Briefing Chat: New narcolepsy drug could unlock host of novel brain therapies

New treatments for narcolepsy

0:00Hello, and welcome to the Briefing Chat podcast, the Friday show where we talk about a couple of stories that have been highlighted in the Nature Briefing, Nature's daily roundup of the latest science news. And here with me to talk all things science this week is Maren Hunsberger. Maren, hi, how's it going? Hi, good. Happy to be here as always. Well, thank you for joining me. And I'm very curious what you've brought to the Briefing Chat podcast this time. I'm really excited about this one. I mean, I'm excited every week because I think they're all really cool. But this one was a really interesting one. I'm assuming you've heard of narcolepsy.

0:38That's where you like randomly fall asleep. Maybe not so random, but you fall asleep when you don't want to, I think. No, yes, that's basically it. It's a little more complex than that. There's basically two types of narcolepsy. There's type one and type two. And that's actually relevant. It's going to come into play later. But essentially, it's characterized by excessive daytime sleepiness. So you have a lot of trouble staying awake during the day. You may fall asleep unexpectedly and without any sort of preamble into like a deep sleep for small chunks of time. You may not be able to sleep at night. You may have night terrors or sleep paralysis. Some people have some hallucinations.

1:14And in type one narcolepsy, you also experience something called cataplexy, which is really interesting. It's where you lose muscle tone. So the ability to have your muscles maintain their stiffness when you're experiencing an extreme emotion like laughter. Oh, so this is when you're awake, you could just not have control of your muscles. That's correct. And that's called cataplexy. And so people have been looking into this for a really long time, right? Narcolepsy is very disruptive to your life, as you might imagine. Exactly. I have a friend who has it, actually. And she described, you know, one of the reasons that she ended up getting diagnosed was because she found herself falling asleep at traffic lights for tiny little increments of time, which is, of course, like, yeah, very unsafe and very disruptive.

1:56So people have been looking into this for a long time to try and figure out what the issue is. And our treatments for narcolepsy up until now have primarily been treating the symptoms. So people get prescribed stimulants to help them stay awake during the day. People get prescribed sleep aids to help them fall asleep and stay asleep at night. But that's not really been looking at what the root cause of this might be. Now there's a new drug that has been FDA approved that is the first of its kind that is designed to treat the root cause of narcolepsy.

2:26Oh, OK. So this is something that could potentially be used in people in the U.S. It's got that approval straight away and could actually treat root cause. But what is the root cause, I suppose? It's a great question. And it's different between type 1 and type 2, which is why I made that distinction early on. In type 1, many scientists believe that the root cause of narcolepsy is because of a lack of a peptide called orexin, which is produced in your brain. And it's supposed to help with your sleep-wake cycle. It basically regulates when we fall asleep and stay asleep and when we wake up.

2:58But in type 1 narcoleptics, their brains are missing this orexin. So this drug is essentially acting. Some people are comparing it to the GLP-1 drugs that are on the market because GLP-1 drugs are technically, as you and I know, Nick, GLP-1 agonists. So essentially, they mimic the function of the GLP-1 hormone in your gut to sort of regulate satiety and how full you feel and how quickly your food is digested. With this drug, it's an orexin agonist. So it mimics the function of orexin in your brain, which is missing from people with type 1 narcolepsy.

3:34OK, OK. So it's just trying to replace that thing that is missing, I guess. Exactly. And what's interesting is that many scientists are saying, you know, type 2 has a different mechanism, probably. There's all kinds of other neurons and a couple of different other pathways that scientists are still looking at as potentially being involved in narcolepsy, especially type 2. So it's not that this is the one singular root cause, but it's definitely involved. And in these clinical trials that people, you know, tested this drug in, it has been, you know, very effective.

4:07Some of the folks who were interviewed for a piece in Nature about it said that it's completely changed their lives. Some of the scientists involved say that essentially when taking this drug, narcolepsy patients become more or less indistinguishable from quote unquote normal folks in their sleep cycle, which is absolutely huge for the quality of life of these folks who struggle with this disorder. And that is, you know, in the millions of people worldwide. Wow. Wow. So what are the sort of next steps then? Are people able to just go and get this drug?

4:37You said it was FDA approved. It's FDA approved, which means that in America, it can be prescribed if you have been diagnosed with narcolepsy, which is, you know, a relatively long and complicated process, but it can be prescribed for this disorder in the United States. And the other reason that this GLP-1 comparison is really interesting is because, you know, when GLP-1 drugs first came out, you know, they were prescribed for type 2 diabetes management and now they're being prescribed for weight loss management. But all of this science is coming out, showing that they're, you know, have an effect on many different systems in the body and may be able to impact inflammation pathways and other disease pathways.

5:16Many neuroscientists hope and potentially believe that this drug, this orexin agonist, could potentially be like a GLP-1 for the brain, where it could maybe also impact other neurological pathways, people are looking to maybe have this tested for use in treating the symptoms of attention deficit disorder, ADHD, and maybe fatigue that's associated with things like multiple sclerosis and Parkinson's disease. So people are really excited to see maybe what other impacts this could have in other neurological conditions as well.

5:48Well, that sounds really promising for those people and maybe your friends as well who have narcolepsy.

Growing brain organoids in labs

5:53And we're going to stay in the neuroscience realm this week because I've also got a story about the brain and, in fact, little mini brain organoids. So I don't know if you're familiar with this term. Organoids are sort of miniaturized and simplified versions of organs. They're 3D structures made from cells and human brain organoids have existed for a while. And now researchers have got them to grow for over five years, which is the longest time ever. Whoa. Yeah. I mean, as a microbiologist, I had trouble keeping cells alive in a dish for like a week.

6:26Five years as a complex organoid? That's really impressive. It is very impressive. I mean, some of the people quoted in this story just remarked on the fact that this is an incredible feat. So this is a study that was published in Nature and I read a news article about it in Nature as well. But fundamentally, yes, these researchers have been able to get these organoids to grow for more than five years by basically manipulating their growth conditions, getting the growth media to be tip top, changing it halfway through and essentially allowing them to grow new neurons and things throughout the process.

7:01Because normally what happens is when you have brain organoids, after a few months, they just start to die. And so they've been able to navigate this process by changing the growth media to encourage more neuron growth. And they've got them to grow for this long period of time. And more than that, they're able to show what the differences were as they grew over time. And it looks like they went through similar stages to what a human brain would go through as it developed. Whoa. So they were not only able to get them to last a really long time in the lab, but they followed the same stages of development as a brain would inside like my head.

7:38I mean, almost like, you know, obviously, this is a simplified, miniaturized version, and it doesn't have many of the things that we would consider a human brain have. Like there's no signs of consciousness, for example. And they don't have some of the structures and things that we have in the human brain. But in terms of like some of the gene expression and things like that, that was very similar. So they looked at brains between 15 days and two months. And in that period, the gene expression looked like basically what it would look like in a fetus in the first trimester.

8:10And then from like three months to six months, it looked like in the second trimester. And then from 12 months plus, it looked kind of like a human baby's brain. So they were able to show this progression. And one thing that was really interesting as well is they were able to then take the brain cells that had come from these like older brains, mix them with younger neurons. And the older neurons still behaved like the older ones and the younger ones still behave like younger. So it was almost like the neurons, the brain cells, they remembered what stage they were in.

8:46They remembered how old they were and they went through the processes that they would do at that age. Wow. They were very secure in their identity. They were not swayed by the crowd. They were not swayed by the other brain cells, by the other crowd of neurons, no. And is that also a new finding? Like has that also never really been looked at before? These neurons being able to maintain their stage of development when mixed with neurons of a different developmental stage? Yeah. Like I say, because these brain organises have been able to grow for so long, the researchers have been able to show that this is a thing.

9:17Before, as I said, after a few months, they would just die. So there have been some signs that they do change over time. But we've not been able to see these like long term changes. Like more than 12 months just didn't happen before. So it wasn't known that the gene expression would be similar to that of like a baby's brain, for example. Sure. Gosh, that's so crazy. And so what does this help us do? And when talking about organoids, I think it's always so important to just like emphasize so much that this is not a human brain. It can't think. It doesn't have consciousness. It's just neurons, you know, in complex. So not singular neurons or singular cells in a dish, but it's neurons in a more, you know, complex structure.

9:52Like they maybe would be more similarly to a brain in an organism. But what do these organoids and specifically these really long lived organoids now help us do? Well, the thing that researchers are hoping that they'll be able to do is allow us to look at conditions that occur later on in development. So there's lots of conditions that occur very early on in brain development and you can use existing organoids for that. But for things like, say, schizophrenia, for example, that occurs much later in development. So the hope is that you're going to be able to use these longer lived organoids to probe things like that.

10:25And also because the neurons seem to remember how old they were, you could make like banks of certain age cells. You could grow cells up to like five years old, for example, take them aside, freeze them down, something like that, and then look at them later to look at different conditions that might be relevant to that age. So you could create like a whole library of different ages of neurons to try and look at different things and create new organoids from those neurons that you've banked. Oh, wow. That's so cool.

10:56I love that. A library of neurons at different stages of development. That's so cool to picture. And so do do the researchers want to take this even further?

Future steps for brain organoid research

11:04Are they going to try and grow neurons that are even older than five years or is five years sort of the limit? So I don't know if they're going to try and make older ones, like theoretically they could. And these ones in this particular study, five years is just when they ended their analysis. The brain organoids are still sort of chugging along and still aging, as it were, becoming older. But what the team are now planning to do is they're aiming to create more complex brain organoids that incorporate like sensory inputs. So like things like sight and smell and that sort of thing to try and get a better understanding of how these processes work and also how they may interact with other disorders and things like that.

11:42And yes, as we mentioned, like these are simplified versions. They're not really like a human brain. But as these things develop, as they get older, as more things are added into, there's going to be ongoing ethical discussions. Like if there are signs of consciousness and things like that, then organoids would be endowed with certain moral rights and things like that. But we're nowhere near that stage yet. Going to be really cool to see where it goes. It'll be interesting to see where it goes. But I think that's all we've got time for on the Briefing Chat podcast this week. If you've enjoyed the show, do write in and let us know.

12:12You can reach us on email. We're podcast at nature.com. Or you can reach us on social media. We're at nature podcast. I'm Nick Petrichow. And I'm Maren Hunsberger. Thanks so much for listening. Thank you for listening. Bye. Bye.