New part of the immune system, and greedier labradors
In the news pod, scientists in Israel discover a new part of the immune system. We’ll find out why it matters. Also, the Blue Ghost mission that just landed on the Moon and could change the way we conduct Lunar exploration. And greedy labradors: we find out why dogs (and their owners) are prone to putting on weight.
In this episode
01:04 - New part of the immune system discovered
New part of the immune system discovered
Daniel Davis, Imperial College London
Scientists in Israel have discovered a new part of the immune system we’d previously overlooked, and they say it may be a goldmine of potential future antibiotics. They’ve been looking at a recycling system present in all of our cells called the proteasome. This normally chews up proteins so they can be reused, and also displays a selection of the fragments on the cell surface to enable passing immune cells to spot when something is amiss; for instance, a viral infection will produce unusual proteins that shouldn’t be there, and this triggers and attack. That much we knew. But now researchers have discovered that when a cell detects danger, the proteasome can also weaponise some of the materials it’s recycling, producing protein molecules that can punch holes in bacteria. We asked Daniel Davis, an immunologist at Imperial College London and author of Self Defence: A Myth-busting Guide to Immune Health, to take us through the new study…
Daniel - This study is very exciting because it seems to have revealed a hidden part of how our immune system works. We already knew that the immune system was incredibly complicated and yet still we can discover entirely new aspects of how our body is able to fight off a bacterial infection. What this team from Israel discovered is a machinery, that we already knew was operational in nearly all the cells of our body, has this specific task of being able to directly fight off bacterial infections which is different to what we already knew that type of machine does in the body.
Chris - Well let's, before we explore how it fights infection, explore what we knew about this already. Where is this entity and what's its normal job?
Daniel - This research relates to a sort of molecular machine inside all your cells called the proteasome and what this molecular machine does is it chops up into small pieces the protein molecules inside a cell. So all the protein molecules that a cell is currently using gets chopped up into small pieces continuously by this little molecular machine and one very important way in which we already knew that the immune system works is that these small pieces of protein molecule from inside your cells are put up for display at the surface of the cells for the immune system to look at. That way, if your immune system sees something that has never been in your body before then it knows that there's some foreign intruder lurking inside your cells making some alien kinds of protein molecules. So this reporting process is exactly what we already knew this machinery does, but what's really exciting now is it seems that as well as just producing small pieces of protein molecule to report the presence of some kind of infection, some of those small bits of protein molecule can be used to directly attack a bacterial infection.
Chris - Is this like turning ploughshares into swords? It's sort of the reverse of the analogy. You're taking things you just have at your disposal and you're crafting weapons out of them?
Daniel - Yes that's not a bad analogy. You are creating from the protein molecules that a cell normally makes weaponry, if you like, pieces of protein that can then directly kill off bacteria. What actually happens in detail is that these small bits of protein insert themselves into that outer part of a bacteria and essentially perforate it.
Chris - How does the cell that makes these things then avoid effectively detonating the bomb in its own hands and blowing itself up in the process, or does it? Is this a suicide mission?
Daniel - Yes, so these particular types of small pieces of protein do tend to insert themselves into bacterial cell walls with some specificity and destroy the bacteria, but that does lead us to a nuance that they're not necessarily, or at least it’s not clear how they would target a particularly dangerous type of bacteria as opposed to, for example, there are lots of bacteria that naturally live in our gut or on our skin or elsewhere in the body that are not dangerous and in fact sometimes do our body some good, so there has to be other processes involved.
Chris - Have the Israeli team unpicked the mechanism behind what makes this happen? how does the cell sense the bacteria and then switch on this response? Has that been disclosed?
Daniel - Yes, so there is a shift in the way in which this molecular machine, the proteasome, is able to chop up pieces of protein so that it does tend to produce more of the weaponry that can attack bacteria in the presence of a bacterial infection. But exactly how it does that, or how important it is, or how it gets triggered isn't entirely understood yet. All of these kinds of details remain to be worked out in time.
Chris - Presumably, there are loads of avenues now to follow from this because can we for instance use these things as a clue towards how we could make our own molecules like this to attack bacteria? And is there another sort of approach which is to say, well, if we can work out how to turn this on, we turn it on with drugs and make the response against any infection that bit harsher so we tip the balance in the body's favour?
Daniel - Yes, all of these things would be possible and yet are untested. It seems like we might find some way to enhance this naturally occurring process to help our bodies deal with bacterial infections, or we might be able to use the products themselves as some kind of medicine given that there's this rise in antimicrobial resistance in the world. Any new way by which bacteria can be targeted is very welcome news indeed, but having said that there's a great biological discovery here and there is still a long way to go in the experiments. They did test in animals whether these weapons could be used to treat a bacterial infection, and that did work, but there's still a long, long way to go to work out whether or not this could lead directly to a new medical intervention.
07:37 - Maths and reading delay cognitive decline
Maths and reading delay cognitive decline
Barbara Sahakian, University of Cambridge
More great new research now, which has found that people who use maths or reading skills regularly do not experience age-driven decline in cognitive skills. Previously, we thought we were all intellectually going downhill from about 40. But this was based on comparing different groups of people at different ages, which may have been misleading. The new study has followed the same cohort of people but over a period of time, and it suggests that it’s a case of use it, or lose it: cognitively stretch yourself and you’ll maintain your brain power into older age. The findings are published in Science Advances, and Barbara Sahakian - a professor of clinical neuropsychology at the University of Cambridge - came to meet Chris Smith at Queens’ College to take me through what the results appear to show…
Barbara - Basically, what it's trying to look at is the idea that if you stay challenged in your workplace and if you start off with a good education, you will not cognitively decline as fast as other people in terms of your maths ability, and also in terms of your literacy.
Chris - What were our prevailing thoughts in that direction? Because I've seen mixed opinions about this. Some people saying, “You do the Telegraph cryptic crossword every day and this keeps you mentally agile.” Other people turn around and say, “You do that crossword because you can and it's a sort of selection bias.” What is the thinking? Do brain games keep us fitter, did we think, or did we just not believe that was true?
Barbara - It has to be something challenging driving the circuitry in the brain and that really has to do with learning new things, so if you're doing something that's simple for you, like a daily crossword that maybe you're very familiar with and you don't challenge yourself by going to more difficult levels, it really won't help you in that way.
Chris - Are you of the opinion though, before we come on to what this new paper has done and found, that doing that kind of ‘keep my brain active’ keeps me in a better cognitive state? Are you of the mindset that that is true or do you think that that's a bit of an old wives tale?
Barbara - No, it's absolutely true, there's plenty of evidence to show that if you do keep yourself cognitively active you will have a better cognitive outcome and you're less likely to decline with ageing.
Chris - What did this new paper add then? What have they done?
Barbara - Well, part of what they've done which is very interesting is, a lot of our data has been cross-sectional and here they've taken a longitudinal approach, so they've actually looked at the same people over time and that helps a lot. The sample size was not that large; it was about 2,500 people, and also the tests they used were quite challenging within the workplace, interesting tests of mathematics and literacy.
Chris - When you say ‘cross-sectional’ versus ‘longitudinal’, so in other words, rather than take one group of people of a certain age, compare them with another group of people of a certain age, and then see who's got the best cognitive function, you're saying we take one big group of people and they just followed them up over time?
Barbara - That's it and that way you get more accurate data on what's happening.
Chris - Who were the people that were being followed and how did that affect - if it did - the outcomes?
Barbara - Well, they came from a German sample but the ones that they were specifically interested in because they wanted measures of how they were using these skills within their workplace were all employed so that's also quite an interesting feature because a lot of the studies that have looked at use it or lose it or keeping cognitively active have been with older age people say 60 or above so this is interesting because they were looking at people who were being employed.
Chris - Can we generalise then, or can you give us some sort of overview findings from the paper? What age do things continue to get better until and then what happens? Because I've been brainwashed into thinking that once you go beyond 40 it's all over. I'm now beyond 50. Is it all over or am I still in good shape?
Barbara - Well, in this study the key points seem to be, early 40s and mid-40s for the literacy and mathematics.
Chris - What? That you peak?
Barbara - Yeah where you start to decline.
Chris - Oh dear.
Barbara - But actually with psychomotor slowing and other functions it could be earlier. There's lots of evidence that it’s your 20s and 30s when you're at your peak for most different kinds of cognitive functions, and then you start to decline. But in this group, especially in the high functioning group, which were in white-collar jobs and had a good level of education, they stayed functioning better for longer in terms of literacy and mathematics. But what I would say is that experience counts for a lot. Experience is basically pattern recognition. When you are in your workplace and you suddenly have to contend with a problem, you might think this problem looks very similar to one I've done before and when I did this it actually was a good solution to this problem, so I'll try it again. Or you might be able to anticipate, if you're in some kind of a white-collar job or some other job, anticipate that this could be a problem if this happens, so I'm going to make sure we avoid this happening so that we don't have any problems. That's experience. Within the workplace experience actually counts for a lot as well.
Chris - In summary then you're saying that although our abilities might peak in our mid-40s, if we give ourselves a good cognitive workout regularly the slope down thereafter doesn't have to be a steep one. It can be preserved for much longer.
Barbara - Absolutely. So the idea is you just keep challenging yourself cognitively and you will have a better outcome in terms of ageing and your cognitive function. The other thing is that cognitive reserve, which is kind of a combination of your intelligence level and your education level, if you keep learning throughout life what you find is that if anything does happen to you, if you're unlucky and you have a traumatic brain injury or if you develop a neurodegenerative condition like Alzheimer's disease, you will actually have a better outcome than most people. It's less likely to impact you in a negative way.
14:42 - Blue Ghost spacecraft successfully lands on the Moon
Blue Ghost spacecraft successfully lands on the Moon
Richard Hollingham
A private spacecraft called Blue Ghost has successfully landed on the Moon. It is just the second commercial vehicle to reach the lunar surface. Richard Hollingham from the excellent Space Boffins podcast has the story…
Richard - Blue Ghost is by Firefly Aerospace and it's landed on the Sea of Crises, which I love. It's a two metre by three and a half metre robotic spacecraft. I've been trying to find out the origins of this actually. They seem to have a lot of talk on the website of ghost riders in the sky. Seems to be all over Firefly Aerospace website and I do encourage you actually to look at the video of it landing because it is spectacular. You can see the dust being kicked off and there's this amazing ghost-like picture, this ghost-like image of its silhouette on the lunar surface. This is the second private landing on the Moon. There was a one around about a year ago from Intuitive Machines that didn't entirely go quite to plan. It sort of landed on the edge of a crater, sort of tipped over. This one seems to be pretty much perfectly landed. On board, it's got 10 instruments and it's part of a bigger programme. So, NASA's essentially commissioning spacecraft to deliver science to the lunar surface. This is one of 11 missions with a total of 50 instruments.
Chris - What sorts of things will it do with these instruments then? What's the game plan?
Richard- It's really to set the stage for further human exploration of the Moon. It's just this whole effort to just get back and exploring the Moon again. This spacecraft actually did some experiments on the way to the Moon. It monitored the Van Allen belts - these radiation belts - in deep space. It had a radiation tolerant computer system on board, which I quite liked. The other experiment I'm quite excited about - because I saw the prototype of it at the Kennedy Space Center in Florida - is the electromagnetic dust shield.
You know you have those kinds of electrostatic dusters at home which are really good at getting the dust off the TV. Well, this is kind of like the space age version of that because dust on the moon, it's really sharp, it's unpleasant, almost certainly will be doing damage to astronauts' lungs if they're there for any prolonged period. So, there's quite an effort to sort out the dust problem on the moon for future human exploration, for clearing dust off, for example, solar panels. And it just removes dust using electrostatics. So, the Moon is negatively charged. It's being bombarded by all these charged particles from the Sun all the time. And this is just like a little electrically charged balloon where you rub a balloon on your hair and it sort of sticks to your head. Same idea but more sophisticated.
Chris - But it's not a duster coming out on a little arm like Wallace and Gromit wiping. Or is it?
Richard - Well, this one is actually attached to the spacecraft, but that's a very good idea. The idea is this would be built into, for example, visors on faceplates for spacesuits that astronauts wear on the Moon. It could be windows if you're looking out of your lunar base to the lunar surface. What I saw when I went to NASA was this idea that you kind of walk in with your spacesuit and you stand in this sort of electrostatic shower, which basically attracts all the particles, all the dust off you, and then you can walk in. It’s a cleaning system. You come into your house, you stand in the electrostatic shower go: “bazoomp” - takes all the dust off, and then you can walk in it. If this works, this could be a bit of a game changer for human exploration and certainly the safety, the well-being, of astronauts on the Moon.
Chris - Does it make that exciting sound as well? I hope so.
Richard - Yeah, almost certainly.
Chris - But more seriously, are we at a sort of watershed moment with this sort of thing? Because we're now seeing a lot of people, countries, commercial entities as well, landing on the Moon. Does this mean technology has marked a step change? Has something changed that means this is now much more feasible than it was before? And if so, why?
Richard - I think we're picking up where we left off from the Apollo missions and the last footprint on the Moon in 1972 and it's just accelerated. It's using new technology. I think the investment of private industry in this is making a huge difference. It's driving down costs. There is, in the background, this kind of space race going on between the US and China. And we don't yet know the US plans for the Moon. It will almost certainly be led by the US. Whatever, Europe, Japan, Canada, decide whether they're going to go in with NASA or not.
NASA has yet to decide what its architecture is for returning humans to the Moon. And of course, we heard Donald Trump talking in his inauguration speech about going to Mars. The Moon might just be a stepping stone to Mars. But realistically, to get to Mars, we've got to understand all these ideas about how we live on a foreign world, if you like, or an alien world; an airless environment, we've got to be able to extract water. How do we live off the land in this dusty, airless desert? So, all these things, it's a lot easier to do on the Moon, which is only three days away from Earth, than it is to do on Mars.
So, that is the bigger picture here, is humans going hopefully in around about a year's time on this expedition out around the Moon. So not not landing on the Moon, but right out into deep space and back again to Earth, and then landing humans on the Moon. But we don't quite know how that's going to happen now, particularly with the Trump White House, what the plan is. Are they going to go with this giant rocket that NASA has built at an enormous cost? Or are they going to go with a much cheaper option like Elon Musk's Starship launcher and lander? So we don't quite know how things are going to pan out. But, there's an absolute drive to get experiments on the moon, get science on the Moon, find out more about the Moon, and ultimately get humans onto the Moon.
21:01 - What makes Labradors (and their owners) obese
What makes Labradors (and their owners) obese
Eleanor Raffan, University of Cambridge
Meanwhile here on Earth, researchers at the University of Cambridge have discovered a new clutch of genes linked to obesity in both labradors and potentially their owners, because we carry them too. These genetic factors drive greediness by tweaking the sensitivity of the brain to hunger signals. Thankfully, the effects can be overridden with a strict diet and exercise regime. Eleanor Raffan from the University of Cambridge met Chris Smith and his labradors to tell him about it…
Chris - The last time we met, you were introducing me to dogs that eat too much because of genetics. But what really is the overriding question this time?
Eleanor - Well, I'm still interested in overweight dogs, but we are ultimately interested in how our genes can control why some people overeat and gain weight. And if we do that via the medium of dogs, then it tells us something about veterinary medicine too.
Chris - So, dogs work the same way we do?
Eleanor: Very similarly. They're another large mammal with very similar genetics, actually.
Chris: How did you approach this then?
Eleanor - Well, we've done what's called a genome-wide association study. These days, we can test markers that are anchor points all the way along the genome. And we can test at each of those points whether one or other version of the genome is associated with obesity. And when we did that, it allows us to map where on our genetic code there is something associated with a trait. And in our case, to map down to particular genes which were associated with obesity in the Labrador population that we were looking at.
Chris - So, you look at a dog and you ask: this dog's fatter, this dog's thinner. Are there any differences in these different parts of the genome? Because if there are differences, genes in that region could be responsible.
Eleanor - That's a beautiful explanation.
Chris - We've got Labradors here. They're making noise and they're definitely greedy. Does that actually help then? Is that why you went for Labradors? Because they're notorious for tending to put on weight.
Eleanor - Yeah, it certainly meant that we thought we might find something interesting because they've got this reputation for being complete chowhounds.
Chris - So, how did you do the study? I mean, was this just domestic dogs, people like me, who would say, well, come and look at mine?
Eleanor - Yeah, exactly. We've got entirely pet dogs in our discovery study and we took slobber samples from them, spongy swabs, mopping up a little bit of saliva and you can get DNA. The thing that we were studying genetically was their tendency to put on weight. So, we just saw how overweight they were. There are ways to put numbers on how fat a dog are. We use something called a body condition score. And then we put a number on how greedy they are…
Chris - How did you measure that?
Eleanor - We developed a questionnaire a few years ago and it's quite simple actually. We've got 35 statements, things like, my dog will eat anything. My dog isn't fussy about food. And so we can put a number not only on how food motivated dogs are, but also on the extent to which owners control diet and exercise. So, what we did was the mapping study to test the genes with the condition score. So, first we said, what genes make a dog more prone to being overweight? And then when we could put a number on that - and combine all of them together as a risk score for obesity - then we said, well, if you're a high risk dog, why are you high risk? And we could use our greed score and see that actually the high risk dogs were at risk because they were more foodie. They were the kind of dogs who pester you for food at the table or always snaffle a scrap when they're out and about. They're the ones who will patiently wait even for something like a carrot when you're chopping vegetables. And they're the ones who are really just forever persisting in their pursuit of food.
Chris - Knowing a shopping list of genes that might be linked to overweightness is one thing, but actually the mechanism of how those genes translate into that, that's the key thing, isn't it? Because that tells us where the interventions might be. So, can you see possible ways in which these genes that you have linked to this behaviour, being overweight, are translating into that occurring?
Eleanor - Yeah, absolutely. What we were really struck by was that our top five genes also have links to human obesity. And our very top gene was called DENND1B. And that's the one that we pursued with studies in the lab. And we found that it acts as a dimmer switch to turn up or turn down a brain pathway, which is quite well studied actually about how the body regulates body weight. And by having probably slightly more of it or slightly less of it, it slightly turns up or down your hunger signalling.
Chris - And that's true in humans as well?
Eleanor - Yeah, the effect we got in dogs was quite big. If you are a dog that carries this risk variant, then you're about 8% fatter than others that don't. The effect in humans is really minute and they could only find it in these huge populations. But the fact that there is shared biology across the species meant that it was worth pursuing.
Chris - And is it not also the point that if you have just a small imbalance in energy terms, in what you need, in terms of what you're actually eating compared to what you really need, because we live a long time, you've got plenty of time to slowly accumulate weight. So, even if it's a small and subtle effect, it's still going to translate into quite a weight gain over a lifetime.
Eleanor - Exactly that. There's an astonishing statistic that if you eat seven calories more a day, it translates to something like 10 kilos extra when you reach middle age. It's only a very subtle imbalance that's needed to end up with quite a profound and health affecting weight gain.
Chris - Implications for clinical interventions then, off the back of this?
Eleanor - Well, our particular niche bit of biology to do with DENND1B is informative because it's acting in a pathway that is already a target of anti-obesity drugs. Not the most common ones that have been in the news recently, but others. And so that's important. We need to understand the nuances of these mechanisms in order to be able to develop drugs to target them. I think the wider implications actually from our study come from the fact that dogs are such a relatable model and the fact that we had this ability to quantify, to put a number on how at risk dogs were, to show that that was acting by altering their appetite. And then we went on to look at the impact that owner management had on that. And what we showed is that if you're a low risk dog, actually it doesn't matter that much what your owners do. You'll probably stay about a healthy weight, maybe a little bit overweight. The low risk dogs tended not to get overweight. Whereas our high genetic risk dogs were really dependent on their owners to exert lots of control over what they were eating and make sure they were really active. So, if you were a high risk dog with a completely on it owner who absolutely regulated your food and gave you lots of activity, you could be perfectly slim. The problem comes that if you're a bit relaxed about the management, those dogs will pile on the pounds.
How do creams permeate the skin?
Professor Richard Guy, Professor of Pharmaceutical Sciences at the University of Bath, helped James Tytko with the answer…
Richard - Thanks James. The truth is, water can penetrate the skin from inside-out (and outside-in, for that matter, but less so) by passive diffusion. The water concentration inside the body is about 50 molar; outside, it’s much less, meaning that there is a strong driving force for water to ‘escape' from the body especially as an adult body’s surface area is 1.5 to 2 m^2 (15,000 to 20,000 cm^2).
So, how can we exist on terra firma without having to continually drink lots of water? The answer, as you point out, is the stratum corneum, a very thin but very effective barrier to water penetration. We say it looks like a ‘brick wall’ with keratin-filled corneocytes providing the bricks, and intercellular lipids, organised in multiple bilayers, the cement or mortar. Transport of compounds across the skin appears to be constrained to the tortuous intercellular, lipid-filled pathway, making the passage of hydrophilic compounds like water, quite limited (but not zero).
James - The result of this incredible bit of bioengineering is that the passive loss of water across the entire skin surface in a day (assuming that you are not exercising vigorously) is limited to about 500 mL or less. So how could we target therapies to traverse this almost watertight frontier?
Richard - Medications and cosmetic creams per se do not penetrate the skin, but the chemical constituents of which they are comprised do... but not all to the same extent. Generally speaking, smaller molecules permeate better than bigger ones and very big ones (for example, collagen) do so negligibly in amounts that cannot be measured by available techniques. A cream containing collagen may feel good when you rub it on but the collagen molecules therein “ain’t going nowhere” (so to speak!) Chemicals that are more lipid-soluble than water permeate better but there’s a limit to how much lipid solubility you want for a chemical to cross the skin. Super lipophilic ones might like being in the stratum corneum but they’ll never leave it.
So, while drugs and cosmetic actives with the optimal properties applied to the skin can be absorbed into the stratum corneum, epidermis, dermis, underlying tissue (the muscle, as Garth points out) and eventually the blood. But the deeper you go, the less you’ll find in each successive layer or ‘compartment’. So, a drug applied topically to elicit a pharmacological effect ‘centrally’ (think a patch containing nicotine where the site of action is the brain) has to be really potent and effective at very small doses.
Comments thus far assume that we are talking about intact, normal skin. Using a microneedle patch creates ‘holes’ through the stratum corneum through which water-soluble compounds (and bigger ones) can penetrate much more easily. Technology has been under serious study now for more than 20 years but - as yet - still no regulatory-approved medicinal product on the market.
Cosmetic companies care a lot about the uptake of the chemicals in their products, especially those used over large surface areas (lotions, sunscreens, etc.), when the amounts absorbed - even if small per cm^2 - can add up if the product is used every day or several times per day (also for products to be used on infants whose body surface-volume ratio is relatively high). They pay a fair bit of attention to ensure that systemic effects are not induced.
James - So, Garth, water struggles to penetrate the skin due to the stratum corneum, a highly effective barrier made of keratin-filled cells and lipid layers. However, certain small, lipid-soluble drug and cosmetic molecules can diffuse through, though their penetration decreases with depth. Techniques like microneedles enhance absorption, but regulatory-approved medicinal products using this method are still in development.
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