This month, new hearing tests to spot those likely to struggle with speech in noisy environments, how your DNA is at risk from hacking on a public database, plants with three parents, researchers recreate endometriosis in mice and show that cannabis might be an effective treatment, and the nerve fibres that make us like a cuddle.
In this episode
00:36 - Struggling to hear in noisy places?
Struggling to hear in noisy places?
Daniel Polley, Harvard Medical School
Do you find that speech is much harder to follow in noisy places? Does background din make what other people are saying trickier to understand? The good news is that you’re not alone: lots of people struggle, and it’s often because, as we age, we lose hearing acuity. By the time we’re 40, we can have as few as half the number of fibres in our auditory nerves that we had when we were 4. But traditional hearing tests are notoriously poor at picking this up. Luckily, “here’s” someone who can help! Speaking with Chris Smith, Harvard's Daniel Polley...
07:36 - Has someone stolen your genome?
Has someone stolen your genome?
Michael Edge, University of California Davis
A common trend at the moment is to get your DNA sequenced; often you learn how much Neanderthal is in you, that you’ve got Irish, Welsh and Cossack ancestry, and some of these resources also let you know about things like disease risk genes. Some people go further and upload their genome to a range of online platforms that use the sequence data to do things like reunite you with your long lost relatives. But, as UC Davis researcher Michael Edge explains to Chris Smith, many of these platforms are vulnerable to some simple exploits, so there’s a very danger that you could end up with your genome getting hacked and stolen…
15:34 - Plants with 3 parents
Plants with 3 parents
Rita Gross-Hardt, University of Bremen
When we reproduce, a single sperm is permitted to fertilise a single egg, bringing together two half-sets of chromosomes to produce a cell containing the full 23 pairs. And if anything goes wrong with this process - such as two sperm fertilising the same egg and contributing too many chromosomes - the result is usually lethal. But plants, on the other hand, seem to be able to tolerate this quite well and may even rely on the process to drive their evolution. When a flower is pollinated, the male pollen grows down the flower stigma towards the egg. When it gets there, it contributes DNA to both the nourishing tissue that surrounds the egg, and the egg itself. The nourishing tissue inspects the DNA and can abort the fertilisation if something is wrong. But, rarely, two pollen tubes, from two separate fathers, can try to fertilise simultaneously. When this happens, the second one doesn’t need to interact with the nourishing tissue and can directly add DNA to the egg, producing a plant with 3 parents. This has significant implications for plant breeding. As she explains to Chris Smith, Rita Gross-Hardt proved how it happens in an ingenious series of experiments...
Rita - Because we were expecting a really rare event, we thought it would be good to have something which is easy for us to score. And the best case scenario, we thought, is that all the seedlings which have just one father dropped dead and only the ones which have two fathers survive. So we decided to use a gene which confers a herbicide resistance. And we kind of "separated" this gene. We put one part into father one, and we took the other part into father two. The rationale behind this is that, if only one sperm from one father is inherited, the gene is not complete and is not expressed, so the plants are herbicide sensitive. By contrast, if an egg inherits the sperm from the two different fathers, the gene would be complemented and the tri-parental offspring would be herbicide resistant.
Chris - And what fraction, when you did this actually survived, in other words, had inherited both halves of the gene, one from each dad and therefore reconstituted a functional gene in the offspring?
Rita - Yeah, that is actually quite fascinating. We had to look at 10,000 seedlings to find one which is herbicide resistant.
Chris - And did you check, when you looked at the seedlings that appear to be resistant and therefore would appear to have three parents, did you go in and genetically confirm that was definitely the case?
Rita - Yes, we felt that was a very important step because, just getting a herbicide resistant plant did not feel comfortable for making such a strong claim that plants can have three parents. So we, in addition, checked whether we could find back the two halves of the gene, and then we also said that we would assume that such plants would have additional chromosomes. So a typical arabidopsis plant gets five chromosomes from the mother and five chromosomes from the father. What we found in these herbicide resistant plants was 15 chromosomes. So that fitted quite well to the idea that actually a second father had contributed its entire genome.
Chris - How does this actually happen though? What's the mechanism?
Rita - Actually there was a remarkable difference between what the first inheritance step was from father one, and the fusion that we observed with father two. The first father delivered its sperm not only to the egg cell but also to the adjacent nourishing tissue. This is normal and quite characteristic for flowering plants. Importantly, this nourishing tissue has a DNA checkpoint. So the first father's genetic material went through this genetic checkpoint. However, to our surprise, in many cases, genetic material from father two was only delivered to the egg cell but not to the nourishing tissue, thereby bypassing this DNA checkpoint.
Chris - Given that you've shown that this can happen, albeit with a lowish frequency, this must therefore be an important way in which plants can share genes, trade genes, gain additional genes from multiple parents. It must be, have been going on in evolutionary terms like this and have played quite an important role in the plants that we see around us today?
Rita - Yes, that is an absolutely correct point. So, during evolution, the increase in chromosome numbers is assumed to be really having played a major role in speciation. Why is that? Well, having additional chromosomes and duplications of chromosomes is kind of like a playground for evolution, so these genes can either be newly functionalised, they can be maintained in their function, or they can be deleted.
Chris - Why doesn't this totally screw up the ability of the plants to reproduce themselves though? Why don't they end up with what we call aneuploidy - the wrong numbers of chromosomes in their own gametes, their own eggs and sperm - when they want to reproduce subsequently?
Rita - Yeah, that's a very good question and I wish I could give you a good answer on that. The point is indeed, we have plants which have now three sets of chromosomes. That implies that, when it comes to the formation of germ cells, that these three sets need to be distributed. This can occur in an even fashion, but typically it occurs in an uneven fashion. Saying that, for example, chromosome number one is represented by one copy in a germ cell, whereas chromosome number two is represented by two copies. And this gives different ratios for gene products and that can cause turmoil and developmental problems. However, we saw that some 40% of these plants which had three chromosome sets were able to give rise to fertile offspring.
Chris - Was that just by chance do you think; just by luck they happen to select just one copy of everything in the one particular gamete that was successful, and so that's the one you saw, or do you think there's a mechanism at play here - nature has made provision for the fact that it's allowing this extra set of chromosomes to sneak through from time to time, so it's got a mechanism to deal with it when it happens?
Rita - There has been speculations, for example, that shutting down chromosome copies might do the job here, but, to my knowledge, this is not a clarified how plants actually manage to tolerate these extra chromosomes in comparison to animals, which are highly intolerant for this scenario.
Chris - Now, what are the implications of this? We've touched on why evolution might want to live with this because the benefits are obvious. Is there any implication in terms of where we see ourselves going from a plant breeding perspective?
Rita - Yes. We think that this has implications for plant because the combination of beneficial traits from three parents in i think a cross can speed up breeding processes. That is one aspect. A second aspect which we consider important is that plant breeders often have the problem that they cannot combine plants because they are not related enough, and this is actually detected in the nourishing tissue, which checks for the DNA quality and quantity. And then if the test is not past, the seed, simply aborts. If we now have a means that the second father is not going through this quality check, then there would be maybe an option to combine plants which we could previously not combine in such three parent crosses.
23:29 - Cannabis treatment for endometriosis
Cannabis treatment for endometriosis
Rafael Maldonado, Universitat Pompeu Fabra, Barcelona
One in ten women has the condition endometriosis; the consequences can include disabling menstrual pain, and infertility. The disease occurs, we think, when the lining of the uterus, instead of leaving the body as menstrual blood, instead passes in the reverse direction, upwards along the fallopian tubes and into the abdominal cavity, where it implants in various places and produces cysts that bleed painfully and provoke inflammation and adhesions. Now, Rafael Maldonado, from the Universitat Pompeu Fabra, Barcelona, has successfully recreated the condition in mice, and gone on to show that THC, one of the main psychoactive ingredients in cannabis, can reverse the activity of the disease, suggesting that this might be a fruitful avenue to pursue in human patients…
Rafael - I'm Rafael Maldonado, from the Universitat Pompeu Fabra, Barcelona. I'm director of the neuropharmacology research group. What we do is we extract some uterus tissue from normal mouth and we just implant this uterus tissue in the abdominal cavity. And of course we have a control animal where we just implant fat in the same places. Only the animal where we have implanted this uterus tissue is the one that express pain, but also expresses other manifestation similar to women that has endometriosis and emotional alteration and cognitive alteration.
Chris - So women who have endometriosis don't just get pain once a month when they're menstruating. They also get these other consequences you're describing, including decision making and cognitive impairments?
Rafael - That's correct.
Chris - So you've got this animal model then; it develops many of the symptoms of endometriosis. It means that you've now got an opportunity to try various therapies.
Rafael - Yes.
Chris - What did you decide to test?
Rafael - Well, we focused on the endocannabinoid system. This system is involved in the transmission and integration of pain; it's involved in day emotional control; it's involved in the cognitive control. So for these and other reasons, we have arguments to believe that we are going to be able to modify the manifestations of endometriosis.
Chris - What did you do then? You give the mice who've got either the control tissue or the mice that have got the uterine tissue, so they are endometriotic mice. You give them some THC - tetrahydrocannabinol - and you then ask what does this do to their symptomatology?
Rafael - Yeah, we give tetrahydrocannabinol at a dose that is equivalent to a medium dose in humans. We administered this cannabis chronically in the animal. And then the animal feels less pain. Then we evaluate the emotional component and we had decreased the cognitive impairment and we had decreased the size of the cyst at the peripheral level. So, we suppose that this effect is the combination of as central and a peripheral response produced by THC.
Chris - And when you look inside the animals, can you see any differences in the way the tissue is behaving when you treat the animals with THC?
Rafael - Yeah, we do. We observe a decrease in the size of the cyst. We observe a decrease in the size of the cyst that generates this disease that is called endometriosis.
Chris - Do you think it will be possible to dissect away some of the psychoactive effects of THC and still achieve these benefits so that people would potentially get the benefits for endometriosis, but none of the central consequences?
Rafael - Yeah. These are, these are the studies that we are doing right now trying to obtain just the beneficial effects avoiding the central psychoactive effects of THC.
27:45 - The nerves that allow us to enjoy a cuddle
The nerves that allow us to enjoy a cuddle
Francis McGlone, Liverpool John Moores University
The nervous system carries information about what touch from the skin to our brains. And different types of stimuli are carried in different classes of nerve fibres. Pain and temperature sensations are conveyed in one group of nerves, while fine touch and itch sensations are signalled by others. And we have a pretty good idea how this information is relayed to the brain. But there’s also one more recently identified class of nerve fibre - responsible for the pleasant sensations that accompany being stroked or massaged - that neuroscientists assumed, on the basis of the characteristics of the nerve cells involved, would travel alongside the pain and itch sensations. But when they did the experiment in humans to prove it, they got a surprise. Speaking with Chris Smith, Liverpool John Moores University's Francis McGlone…
Francis - Well, our research for a number of years now has been characterising the functional properties of a particular class of sensory nerves that innervate the skin called C fibres. And C fibres are classically understood for code for pain and itch. There's been another C fibre identified relatively recently that responds specifically to gentle touch. And this nerve fiber we hypothesise is the basis for why people like a cuddle, or they like to be stroked in, in consensual sort of relationships.
Chris - So in this case it's C for cuddle! But what was the question that you had to get at then?
Francis - Well, the question was its pathway centrally. So we record from these nerve fibres in humans using an amazing technique developed by the Swedes called microneurography. We can put a very fine electrode through the skin into an underlying nerve bundle and we can listen in specifically to particular classes of nerve fibres. So we know this nerve is in the skin and we know its response properties, which are really quite fascinating because this nerve fiber is tuned to respond optimally to the stroking velocities that people would report as most pleasant.
Chris - So you know a lot about basically what excites these nerve cells, but exactly how I become consciously excited when I'm stroked in this way, that that was the unknown?
Francis - Well, we've got the two ends of the, of the equation. We've got the first order neuron in the skin. What we don't know is the second order pathway - i.e. which spinal pathway is a C tactile afferent moving up towards the brain.
Chris - Is that not the same as the pathway that these other C fibres, these very small unmyelinated with very fine calibre nerve fibres take? They classically - we understand from, you know, physiology going back a long, long time - they go into the spinal cord, make some connections and then they go across to the other side of the spinal cord and whiz up to the brain. Is that different than you think?
Francis - Well, that was our major hypothesis. That was the whole basis of this study was to basically establish that the C tactile afferent took the same spinal pathway as the other classic C fibres, the ones that code for itch and the ones that code for pain. So that was our hypothesis that, when that is cut, response to pleasant touch would have disappeared.
Chris - Now when you say when it's cut, would this be in humans who are having either trauma to the spinal cord or purposeful interruption of those pathways for some reason?
Francis - Yes. So I should explain that in chronic neuropathic pain patients, the problem with chronic neuropathic pain, it is very difficult to switch it off, so, some years ago, neurosurgeons came up with an operative procedure where they basically put a needle into the spinal cord and the spinal cord has got loads of pathways coming up it, but there's a specific pathway called the spinothalamic tract, where we know all the C-nociceptors and the itch nerves are. So the neurosurgeon will put a needle into that and then they heat that needle up so that it basically cauterizes the spinothalamic tract and then it's quite incredible actually that, of 20 patients that took part in the current study, I think 18 or 19 after this operation, we're completely pain free. Their itch had gone, and of course we fully expected when we tested their response to present touch, that would have been absent as well - and it wasn't. We're having a real rethink now as to what's going on in terms of how this nerve fiber codes for the pleasantness of touch.
Chris - Do you think they've got a unique fiber bundle: these aggregate in some way within the substance of the spinal cord; they don't join those pain and itch and other pathways; they stay isolated and go up anatomically in a distinct area. And so when you do that lesion, you just miss them?
Francis - Uh, there is that possibility that we may, they may have a sub sort of pathway that travels up the spinothalamic track that we missed. But these operations completely removed itch. They completely remove pain, so they'd have to be hiding somewhere in order for us not to have detected them. There is just one maybe niggling problem is that when the surgeon is stimulating through that needle to make sure that he's in the right part of the spinal column, the patient is brought out of anaesthesia. And they're asked to respond when they feel anything. And of course if you're in the spinothalamic tract and you electrically stimulate it, clearly these patients will respond with "yeah, that's really painful!" So we're looking specifically with the surgical procedure for a response of pain from the participants. Now, it's just vaguely possible that, by doing that, we missed out another sort of sub-tract in the spinothalamic tract that has all the CTs. That's a possibility, but it's unlikely.
Chris - Is it possible that these slightly extraordinary nerve fibres are taking a completely different path entirely? Could it be that they're going up, say, the back part of the spinal cord, what we call the dorsal column pathway, which traditionally there's very fine touch in there, isn't there? If I want to tell which coin I've got in my pocket, when I reach in with my fingers, I'm using that pathway. Is it possible they're going up there?
Francis - Absolutely. I mean that's when we reasoned the um, results in our paper, we did make that point, that it's possible that these fibres are also going up the dorsal columns. And as you say, there is some evidence and some animal literature that that may be the case. It's surprising how little we really understand about the complexities of these afferent pathways coming up in the spinal cord. And what we're going to be doing next now is to let the brain tell us what's going on rather than somebody subjectively reporting whether that touch feels pleasant or not. So these patients, the next cohort of patients, we'll be running an fMRI analysis on them and stroking them again and see what the brain's telling us...