Vivica  0:00
This is this this is carry the one or the one radio, the Science Radio, igniting scientific curiosity, University of California, San Francisco. Hey, everyone, welcome back to carry the one radio. My name is Vivica.

Deanna  0:18
And I'm Deanna. We have a pretty interesting story to share with you today. It's a story about Cronin, who's unfortunately suffering from severe brain damage.

Vivica  0:27
Don't worry, though, there's a happy ending.

Fisherman's Wharf is one of San Francisco's most iconic sites. Each year about 12 million tourists visit Fisherman's Wharf to grab a bite of clam chowder and marvel at the bay. One of the world's biggest attractions is its resident sea lion colony, which is long ago claimed the floating docks as their own, the site of much napping, sunbathing and rowdy disagreements.

Deanna  1:04
Most visitors aren't aware though the California sea lions and other marine mammals off the California coast are in the midst of an epidemic of their own. Over a decade ago, scientists started noticing an uptick in sickness and strandings sea lions were turning up in large numbers on beaches bumbling and disoriented. It wasn't obvious what was sickening the animals or what measures could help. Even as scientists made headway in discovering the origins of the disease treatment wasn't straightforward.

Vivica  1:33
Cronin has been suffering from epilepsy for several years, at least from what doctors could tell. Epilepsy is a chronic neurological disorder characterized by excessive and abnormal brain cell activity. He was starting to lose weight rapidly, and he was becoming withdrawn and a social. Despite his medical team's best efforts. He was not responding to any of the epilepsy medication he was being given. His decline seemed steep and irreversible. Doctors were at a loss.

Deanna  2:05
Amidst all this, researchers at the University of California San Francisco were actively developing a treatment, one that had taken decades to lay the groundwork for that had the potential to treat severe epilepsy that was unresponsive to conventional therapies. We'll discuss the details later. The point is it seemed a promising but untested treatment, had never before been tried in humans or even animals more advanced in rats and mice. Nevertheless, Kearns case was so dire that doctors were looking everywhere for solutions

Vivica  2:36
to first board and I don't think this is much of a spoiler because we already told you this was going to be a happy story. The treatment worked to the delight of his doctors Crona began to recover quickly. He was eating again and gained back much of his weight. His behavioral problems seemed to subside and he was getting back to his regular day to day activities, namely swimming around chowing down pounds of fish and barking at his doctor's coordinates a California sea lion. He lives at Six Flags discovery kingdom, an amusement park and Marine Mammal Center located about 45 minutes north of San Francisco, where the researchers were hard at work, developing the treatment that ultimately gave him his life back. Corona it's a particularly lucky example of an animal affected by an epidemic that is sweeping through marine mammals of the California coast. Lucky not in the sense that his symptoms were milder, but rather he was able to be rescued and cared for by a team of world class veterinarians.

Deanna  3:37
Today we'll hear from some of the doctors and researchers that cared for Corona and helped make this pioneering therapy a reality and possibly for humans in the years to come. We'll also learn more about Crohn's backstory, where he came from and how he got so sick. And what to Cronin and others like him. Tell us about the marine environment today. Let's get to it.

Vivica  4:04
Counted is fixed into a spider like metal structure. He's out cold surgeons and nurses fuss around him getting ready. Brain surgery is a delicate procedure, especially so with a patient is a sea lion. And many of the things these doctors know by heart about the surgical process like the structure of the brain, the depth of anesthesia, and the thickness of the skull to have to be learned a new,

Deanna  4:31
the doctors are as prepared as they can be. They spent weeks examining the sea lion skull and performing sham surgeries in preparation for the big day. technicians have assisted with repurposing a stereotaxis, the metal frame in which skull sits during brain surgery to fit the very different cranial dimensions of an adult male sea lion. It's been a massive team wide effort with a lot of learning and troubleshooting along the way. Dr. Claire Simeon credits longtime veterinarian explains what it was like to work on a team of diverse experts.

Claire Simeon  5:02
It was really cool to have everybody come together and each bring their their pieces of expertise. Because I think we kept saying to each other, you know, we would have these large group meetings and and say, you know, well, I only treat sea lions. So I don't know how you guys do this or that the neurosurgeons would say, Well, you know, in humans we, we do we do it this way. And, and so there was a lot of a kind of back and forth about sharing that kind of knowledge and, and trying to extrapolate it as best as we could. Claire has been Kronus

Vivica  5:33
vet soon after he was washed up in 2017 on a beach in San Luis Obispo and started roaming the parking lots by the beach, finding nothing to be obviously wrong with him. He was released back off the coast. A few months later, he beached in San Francisco, where he washed up looking disoriented, and emaciated. Caretakers at the Marine Mammal Center up the coast from San Francisco realized something was clearly wrong with him and kept him at the Center for observation. Not only was Corona refusing to eat and shedding weight rapidly as a result, but caretakers were now able to see that he was also suffering from violent convulsive seizures that likely damaged his brain and contributed to abnormal behavior

Claire Simeon  6:21
and chronic case. So he was released several times and he re stranded within a short period of time losing weight, so you know, unable to survive on his own. And so at that point, then the government in conjunction with the rehabilitation facilities can can find a permanent home for them. And then from from then on, then it's the challenge of managing the epilepsy again with anti epileptic drugs like phenobarbital. Deza Pam, so there are some cases where animals are quite stable and they can go on to lead relatively normal lives. And in Coronavirus case that that was true for a couple of years. And then his seizures got worse over time.

Vivica  7:03
Couldn't that's not the only one. Marine Mammal rehabilitation centers like the one criminate ended up at are experiencing a flood of marine mammals that are suffering from some of the same symptoms as criminate. The culprit, a toxin called domoic acid, domoic acid has been building up off the California coast as water temperatures rise, and their surrounding area has been increasingly industrialized, toxic algae flourish in these conditions giving rise to harmful phenomena, such as the infamous red tide when they released high concentrations of these toxins.

Claire Simeon  7:38
So domoic acid is a biotoxin that's produced naturally by marine algae. And it is it's influenced its production is influenced by several factors. So we know that when there are increased nutrient loads, you know, say from increased runoff and developed areas, high nutrient loads, lead algae to overgrow, right no matter where you are, and then also increasing ocean temperatures also favor growth of algal blooms. And so And of course, there's there's a lot more complexity that that's that's just sort of a brief overview, but this toxin, it targets glutamate receptors in the brain.

Deanna  8:19
glutamate receptors respond to one of the major neurotransmitters are chemical messengers in the brain. This neurotransmitter called glutamate acts like an energy drink for the brain increasing the activity of neurons. A healthy dose of glutamate signaling is important for keeping the brain on alert. But an excess of it can lead to hyperactivity, which equals seizures,

Claire Simeon  8:37
the toxin will bind to these receptors and it will cause brain damage and you can see acute toxicosis which is characterized by seizures, coma, acute death. And if there's brain damage, then after the toxin has left the body and then that can lead over time to to the development of epilepsy.

Vivica  8:58
The brain damage these animals experience can be remarkably similar to that In humans,

Claire Simeon  9:04
studies have shown that the lesions in the brain are nearly identical to the lesions in temporal lobe epilepsy in humans. And so, so the sea lions can be a sort of a natural model.

Vivica  9:17
After Corona was deemed unreasonable. He found a permanent home in Six Flags discovery Kingdom where he received 24/7 monitoring and care. What

Claire Simeon  9:25
we were able to do is to monitor his appetite and to monitor his weight, and then to monitor him for for any observed neurological signs. And so because one of the things that was most challenging about his case, when he when he progressively got worse over over 2020, that year was really hard for all of us, including chronic. And so he his seizures were getting more and more frequent, but he also had behavioral changes so he would go off of food for really extended periods of time. Like during one month over the summer of 2020, he went off food for 16 days out of the month. And so throughout that time, he lost about a third of his body weight. And what's really challenging, I mean, as you all would understand that it was really challenging to keep his anti epileptic drug levels stable. And so, you know, if he was not eating, it was challenging to get him his medications, and that became more and

Deanna  10:26
more progressive. Time passed, and Kronus just got worse. He wasn't responding to his anti epileptic medication and his weight continued to plummet. His veterinary team was at a loss, his team is considering euthanasia. However, unbeknownst to them, a team of researchers a few dozen miles away held the key.

Scott Durbin  10:58
name is Scott Durbin, I'm a professor in the department neurological surgery, and the neuroscience program at UCSF, and I'm an adjunct professor in the Helen wills Neuroscience Institute at UC Berkeley. I'm a basic scientist running an epilepsy Research Laboratory at UCSF for about 20 to 23 years now, we focus on translational issues, these domoic acid poisoned sea lions, they clearly had behavioral seizures, they've been turning up for decades now, they have a number of behavioral issues, which we would call comorbidities, for example, they have trouble navigating. If you release them, for example, and tag them, they'll travel up to Seattle instead of San Diego in the winters. And most importantly, their seizures have been intractable. So when they've been treated with anti epileptic drugs, at the Marine Mammal centers, it has no effect.

Vivica  11:55
You can probably see where this is going. The scientist who studies epilepsy meets the sea lion with epilepsy, devises a treatment and all as well. While that's the just the story is filled with a lot more ups and downs and a good bit of faith. Dr Bair, Ben, for his part had never worked with anything remotely as large as a sea lion. And I found that

Scott Durbin  12:17
pretty fascinating too, just to kind of meet the patient that he came out. And he came up to one of his handlers, you know, I remember I took some video, just, you know, I have some references and pictures, largely, because he's a lot bigger than I was expecting. Of course, I always feel like when we do translational work, and we actually, you know, put our money where our mouth is, so to speak, you know, whether we find a dragon fish and we want to give it to people, or are this ng projects where we want to do a larger patient, someone has to take that leap of faith with me.

Deanna  12:49
That's someone to start with Dr. Simeon. Dr. Bear, Ben and his team had been hard at work in the lab developing treatments for temporal lobe epilepsy for years, and wanted to explore the translational application of these treatments for the eventual hopes of making them viable for human patients. Research had shown that domoic acid poisoning, sea lions had striking neurological similarities with human patients afflicted with temporal lobe epilepsy, making them obvious candidates for scaling up,

Scott Durbin  13:16
knowing we eventually want to translate our rodent studies to larger animals. I started to talk to the the Vets at the Marine Mammal Center in Sausalito to see if we could potentially treat one of these sea lions one or more of these sea lions that has demonic acid news point, epilepsy. And so we've been kind of talking to them about how to go about doing this for a couple years. And I went out and and gave a talk and showed the basic science and the things we had published in rodents. And so it turned out at one of these meetings where I was giving one of these presentations in Sausalito, Claire Simeon and her husband, Sean, were in the audience. And I guess we're we're taking notes.

Vivica  13:56
Dr. Simeone later reached out eager to hear how Dr. bourbons work could be applied to QUnit in particular, who at the time was experiencing up to 12 seizures a day, a cause for concern given that the recovery time between each seizure within the 24 hour period may not have been that long. The treatment devised

Deanna  14:15
by Dr. Bear ban and his team was based on the fundamental idea of fixing epilepsy by restoring the balance of excitation and inhibition in the brain. Others at UCSF had discovered that inhibitory neurons born in a part of the brain called the medial ganglionic eminence or MGE can be transplanted from embryonic brains to adult brains to restore inhibition. Think of embryonic brains as having a full reservoir of brake fluid. Over time, damage to the tank can lead to the leakage of brake fluid making breaking or inhibition less effective by adding in some of these inhibitory neurons later on in life to the hippocampus, the part of the brain where you see neuronal loss and temporal lobe epilepsy and in these domoic acid poisoned sea lines, you can top off the brake fluid reservoir, improving inhibition and keeping the r&d activity and check. This is obviously something of an oversimplification. Decades of work went into getting to the point of making the treatment work even in rodents. Sea lions, were a whole other ballgame.

Scott Durbin  15:11
We had this idea to treat sea lions, but there were two logistical issues. One, of course is where will we get what what would be the cell source that we would transplant into a sea lion, a large animal. So in rodent studies, it's pretty straightforward. We harvest the energy, but we can put, you know, get get enough tissue out of that to do a larger animal. And so we started to think other ways to go and I decided that we would use Pig cells on the premise that pig heart valves were one of the first Xeno transplants that occurred in humans, that is another one species into another species across feces transplant. And because we had accessibility potentially to pig embryos, from the from the Vets at UC Davis, so we went out to UC Davis talk to the veterinarians arrange to get pig embryos, so we could dissect out mg cells. So that's one of the problems we had a source of mg cells for a large animal. The second problem we ran into, of course, is with rodents, it was a straightforward surgery. So we know where the hippocampus is, there's well established maps of the hippocampus. None of this is of course available for for a sea lion.

Vivica  16:17
Dr. Bear, Ben and his team used a combination of MRI scans of the sea lion brain and sea lion skulls vailable from a museum to get an idea of where the hippocampus was located. The neurosurgeons use this map, coupled with a custom built surgical frame to deliver these embryonic pig cells directly into Chronos. hippocampus. What I even told

Scott Durbin  16:39
the people, the chrono handlers and events at the time I met them was there's really only two potential outcomes in my, in my guess, guess at that time before we did anything. One is that we would put cells in, and maybe we would miss it, or maybe they wouldn't work and nothing would happen. Or he would do better. And he looked same as we did with rodents, which we've been seeing for 10 years. Because of

Deanna  17:05
COVID restrictions, only handful of people were allowed in the building where the surgery would take place.

Scott Durbin  17:10
And so I actually ended up monitoring everything on zoom in the parking lot. And it was a long day, and I think was he was under anesthesia for five or six hours before we got to the point where we're doing the procedure to put the cells in, we're watching a video. And Diane sat next to me and was squeezing my hand and crying. And it was pretty amazing. To see how much you know, these people love Corona. And Corona, you know, it's, it's just a great, you know, story, but he's also you know, it's great to see this help help him and the people who care about. And so it turned out we you know, luckily we were able to deliver the cells to the right place, it's pretty clear that he's been seizure free for for over 14 months at that time. All of that is behavior, his weight, has his weight has gone back to normal. It's actually a little bit above his original, his feeding and other types of behaviors, which were, in a way autistic like or strange have all improved. In fact, Diane Cameron, who's one of his chief trainers sent me an email at the beginning of the month, to say they've seen, quote, extraordinary changes in him over the last few weeks. This is in 14 weeks pet posttransplant. He routinely comes out of his house, in his apartment for sessions, sessions being training sessions, which he didn't participate in before. He's learning new behaviors, understanding the following, following kind of directions for his right or left flipper and other things. They teach them and they're actually hoping that he'll make enough progress up the hill to take him out on stage next summer. And so that's a tremendous functional improvement.

Deanna  18:52
See, like we promised a happy ending.

Vivica  18:55
Corona was one of the lucky ones, that's for sure. But the reality is domoic acid poisoning, and the larger issues that made it a problem in the first place, namely global warming are still unaddressed. 1000s of others, like Corona will fall victim to this disease and won't get the benefit of this life saving surgery. If we want to help the sea lions and the ecosystem that these animals keep intact, we need to address the problem at the root 1000s of others like found that will fall victim to this disease and won't get the benefit of this life saving surgery. If we want to help the sea lions and the ecosystem that these animals keep intact, we need to address the problem at

Claire Simeon  19:37
the root. When you think about it from a from a large scale perspective. The value that I really see is for Corona is as an ambassador learning about him about domoic acid toxicosis and and you know the impact that Harmful Algal Blooms can have on marine mammals and and and the similarities between those lesions and temporal lobe epilepsy lesions. As for example, what we do know about these harmful algal blooms is that they are becoming larger and more persistent. And you know, you may have heard several years ago about the blob or El Nino events where there are these oceanographic events where there's really, really warm water. And that can favor these these types of harmful algal blooms. But biotoxins are definitely an issue that, you know, I think is very important, not just for the health of the ocean, but for human health as well.

Deanna  20:29
domoic acid in particular can cause something called amnesic shellfish poisoning, which is exactly what it sounds like memory loss, brain damage, and even death and humans that have eaten shellfish contaminated with high levels of domoic acid. But in addition to raising awareness about how these problems can affect people in the short term, they make these bigger issues, global warming, healthy ecosystem, loom larger and our consciousness,

Claire Simeon  20:52
just the fact that these these kinds of strides are being made you never know the kind of connections that are important for people, whether they, you know, see themselves in the value of this type of a procedure, or their loved ones, or it, you know, inspires them to kind of dig deeper about what's happening with the health of our ocean and our planet.

Transcribed by https://otter.ai
