katrin - First of all, what people notice is a visual alteration. They see the floor moving; they see colours changing; things might appear brighter. People feel kind of disembodiment; boundaries between yourself and the environment tend to dissolve, as well as feeling more connected to other people and to your environment. So, people tend call this "alterations in self experience".
Chris - When you then put them in the brain scanner, do any of the changes you see explain the experiences that the people describe?
Katrin - Absolutely. What we see is that there are certain areas in the brain which are dedicated to our sensory and sensorimotor experiences. Those areas are connected more strongly with each other. So they communicate more. And there are other areas in the brain which are dedicated to integrating these experiences and making decisions, planning and associations. And those brain areas they are collected less under the influence of LSD; and if you think about what LSD does, I think that makes a lot of sense. So sensory awareness is enhanced, but it can maybe not be integrated as well, which then leads to hallucinations and differences in self experience.
Chris - What about when you gave them the ketanserin - the blocker for the serotonin receptors, that you think might interrupt the LSD signal? Did that change their experience?
Katrin - Absolutely. And this was actually quite surprising for us, because LSD stimulates quite a lot of receptors, not only this particular one that we were blocking. And from animal studies we knew that more of the receptors that LSD stimulates are involved in the subjective effects. However, when we block this particular receptor using ketanserin, all the effects basically went away. They got normalised to placebo level so participants weren't able to distinguish between LSD plus ketanserin and the placebo condition. That means that the serotonin 2a receptor is crucial for the effects of LSD; and also when we looked at our fMRI data, all the effects that LSD was having on brain connectivity were basically gone. There was no difference anymore between the ketanserin plus LSD and the placebo condition.
Chris - Given what you've learned from this study, what are the implications of this and might there even be therapeutic implications?
Katrin - Yes. We know that LSD induces effects similar to some of the symptoms we see in schizophrenia for example. So one of the ideas is that we could, for example, use the functional connectivity maps that we have seen here and compare them with the functional connectivity maps from patients and therefore find out who would be most likely to respond to a particular medication. The other one is as we see here, we see that the alterations in the functional connectivity that lead to these loosening of self boundaries, that might be something that is actually helpful in patients like depression who suffer from rumination and an increased self focus; and I think the alterations induced by LSD here might explain a mechanism why these psychedelics might work in a patient population.
25:35 - Gender Bias in Peer Review
Gender Bias in Peer Review
Jennifer Raymond, Stanford University
Here are the eLife Podcast we try to create audio abstracts of some of the most important papers carried by the journal in recent weeks. But in each episode we also try to shine the spotlight on some significant issues faced by practising scientists. One of those is the rigour of peer review, where new science is scrutinised by authorities in the field before it’s accepted for publication. But is it done fairly? In the spirit of transparency, eLife made available to one of its editors, Jennifer Raymond, details of every manuscript submitted to the journal since its launch. She told Chris Smith what she and her colleagues discovered when they analysed the data…
Jennifer - Well the fundamental question is whether journals when they review scientific papers are finding the best science or whether there are other factors biases that could be influencing the review process.
Chris - The journals used to decide which research to publish now would you say finding the best science of course journals don't go looking for publications is the other way round isn't it correct.
Jennifer - The processes authors submit a manuscript that they would like to have published in the journal and then the editors first make a preliminary decision. Is this work interesting enough or potentially interesting enough to send out to members of the scientific community for peer review and typically three reviewers will write comments about the paper send it back to the editors and a decision is rendered.
Chris - That sounds fair enough and in fact peer review is held up as the gold standard in how we should do things. So what's your beef with that.
Jennifer - The problem is that scientists are people and we know that people are influenced by all kinds of cognitive biases.
Chris - So can I paraphrase by saying Then I get your paper and I decide for whatever reason best known to me. I don't like you. So I'm actually going to scan your paper. I'm going to say it's really bad. It's lots of methodological flaws or whatever. And I'm going to say let's kill it. Let's not publish it.
Jennifer - Sure that can happen. What we found in this study is more that people tend to give kind of an advantage to people who share certain characteristics with themselves and those characteristics include gender and nationality.
Chris - That's quite a claim. So how did you actually do the study. Let's look at the method first and then we'll actually look at the results so talk us through how you approach this.
Jennifer - First of all we were very excited to get access to these data. Every manuscript ever submitted to the Journal is life since its inception. First of all we did but it has been done a number of times. Look at the differences in success rates of authors with different demographic characteristics of women versus men. People from the U.S. U.K. Germany China Japan.
Jennifer - So we asked what are the differences in success rates. But there could be differences in success rates that are not reflecting bias because it may be that papers coming from certain groups are just of better quality either because they've had certain advantages like access to research resources or time or encouragement or other kinds of things. So seeing differences in success rates doesn't mean there's bias and conversely equal success rates doesn't mean there's no bias because it could be that one group was actually better but had that equal success rate. So to try to get beyond that we looked at how successful men were when reviewed by all male reviewers versus reviewers of mixed gender and how successful they were when reviewed by reviewers from the U.S. versus other countries.
Chris - And just to be clear when you say success that's a paper get sent to the journal it passes muster and ends up in print. That's right. And what does that show when you feed these data through your sieve. What trends come out.
Jennifer - What we found is that the decision that the reviewers made about whether a paper should be published was not just influenced by the contents of the paper but it was influenced by the demographics by the gender and by the nationality of the authors and by the gender nationality of the reviewers male reviewers were more likely to accept a paper from a male author people from a given country were more likely to accept a paper from somebody from their own country.
Chris - So we call this homo Philly was it just that one way street was it just men favoring men or did women tend to give more benefit of the doubt to other women authors.
Jennifer - There was a suggestion that it may be the case that women also give the advantage to women but there were not enough cases of papers from women being reviewed by all female reviewer panels because women are highly underrepresented at every stage of science and in fact we found that they were underrepresented as reviewers too. And when I say underrepresented I don't just mean that not 50 percent. I mean compared to their compared to the number of women in the scientific community they were invited to review papers less often than their male colleagues.
Chris - It's about 30 percent isn't it if you look at the workforce about one in three scientists is female. Two in three a male. That's right. And that's going to inevitably be reflected. If you think about well that's the pool of expertise we've got to rely on. It's probably going to be reflected in editorial boards and review panels and referee ship as well.
Jennifer - It's worse than that. We see that women are less represented as reviewers than they are as authors so that the authors pool should be the same as the reviewer pool. And so we find that there's even less representation of women than we'd expect based on how many of them are submitting papers.
Chris - So you find that there's this a monthly effect. Men look after men women look after women. Does that apply regardless of who else is in the author list. So if you've got say a female first author but a male senior author Does that skew things or does it all ride on whether there's a woman's name there.
Jennifer - We did not find any effect of the gender of the first author. And it's really the senior author kind of the head of the research laboratory whose gender matters. And that makes sense because I think often the reviewers know the head of the lab but might not know who the graduate student or postdoctoral fellow is who's doing the research
Chris - Is one interpretation of that that if I work for a female senior author and I send my paper off - I'm male - I nonetheless might face a publication bias against me owing to the fact that I've got a boss who's a female?
Jennifer - That's true; it looks like papers coming from a given laboratory are influenced by the demographics of the senior author.
Chris - And these were statistically significant differences?
Jennifer - These were statistically significant differences, yes.
Chris - But, obviously, as a statistician knows, that could mean if you do a big enough study, which you did do a huge study it's thousands of papers, you can detect a very very tiny difference; so how big was the difference?
Jennifer - In practical terms what we saw was overall scripts submitted by female scientists were accepted at a rate of thirteen point six percent whereas fifteen point four percent of the manuscripts from male researchers were accepted. So you know some people have said well that's tiny. That's 2 percent. Why are we worrying about that. But if you think of it another way it means that the papers from the women are being accepted at only 88 percent. The rate of the men so there is kind of a 12 percent success gap there. And the effects are even bigger for some nationality effects. So for example papers from scientists submitting from China had success rate of only four point nine percent compared to twenty two point three percent for researchers from the US...