A (2:20)

And finally, is a cure for hearing loss possible?

B (2:24)

We think it is. And we are developing something which we think could change the landscape.

A (2:30)

My podcast producer, Rich, has actually talked to me about how in his teenage years he was running these underground raves. And that means now in his 30s, his hearing is actually damaged. And in my case, I remember the time that my son aged about 11, so it's about seven years ago, just joyfully showed me this app on his phone that played these, like, high pitched noises. And I discovered that not only I couldn't hear lots of noises that he said he could, but really depressingly, there were lots of noises my wife could hear that I couldn't hear. And I think since then I've really noticed that in noisy restaurants, like, I can really struggle to hear people who are further away from Me, you know, I'm aware that like, I'm not quite as good as hearing as I was, you know, when I was 20. So then when you're telling me that hearing loss is becoming more common, I think that's very worrying. Why are we seeing this rise in cases?

B (3:24)

One of the reasons why it's becoming more common is because as a population we are aging. It's more common to have older people and we live longer. And one of the key factors that influence hearing loss is aging. And as you said, that loss of the very high pitched sounds that you tend to have sort of from middle age onwards is just the opening of the door of more substantial healing loss that will happen later in life. And we as a population, we are growing older and it's more common to have older people. So that's one of the factors. But the other factor is we live in a noisier, in a more loud world. We have a lot of noise exposure. The use of headphones is probably prevalent and sometimes we don't tend to respect the kind of the volume controls that most of the devices have. And the exposure to loud noises is really impacting the incidence of hearing loss in general.

A (4:22)

And I'm interested that you already started talking about headphones. Are headphones safe or am I inevitably leading the path to becoming deaf if I'm using them?

B (4:34)

I think the headphones, the way that they are built, they have safety limits. There's strong advice built by the manufacturers of what is safe and what is unsafe. But we tend to do, particularly the younger age groups tend to use it beyond those safety limits because get a more thrill of listening to very loud music. And also when we go to gigs and music festivals, we are exposed to very, very loud levels of noise and sound the that tend to be a bit unsafe.

A (5:05)

And so if I listen to this very loud sound, that's not just something temporarily that's causing me harm. Like if I'm listening to this very loud sound, this can lead to a permanent impact.

B (5:16)

It's a very good point. It's like everything is a matter of a spectrum. If you listen to a certain level of sound for a short period of time, it may be a temporary shift. You may have a temporary sort of loss of perception, what is called your threshold, sort of, but they are reversible. But once you get to a certain critical point, then you're producing permanent damage and then that's not reversible.

A (5:40)

And how long does it take for this permanent hearing loss to happen?

B (5:44)

It depends on the aggression. It can be immediate if you are exposed to a very loud noise, or it can take years or decades of aging for that to develop.

A (5:56)

So if I'm listening to really loud music on my headphones, like, all the time, for hours a day, like, over what sort of time period would I expect to see an impact that will.

B (6:10)

Anticipate the onset of this heat loss? But if you are exposed, for example, to an explosion, it can be loud enough that produce permanent deafness there and then. So it all depends about the impact of the. Of the aggression.

A (6:25)

I want to talk for a minute more, actually, about the headphones, because I don't know at what level my headphone is safe and what level my headphone isn't. I've noticed that parents tend to be quite cautious now with little babies, which I never saw when I was young. But now I've noticed that sometimes you're going to some sort of concert or party where there's loud music, and you see, like, parents have put these sort of ear protectors over little babies, but I notice nobody else is wearing these protectors. How do I know at what point with my headphone this is sort of safe?

B (6:58)

It's very difficult to give general advice because it all depends very much of the device or the particular device. Some devices come with very clear guidelines of what is safe and that you should turn your volume down. As a general rule, I would say you have to keep the level of sound to a comfortable level without getting too loud. The way that we measure sound intensity is in decibels, which is a scale, and it's basically the pressure that the sound makes, because at the end of the day, the sound is a mechanical pressure. So anything I will say probably about 60 decibels, it will be potentially a problem. 70, 80 will be quite loud. To give you an idea, about 100 db db is for decibels is the sound that a pneumatic drill does on the street. So we're talking about very, very loud noises. When you get that. And the scale is logarithmic, so an increment of 10 points is a hundredfold, basically.

A (7:56)

So just to play that back, you're saying if I'm listening to music at 60 decibels, that's potentially a problem, and at 70 to 80, that is definitely a problem.

B (8:06)

That is definitely a problem. I would not recommend to go at.

A (8:10)

Those levels with headphones attached to phones. I could be in a position where I've got more than 60 decibels in my ear.

B (8:15)

It is possible. And in general, it will be the advice will be just put the volume down.

A (8:20)

It's really interesting hearing you talk about this, because it reminds me, we talk a lot about Health Span on this podcast. The way in which we are, on average, living longer than our ancestors, but actually the number of healthy years that we're having is actually much worse now than it was 50 years ago. And I'm thinking that there's some analogy here a bit with my hearing, which is, again, it was. We're living longer, but it sounds like you're saying potentially, absolutely. We might have fewer years of good hearing.

B (8:47)

Absolutely. My grandparents and we want to increase the lifespan of healthy years. And that has an impact, not only a personal impact, but also a socioeconomic impact. The ability to increase your healthy years is very, very important from a point of view of community as well, not only a personal point of view.

A (9:06)

What's it like to suffer hearing loss and how does it impact your life?

B (9:11)

It can have a very, very substantial impact. One of the things, and I think probably a lot of people in the audience may relate to this, you start having to put the volume up in certain devices because you cannot get the same kind of information, the same kind of kidney that you had before. But that, in a way, is more of a symptom. The thing when it starts impacting your life is when it starts affecting your communication with other people. There is a very telling sentence that Helen Keller was a teacher, suffered from blindness and hearing loss in the first part of the 20th century. And because she was blind and deaf, she was asked sort of, which one was impacting her life more, the loss of sight or the loss of hearing. And she very poignantly said, and I'm paraphrasing here, but it was without a doubt hearing, because blindness sort of cuts you off from things around you. But hearing cast you from people because affects communication. You go to a pub to have a conversation with some friends, and all of a sudden you are in that very loud environment and you cannot understand what they are saying. And you start asking sort of for them to repeat things. And after a while, you just feel embarrassed. You don't want to ask the same thing over and over again. And then you start feeling more withdrawn, more ostracized, and then you stop going to the pub because I can't. I can't hear what they're saying. I can't have a conversation. And that is impacting your ability to communicate, your ability to interact, but force you to kind of almost withdraw from your social life. And that has a huge impact on Your daily life and on your future sort of welfare as well, your social.

A (10:49)

Interaction, how does that then affect your health?

B (10:52)

One of the things that healing loss has been shown in the last few years and there is an increasing volume of research I think identifying a link between for example hearing loss and dementia. Roughly it is said for those people that develop severe hearing loss in sort of midlife, they have a five fold enhanced risk of developing dementia later on.

A (11:17)

Hey everyone. I'm sure some of you are listening and wondering about the health of your hearing. I'm Rich Zoe's producer and I know firsthand it can be hard to know the best place to start when you think you may have hearing loss. And then if you learn you do, knowing what are the best treatments on offer. Well, we made this really easy for you by pulling together the most up to date information from the most trusted sources into a five step plan so you can best understand your symptoms and how to treat them. To get your free five step plan, simply click the link in the description. They have a five fold higher risk of getting dementia if you get hearing loss.

B (11:59)

If you get severe hearing loss, if you had a moderate hearing loss is about twofold the risk later in life. Why is that? It is still not clear. There are different theories trying to explain this. One is cognitive overload. You need to make more effort to listen and to understand. So your brain use a lot more brain power to call it in a simple way. And that sort of produce kind of a more intense sort of world there. There are other theories that perhaps the conditions that lead to develop hearing loss are underpinning and underlying the condition that will develop dementia as well. Whatever the explanation and the justification of the link is, it's clear that the link seems to be there and we can minimize that risk by intervening early with your hearing loss when you start feeling that you are losing your sense of hearing.

A (12:51)

I find it rather extraordinary that hearing loss should have such a big impact because we've done podcasts talking about dementia and people are often talking about this thing is like a 30% increase or a 40% increase in risk. So it's like fivefold is enormous.

B (13:05)

It is one of the highest sort of links, but also one of the things that can be modified because other things like for example genetics are more difficult to impact. But hearing loss is one of those. That is something can be done in order to prevent the higher risk later in life.

A (13:23)

If I was having hearing loss, but then I had some sort of device that meant that I can hear better, does that reduce the risk. Reduce the risk of dementia?

B (13:32)

Yes. Even with the devices which are currently available, for example, the use of hearing aids, they reduce the risk. Because this theory of the cognitive overload, if you need to make a lot more effort to understand what people are saying and use a lot more your brain space to follow a conversation, you reduce that, you take it back to more normal levels by using something as available as a hearing aid.

A (13:58)

So one theory is somehow my brain is doing so much work to try and understand a conversation that somehow its normal processes are being described.

B (14:06)

It's an overload that then tends to more wear and tear, that then impact. That's one of the theories, but it seems to be one of the more prevalent theories at the moment.

A (14:13)

And so therefore, if I can use some sort of device that makes it easier to understand.

B (14:18)

Absolutely.

A (14:18)

Then my brain can continue to function in a healthier way. Well, it's definitely a very big argument, I guess, for looking after our hearing and thinking about it. I know scientists have been working on a cure for hearing loss for many decades and also really understanding what's going on in hearing. Could you maybe start at the beginning? In simple terms, how do we hear and why does it stop working?

B (14:44)

The way that we hear is inside our heads. In what's called the temporal bone, there is an organ called the cochlea. And cochlea comes from a Greek word which basically means snail. And it has the shape of a snail, the one that you can find by the sea, for example. It's a bit of thin bone, but inside a big piece of bone which is on the side of your head, basically.

A (15:05)

And for those just listening, you're sort of pointing to just inside your ear. That's where we're going.

B (15:09)

That's exactly what it is. This cochlea has a lot of important cells, but we can sort of take it to a core of like two critical cell types. One is called the hair cell and the hair cell, which is inside the cochlea. Remember I said sound is a pressure wave, it's a movement. So it takes the sound that comes through your outer ear and then through your middle ear. The movement of those little bones that you have in the middle ear, all that pressure gets transmitted to the cochlea. And the hair cell is called hair cell because it has something on the top that look like hair. They're not really hairs, but that's what they look like. And they move. And that movement converts that sound into an electrical signal. That cell converts a mechanical input into an electrical signal. That is then the way that signal travel in the body, sort of through the nervous system, basically. But that electrical signal which is there in the cochlea needs to be transmitted to the brain so the brain can make sense that we are hearing something. And that transmission is done by a second cell in the pathway, which is called the neuron. So you have the hair cell, which is the mechanotransducer, converts sound into electricity, but then the electrical stimulus is transferred to the brain by this cell called the cochlear neuron. So the cochlear neuron is the cable that connects the hair cell with the brain.

A (16:41)

I think most people are used to this idea that a speaker is like, if you think about being at a, I don't know, like a rave or somewhere big, you can literally see it bouncing backwards and forwards when it's making these really big noises. And so I guess that is the sound pressure. You're, you're absolutely.

B (16:56)

You can, you can see it there.

A (16:57)

You can see it. And I know that my microphone is sort of the other way around, isn't it? That when I talk at it, it's sort of bouncing around something inside this and that's turning it into electricity?

B (17:06)

Absolutely. It's a very good analogy.

A (17:07)

In my head, I have almost the same thing, only it's like little hairs bouncing around, but they are literally doing the same thing of turning the pressure in the air into electrical signals. So very similar to, you know, anyone who's on a zoom call or whatever, like with their computer. It's actually something quite similar in my head.

B (17:25)

Yes. The way that this machinery works is absolutely incredible. But the bottom line is precisely that the hair cell converts this mechanical pressure wave into an electrical signal, and that's why it's the first cell in that part. But then if you have that information out there and doesn't reach your brain, then you have a problem because there's no transmission. So you need to take all that information in a very sophisticated way to the brain. And that job, the cable of your microphone is done by the neuron that connects the hair cell.

A (18:04)

So for people who are having hearing loss, what's going wrong?

B (18:09)

We're going to concentrate only in the one affecting these cells, because you can have what is called conductive hearing loss, which affect the middle ear in those ossicles. But that is not as prevalent as what is called senso neural healing loss, which is the healing loss that affects the hair cells or the neurons healing loss that affect the cochlea. So, for example, if you have very Loud noises, It could affect the hair cells and then damage and destroy the hair cells. But in the last 10, 15 years, it has become more obvious and there is more information and we are more aware now how important the neurons also are. And it seems to be that we tend to lose the neurons, and actually the connection between the neuron and the hair cell, we tend to lose that way before we lose the hair cells. So the loss of the neurons and the loss of the innervation that is called the connection between the neuron and the hair cell tend to happen at an early point in the process of becoming deaf.

A (19:17)

The neurons are like the cables that are plugged into my microphone, which in this case is these hair cells. And you're saying that the reason why you might lose your hearing could be like the damage to these hair cells, but actually, before you even see damage to hair cells, it's almost like these unplugged.

B (19:33)

Yes, absolutely. That is a very good analogy. And that's something which is relatively new in the field, because the traditional view was that you lose the hair cells and that is the most important thing. And then eventually down the road, with time, you start losing the neurons. But actually, it seems to be that the case is a little bit the way around the neurons become unplugged first, and then you start losing the neurons and losing as well the hair cells. And then you lose the hair cells and you lose the neurons. And depending of which one or the other you lose is the balance. But one thing I haven't said, which is very important to understand why all that is important, is that we don't have the capacity to repair or to regenerate these cells. We as a species, so humans, but also mammals in general, because the, ER is so sophisticated, we have lost the capacity through evolution of regenerating these cells. Some other vertebrates, for example, amphibians, will have the capacity to produce new hair cells through the lifespan. But mammalians in general, and humans, we are mammals, we don't have that capacity. So you are born, and this is fascinating, you are born with the cells which are meant to last your lifetime. So if you are 80, 85 years old, your hair cells and your cochlear neurons are 85 years old, as old as you are. And that's why aging is an important factor in the incidence of hearing loss, because obviously they have worked all your life and they're starting to grow a little bit unfunctional.

A (21:10)

You've talked about how maybe a very loud noises are bad for our hearing. If I Have them for my entire life. Are some of them just sort of dying off, like old age of those cells over time, as cells will start.

B (21:24)

Dying off with time, and there is almost like a normal rate that we lose in them, but you can improve that rate of losing them. You can anticipate that by exposing them to loud noises. There are kind of environmental factors that can also impact, for example, certain medicines, certain antibiotics, for example, can damage your hair cells, can damage your neurons. So there are other things that could impact. But the bottleneck at the end is that because we cannot regenerate, these cells, once they're gone, are gone for good. And that's why deafness is permanent.

A (21:57)

So it's very precious. It's like I've got this fixed number. What? But that's all I've got. You know, if I live long enough, I'm going to end up deaf, basically. One bit I don't understand yet, Marcelo. Why does loud noise cause this damage?

B (22:16)

It's a very good point, and there's been quite a bit of research on that. One impact that the loud noisy has is that because you are forcing the system to overreact, you are overstimulating the system. Then the connection between the hair cell and the neuron become, what is called cytotoxic or neurotoxic, stimulated so much that then you produce that unplugged between the neuron and the hair cell. But also, if the damage continues, if you have that continuous stimulation, those hairs, those bundles on the top of the hair cell, can also get physically damaged as well. So you start the system can have a mechanical impact, sort of the loud noise, but also damage by the stimulation becoming sort of quite toxic to the system. And then you have inflammation that come after that, and that also can damage the hair cells and the neurons. So the loud noise can act in different ways. But the bottom line is that you will damage and lose your critical sensory cells and neurons.

A (23:21)

So now you've explained that they can't fix themselves. And like the damage that happens, it makes me feel like I should probably take my hearing more seriously than I have done. It's a shame. I'm already 50. I probably should have had this conversation with myself when I was 16. How worried should I be about, for example, going to a really loud concert for two hours?

B (23:42)

The more precautions you can have, the better. If you're going to go to a very loud concert, you can use some ear defenses, some earplugs that will sort of attenuate the intensity of the sound. If you're listening to music in your headphones, turn the volume down a little bit. Very loud blasts can have permanent damage.

A (24:06)

And what about when I'm walking past the person digging up the road with the pneumatic drill? So just thinking about that, I had that experience only last week and was thinking, wow, that is really loud.

B (24:16)

Yeah. Sometimes just protecting your ears with your fingers, sometimes it's a very loud bang. You're completely caught by surprise and unprepared. But it's something that you can see it coming or hear it coming, then you can at least try to minimize it.

A (24:30)

Can we talk about fixing this?

B (24:32)

Sure.

A (24:33)

Because hearing aids have been around for a long time. Don't they just solve the problem for everybody?

B (24:40)

No, I'm afraid not. Let me put it this way. At the moment, there is no biological treatment for hearing loss. We have two therapies, which they do a fantastic job, but they have their time and place. These two therapies are basically prosthetic devices. One is the hearing aid. The hearing aid is pretty much an amplifier, to put it in very simple terms. So the noise that comes through your ears, it gets amplified in a very kind of intelligent way. But the bottom line is you need to have quite a bit of residual hearing in order to use hearing aids. So basically, take your hearing from a level to a better level. But then you have the cochlear implant. It works in a different way. You may know somebody that has a cochlear implant. It has a speech processor or a mechanotransducer. The big difference between the hearing aids and the cochlear implant is that the cochlear implant is implanted surgically because it needs to go all the way into your cochlea.

A (25:43)

So that's the bone inside my head?

B (25:45)

The bone inside your head. And it has a bit which is put outside your head, which is this mechanotransducer or speech processor, and that converts sound into an electrical signal. And then that electrical signal is transported through an electrode, through a piece of cable, piece of wire that goes all the way into the cochlea and stimulates the nerve, so it does the job of the hair cell. So the cochlear implant replaces the hair cells.

A (26:17)

That's amazing. So basically, if I don't have any hair cells, but I do still have some of these neurons that you were talking about, like these cables, we can now sort of put an artificial ear on the outside and a wire that goes into my brain.

B (26:29)

Absolutely. It doesn't go into Your brain, it goes into the cochlea, which is kind of outside the brain. But you say something there which is critical, which is like if you have enough neurons. So you need to have neurons, you need to have the cable to be stimulated with the cochlear implant for the cochlear implant to work. The problem is not all the patients that have healing loss have enough or have good quality neurons to work with the cochlear implant. Don't get me wrong, the cochlear implant does an amazing job and has done a lot of good for the deaf population. And it's really, at the moment, the best solution that we have for many of these conditions. But you need to qualify for that. You need to have a very profound level of deafness, but enough neurons to be able to work in a reasonable way. The problem is, if you don't have the neurons, you basically have no alternative, no solution. There's nothing that can help us to fix that kind of, what is called neural heating loss. And another limitation of the cochlear implant is that the type of hearing that you regain, sometimes people complain that it's not a very natural hearing. It's more kind of a metallic kind of sound. And there are some strategies that engineers are developing trying to overcome that issue, but it's not a biological prosthetic, it's not a biological replacement. So that's why the field is desperately in need of a solution that is more biological, more natural with your system as it was at birth.

A (28:09)

Is this a sort of progressive thing? So do you start as your hearing loss is worse by being able to have a hearing aid, and then it reaches a point where that no longer works and you need to have this cochlear implant because the hairs have broken? And then does it end up that the cochlear implant implant stops working because the neurons are broken, or is it just there's a fraction of different people with.

B (28:32)

The progression from hearing aids to cochlear implant is probably true. You start with, particularly with progressive hearing loss. You may be able to use the hearing aids for a number of years and then become so profound, your deafness, that you need a cochlear implant. Whether the cochlear implant and the nerves will deteriorate with the cochlear implant is not very clear. Some people will. The cochlear implant will not work from the very beginning, and in some they will work and it will remain working. So it's not as clear cut once you have the cochlear implant implanted, basically set up.

A (29:06)

Is this, like, done once and it lasts for the rest of my life or does it wear out?

B (29:11)

That's a very, very good question. Most of the time, yes. You put it once and it lasts a lifetime. However, particularly in those cases where you have to implant very young patients, it may need replacement later in life, and surgeons will replace that. It's doable. It's not extremely common. Most of the patients will have it and they last decades.

A (29:34)

So I'm going to come on to your amazing research in a minute. But just to wrap up listening to you talking about the hearing aids, you were saying before that loud noise makes my hearing go worse. But then you told me that hearing aids are like an amplifier to make the noise go louder. And to my ear. Doesn't the hearing aid end up making my hearing worse?

B (29:53)

Worse? No, because obviously at that point, what it does is in a very controlled manner, it sort of amplifies the sound that gets to your ear, but within a safe limit, and basically stimulate the areas which you need more stimulation. There is a little bit of an internal amplifier within the cochlea as well, and that helps to get that, what is called the gain in the way that we hear. So having a hearing aid is not equivalent to having very loud noise with a headphone.

A (30:22)

And how have these hearing aids got better?

B (30:25)

Over the last few years, the technology behind the hearing aids have helped them to discriminate the different frequencies and to compensate for different frequencies in a differential way so they can sort of enhance certain sounds better than others. And there is other ways of where, particularly the. The software that they use that make your healing experience a lot better. But the bottom line is that they will only work if you have enough residual natural heating left.

A (31:02)

I think you've done a brilliant job of explaining how important this is, like what you can do today, but also the limitations of. I would now love to talk about the really amazing research that you're doing because you're explaining that for many people the current solutions aren't enough. Could you tell us about what your lab is working on?

B (31:22)

Yes. We started with this work a long time ago now, more than 20 years ago, at the University of Sheffield, where my academic lab is. And what we're trying to do is harboring the potential of stem cells to. To develop a treatment for healing loss. And the reason why we're doing this is because, as I said, one of the main problems that you have on healing loss, regardless of the cause, what we call the theology, whether it is because of loud noise or because you're exposed to an antibiotic that destroy your cells. Regardless of the cause, the problem at the end of the day is that you lose an important cell type. You lose your hair cells, or you lose your neurons. So because if you lose a cell type, then our strategy is that we're trying to recreate those cells in the lab in the test tube, and then transplant them into a patient that has that deficit. The way that we do that is we don't transplant the full mature cell. We transplant the cell which is called a progenitor. A cell which has like, progenitor comes from, like, as a parent kind of cell. It knows that it's going to be, for example, a neuron, but it's not a neuron just yet. So it has the potential to follow that path. And the way that we produce these progenitors is by using stem cells. They are these amazing cells which are basically a complete white canvas. They are cells which are very, what we call it, undifferentiated. So they don't have a particular identity. Well, they know they are undifferentiated. That's their identity. That's why they are stem cells. And particularly the ones which are called pluripotent, they have the capacity to produce any cell in the human body. They can produce cells in the skin, brain, any cell in the human body. The critical thing is to know or to understand which are the signals that you need to give this cell to. To become the cells that you want. So one of our initial developments in the lab was to put this, to develop methods to drive these stem cells, these very early undifferentiated stem cells, into becoming ear progenitors. Cells that know they're going to be an ear, but they haven't been fully mature just yet.

A (33:49)

So you're saying that this cell could become anything. It could become like a bit of bone in my foot, and somehow you just say, no, don't do that. Levite cell in my ear.

B (33:59)

You give a series of chemical instructions, because the language the cells understand is by chemicals. And what we've done in the test tube in the lab is mimicking the chemicals. That is because these cells will see those molecules during development, in embryonic development, they will grow, and they will be exposed to this series of molecules, and they will then become a whole embryo and then a whole individual. So we mimic that in a very restricted way. We don't want them to become, as you said, bone or cartilage or anything else. We give them the chemical instructions that make them to become ear, we call otic cells. And those are the cells that then we can make them differentiate further into becoming hair cells or becoming neurons, for example. And we developed that initial method how to push them in the right direction. And then we tested in animals that we call preclinical models, we tested in a model that hasn't had the neurons, because at this point, where we made the decision is, as I explained before, the two most important cells are the hair cells and the neurons. But for the hair cells, we have the cochlear implant. So we have something in the. We can do about it. But if you don't have the neurons, then you have a problem because there is nothing that the ontologist, nothing that your ENT doctor can do for you of very, very limited choices. So we thought, well, this is where the priority is. So we concentrated our development in trying to produce this progenitor that can create the cochlear neurons. And what we did in a model that doesn't have these neurons, we transplanted the cells, and we showed that the cells sort of engrafted. They kind of. They survived and they got to the right place in the cochlea and they made the connections and they restored the connections. And we were able to measure auditory function by putting sound through the ear and then measure the way that the different parts of the pathway response and showed that the pathway was being reconnected.

A (36:17)

And, Marcella, you talk about a model, but do you actually mean like a living animal?

B (36:20)

Yes. The model that we use mostly are gerbils.

A (36:25)

So you're saying there's a gerbil that is completely deaf, it doesn't have these neurons, which you described as being like the cables for my microphone. Yes. And then you've injected these special cells that you've figured out how to train to become these neurons into these gerbils and they can hear again?

B (36:43)

Yes, absolutely.

A (36:44)

You say that very casually. Isn't that rather amazing?

B (36:47)

Yeah, yeah, yeah.

A (36:48)

How long have you been working on this?

B (36:49)

Well, we got those results that we published more than 10 years ago. So it took 10 years to develop it to that point. It's not a full recovery, it's a partial recovery, but as you clearly identify, was very substantial achievement. Yeah, absolutely. And since then, we started to develop the whole path of taking this all the way to the clinic. And there is a team now within Rinri developing this, taking this from the basic research academic lab all the way into the clinic and try to make it into a real sort of clinical solution.

A (37:26)

So I'm sure you get asked this all the time, but how long do you think it will be until you, you know, what has obviously been like this really basic science research actually gets into the clinic for human beings.

B (37:39)

We are, I will say, at a very, very exciting moment because we have taken a lot of work to get it to this point. But now we are at the point that we are preparing the ground to be able to start the first time testing these cells in a human patient. If plans go as we have planned, that will happen next year. And from then on, it depends how things progresses. Because obviously there are different levels of what is called clinical trials. The first phase of clinical trial is just to make sure that your cells are safe, there are no adverse effects, there's nothing of a concern. And also, see if they initially work or you do that in a smaller population, and then you use. In the second phase, you just take more patients and you do it in different centers. So all that may take perhaps something like five to six years, and then if it all progresses really well, there will be a solution for that type of patient. At the moment, we are concentrating on patients that have this neural healing loss, which is a huge population, a lot of people affected by this. But we are not at this stage trying to replace the hair cells. I want to make sure, because sometimes people, they think, oh, my hair cells are gone. Is this going to help? Is that not at this point? And also, the initial phase of this study that we are planning to do will be in combination with the cochlear implant, because remember how the cochlear implant works, replaces the hair cell, and we need to make a torque with the new cable that we are creating with our stem cells with our neurons.

A (39:15)

So how do you deliver these stem cells, like, into my head?

B (39:21)

Yes, that's a very, very good point. And we haven't covered that just yet. We are using surgery which is very similar to the surgery of the cochlear implant. And because they're going to be delivered with the cochlear implant is the same intervention, basically. And a group of surgeons have developed this approach, which is just a minor modification of what is sort of standard for the use of the cochlear implant. But it's a surgery, it's part of the surgery. Eventually we are hoping to be able to develop perhaps a little less invasive way of doing it. But because the cells need to be in the right space within the cochlea, these are going to be through a surgical intervention.

A (40:06)

So firstly, you've been Working at this for a long time.

B (40:08)

Long time.

A (40:09)

You said you started, I think 20 years ago, 10 years ago, you proved you could get this to work with durables. Next year, for the first time ever, you're actually going to be testing this with human beings, which is amazing. The first stage is actually just to check that it's safe. So you're doing something with humans and you need to know that safe. Then you go into second phase with large number of people where you actually understand whether this works. It's going to be for people who are profoundly deaf because you're describing the fact that they have none of these cables and even the thing you were describing before with a cochlear implant which solves if you haven't got hair, it's like it wouldn't work here. And if all goes well, you know, listeners, like in five to six years from now, this could be something that is therefore past all of these clinical trials and therefore could actually be available for somebody through the medical system.

B (41:01)

Yes, yes, that's the plan then the pipeline. So things which we hoping to do is that there are patients which they have some hair cells but they have lost the neuron. This is patients which is called auditory neuropathy. Some of these patients are going to be tested in this initial trial that we're going to be starting next year. So initially we're going to try with a cochlear implant, but in the future we think that this may work as a monotherapy. So because you have your own hair cells, so you don't perhaps need a cochlear implant, and in that particular type of patients, we may just replace the neurons with our stem cells. So depending on the context and depending of the patients, some patients may need it with a cochlear implant, but some patients may be just a monotherapy without the cochlear implant just replacing the neurons.

A (41:57)

Before this podcast, I had no idea that hearing loss was on the rise. And I was shocked to learn that it was like deeply linked to dementia. I really believe this episode is a must listen for everyone, especially younger people who may not be aware of the risks. So please share it with your network so we can help everyone maintain their hearing well into old age. I'm sure they'll thank you. Can I ask a question around the hair cells? Because it sounds like there are a lot of people whose hearing is suffering because the hair cells are being damaged and today you're saying, well, you could have a hearing aid. Is it possible that this same approach, which is focused on the neurons could end up being able to also replace the cells that you said would never get replaced naturally in my body.

B (42:44)

Yeah, yeah, yeah. That's our ambition and aspiration. The fundamentals of the method that we use in the lab to produce the neurons are very similar to produce the hair cells. So it's part again of our development pipeline. It's part of the future things that we're planning to test conceptually we think is feasible. There are challenges also how you put them in the right part in the ear that will need to be kind of addressed and overcome. But we think it's something that it can be addressed, but it's a much earlier stage than the neurons.

A (43:19)

And when you do this, is this like a one time intervention?

B (43:25)

We think based again on the data that we have preclinically that it will be probably just one intervention that may not need to be re injected. But as I briefly explained at the beginning, we had the present with the cochlear implants that sometimes the cochlear implants needs to be replaced. So there is a possibility for a second intervention down the road if that is needed. We don't know just yet. We are something that these studies and these clinical trials will help us to address as well.

A (43:55)

So we had a number of questions around tinnitus as we're talking about doing this episode, which I know is not exactly the same thing, but the question was, could your technology be able to help at all and maybe you could explain a little bit what tinnitus is and then whether or not.

B (44:10)

Yes, tinnitus of tinnitus is the perception of a noise that people refer to as like inside your head. And it's relentless. It's another kind of things that produce a huge impact because the impact on mental health that tinnitus can have is substantial. The causes and the reasons why this develop are not fully understood. But there's a clear link with hearing loss. And one of the more likely explanation is that when the damaging that occurs to the hearing organ, to the cochlea and this damage to the hair cells and the neurons, then you create almost this state of constant stimulation and that perception of sound that is not really there. So it's very closely linked with the onset of deafness and hearing loss. And normally patients that have tinnitus will have hearing loss. Whether our technology will help, the honest and quick answer is we don't know. But because it's closely linked to hearing loss, we think it could impact and it could sort of be very beneficial. But Again, it's something that we are going to be exploring as a measure in our clinical trials.

A (45:17)

Got it. So you don't know, but you think.

B (45:19)

That this approach, we think this approach could help.

A (45:22)

And are there any treatments today?

B (45:23)

None that work. There are treatments, there are ways of like masking the idea of and basically distracting your mind so you don't pay that much attention to it. But to my knowledge, there is nothing really that solve or cures tinnitus at the moment.

A (45:38)

All sounds incredibly exciting and everyone listening to this can't access it. So I'd love to sort of conclude with your advice to anyone who's thinking today, how can I reduce my risk of either developing hearing loss or having my hearing loss get worse? What would your practical advice be?

B (45:58)

Yes, absolutely. I think that's a very good point to conclude here. We have covered it during the conversation that we had. I would say that you have to protect your hearing. Remember that those cells are your lifetime companion. So you have to look after them, you have to protect them. Trying to be not exposed to very loud noises. Use the headphones in a very sensible way. But also, and this is also very important, when you start having symptoms of losing your hearing, do something about it. Go and see your gp, go and see your audiologist and they will advise if you need hearing aids and if you need hearing aids, use them. We talked about how important is the use of hearing aids to prevent the onset of dementia or minimize. Reduce the risk of dementia. And we have to overcome because that's something that I also like to mention, this kind of a stigma. We all have a certain time in our life, we use sort of glasses and nobody blink an eye. If you have glasses, it's completely natural. However, it's not the same with hearing aids and we need to overcome that presumption that, oh, hearing aids make you look different and make you look old. That's not true. It shouldn't be the case. Hearing aids are there to help and if you need them, you should wear them.

A (47:19)

Amazing. Marcel, just before I wrap up, there's just one thing I wanted to pick up on that I thought might come up, but hasn't done because you mentioned a number of times during this episode that there might be certain antibiotics that could hurt your hearing.

B (47:32)

It's part of a family of antibiotics called aminoglucosides. They are not commonly used because of these known side effect. But unfortunately for some conditions, and in certain countries are still an antibiotic of choice, there are genetic predisposition that will make the toxicity of antibiotics more apparent. And sometimes you can be screened and say, well, if you have this particular gene background, then we will not give it to you. But obviously if you have a very rampant infection and this is the antibiotic that needs to be given you, you will get it. And that could damage your hair cells. So they are known to be autotoxic. But sometimes the choice is life or.

A (48:20)

Death, might be life or death. And this is a byproduct. This is something you're more likely to have. You're in hospital and you're very sick.

B (48:24)

Exactly. And also there are some treatments for cancer, for example, that may have the same. And there is a big area of research trying to prevent these needed medicines to the side effect of becoming autotoxic. And this is the area which is called auto protection. And there are different groups around the world trying to develop drugs that will minimize or prevent the antibiotics or these cancer treatment drugs to impact your healing system.

A (48:55)

Amazing. Thank you for that. Marcela. I'd like to do a little summary and please correct me if I've got anything wrong. The thing I'm most struck by in this conversation is this extraordinary link between hearing loss and dementia. So you said that there's a five fold higher risk of dementia with high hearing loss, which is extraordinary and we don't actually know why. But you said that there's like, the leading theory is like my brain is working so hard to try and understand the conversation that this is actually somehow sort of wearing it out or causing a bad situation. There's obviously an incredibly strong reason to make sure that you don't have that sort of hearing problem. And you said that if you were to wear a hearing aid and it works for you, actually, that then removes this risk. So clearly, really strong reason to be checking on your hearing and to protect it. You can't repair your hearing as a human being, so you get it when you're a baby and it wears out. It's got to last a lifetime. And again, that's why you have to really protect it. You said we tend to not take our hearing seriously enough. We think that sight is much more important than hearing, but actually hearing cuts us off from other people because we're no longer able to have conversations. And once you lose that, you become isolated and it has a terrible impact on your quality of life. So it is really important, and I think I hear a little bit of a crusade to sort of take it more seriously than we tend to. And the problem is it's all getting worse. We're actually losing our hearing much more than in the past, partly because we are older, but partly because we have these new devices, particularly headphones. And I guess longer term, all of these concerts that are, meaning we've got a much louder environment than we had, there are things we can do about hearing loss. And you said there's these two technologies today, the hearing aid, which I think probably everyone listening to is familiar with, which amplifies the noise and is much smarter than the hearing aids of 30 years ago. But you do need to be able to have these hair cells to be able to listen to it. And then there's this newer thing, the cochlear implant, which amazingly means you can hear even if you haven't got any hair cells. But you still need to have the cables, you still need to have the neurons that are connecting your ear to your brain. You are working on solving the problem for many people as their hearing loss gets worse, which is actually, those cables aren't working. And, and after 20 years, really amazing, you're going to be tested on human beings next year, and hopefully in five or six years, they could actually be a treatment in the meantime. And I think you're saying, anyway, you know, what should you do? We should be thinking about protecting our hearing in the same way that we think about looking after other aspects of our health. And the biggest thing is thinking about how are you protecting yourself when you might be exposed to loud noises. So I think you're saying if you're going to a concert, you should be wearing some sort of ear protection. You can enjoy the concert, but that way you're not going to do yourself permanent harm. And every day it sounds like you should be thinking a lot about whether or not your earphones, the headphones that we're wearing all the time, are too loud. Because if they are, I'm sort of just damaging these hair cells and these. These neurons every single day. And then finally, I think they're saying, if you're losing your hearing, and I think as we get older, it sounds like all of us are going through this. And I know it's true. For me, you need to see a professional. So you see your audiologist, get yourself tested, and if you need a hearing aid, you should embrace it, because actually that's to avoid dementia, rather than saying, oh, it's a stigma, it makes me look old, and so not wearing it, even though, you know, obviously if you needed glasses to see, you would wear glasses.

B (52:47)

I think that's an excellent summary. Yeah. Covered all the points that we discussed.

A (52:52)

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B (54:08)

Sam.