Frog toxicity, and what a year's schooling does to the brain
What is the impact of an extra year at school on the brain? Also, how poison dart frogs come by their toxins, using movies to track the developing infant nervous system, the insect-spread bacterial plant parasite that is a mastermind of matchmaking, and a new cancer tool to link disease with the best drugs. Chris Smith takes a look at some of the most powerful papers out this month in eLife...
In this episode
00:37 - Does an extra year in school change your brain?
Does an extra year in school change your brain?
Nick Judd & Rogier Kievit, Radboud University
In 1972 a pint of milk cost 6p, and a litre of petrol - leaded of course - was only 8p. Weren’t those the days! But in that same year, when Alice Cooper released the hit song Schools Out an important change occurred in the UK education system: the school leaving age was upped by a year, from 15 to 16. And this presents scientists with an opportunity: if education boosts brain power - which it arguably must - then what would we see if we compared the brains of broadly similar people who either did, or didn’t benefit from that extra year in school? That was what Nick Judd and Rogier Kievit, at Radboud University, wanted to know. Nick first…
Nick - We know that education is one of the largest positive impacts out there. It's a major contributor to socioeconomic disparity and it's correlated to almost every positive life outcome. So we were really interested in if it had effects on long -term structural changes in the brain. So we looked at around six different structural brain metrics, so how big your brain is, how thick your cortex is, the surface area of your cortex, also the volume, fractional isotropy, which is pretty much just how white matter diffuses in the brain. We pretty much took an approach to try to look at almost every structural property.
Chris - And Roger, what was your approach here? Where did you get the data from?
Roger - Yes, so we used a very large project from the UK called Biobank, which has hundreds of thousands of people in it. And we use the fact that in the UK there was a law change in the 70s where people were forced to go to school for an additional year. So before every child had to go to school for at least 15 years and after that for 16 years. So we could use that change in the law to compare children who were born just to one side of that cutoff. So we could use that data to look at their brains years later and compare the people who only differed in how long they had to go to school.
Chris - That's quite a considerable intervention, isn't it? An extra year of education. So if something, I suppose your rationale is if something's going to make a difference, this will be it?
Roger - Yes. So for years, people have used brain training games for sometimes minutes or hours in the hope that that would yield long lasting consequences. So we thought if you go to school for a whole additional year, we might stand a chance of seeing something in the brain even a few decades later.
Chris - And what do you find, Nick? Is there an impact of doing an extra year of school?
Nick - Yeah. So we didn't find an effect on any of our measures. So we also looked at different regions of the brain and we didn't find any effect on any structural brain measures. A key distinguishing part of our approach to prior research is this natural experimental approach, which allowed us to really isolate and tease apart education in itself from all the societal factors that might lead some people to receive more education than others.
Chris - You must have been a bit disappointed, Roger, when you got that result. You must think, well, actually, we were hoping we were going to show this dramatic difference. You saw nothing.
Roger - Well, we tried to be dispassionate and not be too disappointed. But we also thought it's interesting precisely because we do know that education does have long term benefits on your cognitive ability. So how well you can remember things or think about problems and on health. So we know that this educational intervention did have an impact in the same people we looked at, but we just weren't sure whether the impact would be in the brain in the long run. And the way we thought of it is maybe it might be like going to the gym that might bulk up your muscles for a few weeks or days or months. But maybe if you don't use the same muscles for a long time, then maybe 20, 30 years later, you don't see the same impact.
Chris - We've just seen a paper in Science Advances where a German study has looked longitudinally at a relatively small group of people, but they find people doing cognitively demanding jobs, which appear to stretch the participant, do appear to maintain their cognition for longer than people doing less demanding jobs. So do you think that the education just gives you access to the lifestyle that gives you the sorts of benefits, Nick, that you're saying accrues through education? Or is it something else that's going on here?
Nick - Just to clarify, the effect of education on IQ and other cognitive abilities is pretty well established with natural experimental designs. So it's really, we don't pick it up in the brain. But the beneficial effect of education on cognition is there.
Chris - Do you have a reason for why that might be, Roger? Can you speculate as to why it can have these profound effects, but it's not reflected in the brain? Are we just not looking hard enough? Or is the resolution of our imaging not good enough to pick up something that's probably a bit too subtle?
Roger - Yeah, so those are a few of the things we've been discussing. One thing we would have liked to go back in time and study people's brains right after they had the additional year of education, because that would be the best comparison to see right when the children spent an additional year in the schools, do we see effects on their brains at that moment? Because maybe there was an effect initially, and then it essentially faded out. And there's some ideas that your brain might have this short -term reorganization that is visible. And the way we think of it is like roadworks. There's a lot of noise and mess, but after a while it reconsolidates. We call that renormalization. Your brain goes back to normal and it's almost as if nothing ever happened. But those benefits for your brain are still there. They're just not there at the level we can pick up with an MRI. So the other possibility is that using a different scan or looking at functional activation that we might find these traces of the effect there. But given how much people use this exact MRI technique, we thought it was valuable to see, can we find these effects using this type of scanner?
Chris - The take home messages, what do you think is really the bottom line here then?
Roger - Well, the bottom line I think is that to understand how the brain develops, we have to study it developing. And that sounds a bit obvious, but for a long time we only had the techniques and the money and the resources to study one brain once. So you come in, you get scanned, but increasingly we're realizing to really tease apart this puzzle of how our brains develop and how they allow us to do all these wonderful things. We need to see how your brain changes over time. So more and more neuroscientists are scanning people, say, every year while their life unfolds. I think that's going to give us a lot more new insights over the next years and decades.
07:18 - How did frogs become toxic?
How did frogs become toxic?
Rebecca Tarvin, University of California, Berkeley
Although they were first documented scientifically in the late 1700s by the French biologist Georges Cuvier, brightly-coloured poison dart frogs were known for centuries before this by native South Americans who laced the tips of their blow darts with the animal’s toxic skin secretions; hence the name. But are the colourful frogs the only toxic ones in the family, as is widely believed, or are their duller-coloured brown cousins also capable of packing a chemical punch? That’s what Rebecca Tarvin, from the University of California at Berkeley, has been looking into…
Rebecca - We are very interested in understanding how frogs become toxic. Most people have focused on brightly colored frogs and finding out how toxic they are, but very little focus had been put on the brown frogs. So we actually didn't know how frogs transition from brown to brightly colored and from non -toxic to toxic.
Chris - Where do the frogs come by their toxins?
Rebecca - Poison frogs and other animals that have this trait, they get their toxins from what they eat. Things like mites and ants and occasional beetles or fly larva, things like that. And those arthropods have lots of different chemicals. Some of them you might call like a toxin bomb. Some of these mites are referred to that way. Ants also have a really broad diversity of compounds. Most of these toxins are not even studied. We don't actually know what the effect is on an animal and how toxic they are. They could just be distasteful, which is also useful to deter predators. You don't have to kill a predator to keep it from eating you.
Chris - I suppose there's a number of different problems to surmount then if the frogs want, in inverted commas, to do this. Because not only have they got to not die from the toxin themselves, they've got to be able to separate it from the useful things they do want to digest and then put it somewhere in their body. And then keep it there so that it's useful. That's a lot of evolutionary steps.
Rebecca - That's right. It's quite complicated. And actually we have very little understanding of how it happens aside from it does happen. So there's a couple of research groups, including my own, where we're really interested in trying to understand how exactly the toxin goes from even starting at the mouth or the stomach, how exactly it gets into the skin, because that's present in really high concentrations.
Chris - And what by studying the darker, uncolourful brown frogs and asking how are they different from the bright colourful ones, despite being very closely related, you're hoping that there'll be some of those mechanisms disclosed.
Rebecca - Yes, that's right. So if you want to understand the evolution of any sort of trait like this, you need to kind of be able to compare animals that have that trait with animals that don't. And so that's where these brown frogs come in. We didn't previously know if they actually lacked this trait because there's a sort of bias. People look in the wild and they see these brightly coloured animals and they think, hmm, I wonder if that species is toxic. So they go and they collect a sample and show whether or not it has toxins. But people, not surprisingly, aren't as curious about the brown ones. So there was a huge oversight in the literature about what these animals were doing.
Chris - And are the brown ones toxic?
Rebecca - They do seem to have alkaloids, which are the compounds we find in the colourful frogs, at levels that are clearly measurable. In some cases, I would think it has an effect on their predators. But in a lot of cases, they have quite low levels. So it's something that's detectable, but not necessarily toxic towards predators, although we actually don't know that.
Chris - These brown frogs then, they are a step towards becoming brightly coloured, highly poison colourful frogs, but not the whole hog. So have they got some of the right apparatus, but not all of it then to move down that evolutionary path?
Rebecca - That's what we think. So before our study, there was an assumption that the main difference driving whether or not a frog was toxic was what they were eating. And that's because we know that they get their toxins from their food, they actually can't synthesise any of these toxins. And so people assume that, well, these toxic frogs, they must be eating a different diet. And in our study, we show that actually, they eat a lot of the same arthropods, same mites and ants. And so it's not just diet that's driving this. There's something else different about the physiology of those accumulators, the sort of colourful species.
Chris - Apart from busting a myth that brown frogs are not taking on board some of these toxins and maintaining them, at least at a low level, what does this study add then? Where next with this?
Rebecca - The question we set out to answer was how do frogs accumulate toxins? And in order to do this, we have to understand not just the brightly coloured frogs that do accumulate toxins, but their close relatives that aren't as toxic or as colourful. And so what we're working on now is more direct tests of this, where we take a known quantity of an alkaloid and feed it to a colourful frog that we know sequesters it very well, and also feed it to a relative, a dull coloured frog that in the wild doesn't show as high of an ability to sequester the toxin. And then we can compare, you know, what happens to that toxin? Does it reach the skin? What quantity of the amount that we give them reaches the skin? And how does that differ? So we're starting to dig deeper into these mechanisms.
13:29 - Using movies to probe infant brain development
Using movies to probe infant brain development
Cameron Ellis, Stanford University
There’s an old adage, “never work with children or animals,” because it’s known to be notoriously difficult, especially when it comes to certain aspects of science and wanting to generate high quality data from repeated measurements. And that’s where kids can be particularly tricky. But Cameron Ellis, at Stanford University, has partly solved the problem, with the help of movies! He’s interested in how the developing human brain wires itself up and responds to different experiences and stimuli over the initial months of life. When it comes to the visual system, the current gold standard for doing this is to present various defined shapes and colours. But it can be hard to keep subjects still and motivated to remain engaged, which can marr the quality of the data. So can movies, designed as they are to be compelling and immersive, be used instead, he wondered...
Cameron – It's a real curiosity as to why we are born immature. If you look at horses, they can walk within a few minutes, maybe an hour after birth, whereas we take 9 to 12 months to learn how to walk. The same is true for our visual system. Although other animals might have a relatively mature visual system—meaning that the way in which they process visual input is similar in infancy to how it is in adulthood—that’s not the case in humans. Our visual system is really different.
Why it's different is a curious question to which we don’t fully know the answer, but one explanation is that to acquire the kind of expertise we use for processing the visual world in adulthood, it can’t all be genetically pre-programmed. Instead, some of that has to happen through learning during our lifetime. We need to learn how to see the world, and that's part of what happens in that first year of life.
Chris – Are you suggesting there's a rough map there—that things seem to be wired up roughly right—but what we need is the icing on the cake, the finessing of that system, in order to develop the amazing visual system that humans have when they're older?
Cameron – Yes, so when we started this work about five years ago, we didn’t know whether the macrostructure or the general organisation of the visual system in infants was in place. When we found that it was, that was very surprising. In general, the large-scale organisation present in parts of the visual processing system is very similar between infants and adults.
But despite that similarity in the big-picture structure, we still think that over the course of development, there are many changes in the finer details—perfecting the fine-grained aspects.
Chris – So what does using movies bring to the table in this context?
Cameron – Movies are an amazing stimulus for showing to infants and other populations, such as patients who might otherwise be uncomfortable in the neuroimaging environments we use to measure brain activity. The reason is that movies are naturally engaging. When you use a highly engaging stimulus, you're more likely to get better quality data. This is something we’ve seen in our own data—infants show more attention and move less when watching movies.
So in one sense, it’s a data quality issue—we want to see how good the data can be when using movies. But there’s another reason as well: it’s useful to observe how the brain responds to more naturalistic stimuli. While not entirely natural—they are still directed and edited—movies resemble everyday experiences more closely than artificial lab stimuli. Yet, they still evoke brain activity similar to what we see in more controlled experiments where we show specific shapes with precise timing.
Chris – And do your results align when you show movies compared to when you've done more controlled experiments with artificial stimuli like shapes? Do you get broadly the same outcomes?
Cameron – When we use these well-controlled stimuli like colourful shapes, those methods are considered the gold standard for identifying visual organisation in both adult and infant brains. But with movies, we can get rough approximations of those same maps by measuring brain responses. That tells us that the way in which the infant brain processes movies mirrors the structure we would expect to see using those precisely controlled experimental stimuli.
Chris – That must give you confidence to push forward. But also, because you can vary what's in the movie, you can more easily adapt the stimulus, probe different things, and repeat experiments—especially since the children are engaged and actually want to watch the film.
Cameron – Exactly. Beyond proving that movies are a good way of evoking brain responses in less controlled environments, it's also evidence that they are a powerful tool we should be using in a variety of contexts for studying the infant brain. For example, you can use movies to examine how infant brains respond to different languages or to test their understanding of social events and interactions.
You can even study how infants reason about others’ minds. We believe this is a strong case for making movies a central part of the experimentalist’s toolkit for researching the infant mind.
Chris – So what will you go on to explore next using movies, now that you've got the confidence to rely on them?
Cameron – One exciting current direction is using movies to study infants’ brain responses to language. In one experiment, we’re comparing responses to familiar languages—like English for English-speaking infants—against unfamiliar ones like Japanese. We want to see how the brain differs when processing a familiar versus an unfamiliar language.
Another line of research, made possible by this paper, is comparing directly how infant and adult brains process the same movie. That lets us ask: what makes infant brains unique? How do their experiences differ from those of adults?
20:41 - Plant parasite matchmakers
Plant parasite matchmakers
Zigmunds Orlovskis, Latvian Biomedical Research Study Centre
Next comes a tale of deception, seduction and sexual exploitation, all by a parasitic bacterium called phytoplasma. This infects plants, into which it secretes a protein called SAP54. This turns flowers into leaves, making the plant a better food source for leaf-hopper insects, which spread the bacteria when they come to feed. But, even more incredibly, it also makes the plant even more attractive to females, if there are males present, further reinforcing the population of vectors to spread the infection! As Zigmunds Orlovskis, who’s from the Latvian Biomedical Research and Study Centre and unpicked all this, puts it, it’s effectively operating like a molecular matchmaker…
Zigmunds – Phytoplasmas are parasitic bacteria that infect plants. They are transmitted by insects—so when an insect feeds on a plant, it picks up the bacterium and transmits it to another plant. It's very similar to how malaria is transmitted by mosquitoes.
One of the things this bacterium does is change plant development—specifically, it turns flowers into leaf-like structures. You might wonder why it does that. One hypothesis we had was that these manipulated, leaf-like structures might be more attractive to the insect vectors. So we tested that, and it turned out that those structures aren’t necessary for the increased insect attraction.
Chris – If the plant no longer produces flowers and only makes more leaves, does that render it sterile? And is it possible the bacterium does this just to make the plant grow itself to death—producing loads of tissue for the parasites to feed on?
Zigmunds – Yes, that’s an obvious question—and it puzzled us too. The plant does indeed become sterile and can no longer reproduce. So then, why would the parasite do that—why kill its own host—unless it helps facilitate its own spread before the plant senesces and dies?
Chris – Do you think that’s what’s happening—that the bacterium makes the plant sterile so it becomes a bacterial factory, feeding more insect vectors and ensuring wider spread?
Zigmunds – Yes, that’s one potential explanation.
Chris – And have you figured out how it’s doing that? Do you know what signal the bacteria release that causes the plant to behave this way?
Zigmunds – The bacterium secretes a specific protein into the plant. This protein not only alters floral biology but also affects the leaves, making the plant more attractive to the insect vectors. It does this in a peculiar way—it mainly biases female insects towards plants producing this bacterial protein, compared to those that don’t.
Chris – The protein itself—perhaps you could tell us its name in a moment—but to summarise: the bacterium makes a protein that alters plant development and makes it more appealing to female insect vectors, helping spread the infection?
Zigmunds – Yes. Curiously, the bacterium also requires the plant to be exposed to male insects and for the protein to be present, in order for the host to become more attractive to females for reproduction.
Chris – It's incredible how intertwined it is—it’s integrating all these signals. But how does the bacterium know male insects are present?
Zigmunds – Male and female insects produce different elicitors, and the plant mounts different responses to each. Both feed on the plant, but only females lay eggs. It’s likely that the egg-laying stimulus creates additional responses that males don’t. When we compare male- and female-exposed plants that produce the SAP-54 protein, we find that male exposure is required for those plants to be more attractive to females.
Chris – How did this evolve in the first place? It’s such a complex system—a bacterial parasite secreting an effector that manipulates plant and insect behaviours in very precise ways. It’s almost unbelievable.
Zigmunds – It is a remarkable adaptation. Work from other labs, including Philippe Raymond’s group in Switzerland, has shown that insect eggs contain elicitors in their shells that trigger plant responses similar to bacterial infections. Plants have evolved to detect and react to these natural stimuli. This bacterium appears to hijack the insect sex-specific responses to manipulate plants for its own spread.
Chris – And it’s also manipulating the insects by luring in mates. It's like a dating app for vectors, drawing them in when there's most to gain from them mating.
Zigmunds – Yes, that’s why we think of this system as a kind of molecular matchmaker—making male-exposed plants more attractive to females. It’s a fascinating phenomenon.
27:19 - What is the right cancer drug for me?
What is the right cancer drug for me?
Marieke Kuijjer, University of Oslo
Cancer is a genetic disease. And different cancers are driven by different constellations of genetic changes. And if we read those changes, in some cases we can make predictions about the likely aggressiveness of a tumour, and which treatments might produce the best responses. A good example is breast cancer, where some tumours express oestrogen receptors that promote growth but are also an opportunity for intervention. Now, with her system called “Retriever”, the University of Oslo’s Marieke Kuijjer, is trying to go a step further. By picking apart a patient’s cancer, cell by cell, and reading the patterns of gene expression being displayed, and then comparing those patterns to similar profiles obtained from lab-grown cancer cell lines with know responses to drugs, it’s possible to make highly accurate predictions about what treatments are the best fit for the individual’s disease. It’s a further step towards true “personalised medicine”...
Marieke – We developed a computational tool called Retriever. It works by starting with a tumour sample and examining what’s happening in each individual cancer cell. This allows us to see which genes are active or inactive. We then compare those profiles to a large database of cancer cell lines that have been tested with various drugs.
The idea is that we can match tumour profiles—especially those reliant on certain survival pathways—with drugs that disrupt those pathways. Essentially, we’re trying to detect what makes the cancer aggressive.
Chris – So you’re saying someone has already tested various cell types with different drugs, and you're using that data to find the best drug combinations for an individual’s cancer?
Marieke – Exactly.
Chris – But how do you know those drug combinations will work together, especially if they’ve only been tested in isolation?
Marieke – We used computational inference—computer models—to predict whether two drugs might work well together. Then, we tested those predictions in the lab using cell lines. In two out of three cell lines we tested, the drug combinations effectively killed the cancer cells.
Chris – So it seems promising. When tested against real samples, you’ve found good drug combinations tailored to specific cancers.
Marieke – Yes, that’s correct.
Chris – Have you tried this in real patients yet?
Marieke – Not yet, but that’s definitely the next step.
Chris – Real tumours are heterogeneous—lots of cell types and mutations. Is that a limitation? You might be targeting one bit of the tumour while missing others.
Marieke – That’s partly true. We do use actual tumour samples, and the data we analyse are single-cell data. That means we can look at individual cells and identify the aggressive ones. We can then target the cancer cells specifically, which are the real threat.
But yes, we’re basing our method on lab-grown cell lines, so there's a gap when applying it to real tumours. The tumour microenvironment—including immune cells—might also affect whether the drugs work.
Chris – Can this be applied to other types of tumours?
Marieke – Absolutely. The database we use includes information on around 13 different tumour types. The method can be applied to other cancers, particularly well-studied ones like breast, prostate, and skin cancer. But for rarer cancers, we may not yet have enough data.
Chris – What you’re describing is the dream of personalised medicine—tailoring treatment to each patient. Critics say it’s too expensive to be realistic. Could this be scaled to something like the NHS?
Marieke - I think it’s possible, with adjustments. Our study used single-cell data, but there's also a method called bulk sequencing that could work with our tool. It’s less specific but still gives a general idea of active pathways. That could potentially be used in healthcare settings within the next five years.
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