Dwelling in perpetual darkness, Mexico’s blind cave fish have evolved in isolation, adapting new genetic traits to match their cloistered, crypt-like environment.

Unlike their ancestors who swam at the water’s surface, cave fish have no eyes. They struggle to sleep. They don’t socialize. Elevated levels of stress hormones pulse through their small, translucent bodies.

Cave fish also have an inexplicable tendency to swim in tight, repetitive circles. In an aquarium environment, the fish will sometimes appear to get stuck in a corner, lingering in place for long periods of time.

Now, a unique collaboration of Honolulu biologists and pediatric disability specialists is exploring the evolution of cave fish behavior and its implications for children with autism.

Yoshizawa dissects a small cave fish in his science laboratory at the UH Manoa campus in Honolulu, HI, Tuesday, November 13, 2018. Yoshizawa is studying cave fish in hopes of finding new treatments for humans with autism through his research with the fish. Civilbeat Photo Ronen Zilberman.

Biologist Masato Yoshizawa dissects a small cave fish in his science laboratory at the UH Manoa campus. Yoshizawa is studying cave fish in hopes of finding new treatments for humans with autism.

Ronen Zilberman/Civil Beat

“It’s amazing just to look at the movement patterns of the fish in the tank and realize that’s exactly what we would see if we were watching one of our autistic kids walking around a room,” said Miki Wong, director of research at the Honolulu pediatric disability treatment center Milestones.

“Autistic children tend to play alone,” she explained. “They’re the kid that will be in the corner by themselves. Some of them will have hand-slapping or another repetitive form of motion that doesn’t seem to have any function. They’ll walk around treating people no different than all the other objects in the room — there’s no interest. And that’s really what we are seeing in the fish, too.”

The ‘Keto’ Diet

Scientists have looked to mice and zebrafish as models to study the causes of autism spectrum disorder. But University of Hawaii Manoa biologist Masato Yoshizawa is the first to seek new insights into the symptoms of autism through the study of cave fish.

After discovering a shared set of genetic anomalies present in cave fish and people with autism in 2015, he partnered with Milestones researchers Wong and Dr. Ryan Lee, who led one of the world’s first studies of the behavioral effects of a ketogenic diet on children with autism.

The interdisciplinary team is exploring how cave fish respond to a ketogenic diet, and the implications of those responses for autism research. 

In his lab at UH, Yoshizawa has at his disposal thousands of cave fish and their cousin surface fish, which provide a cheap and relatively easy study model.

Masato Yoshizawa in his science laboratory at the UH Manoa campus in Honolulu, HI, Tuesday, November 13, 2018. Yoshizawa is studying cave fish in hopes of finding new treatments for humans with autism through his research with the fish. Civilbeat Photo Ronen Zilberman.

Partnering with local pediatric disability specialists, Masato Yoshizawa is studying cave fish in hopes of finding new treatments for autistic children.

Ronen Zilberman/Civil Beat

By contrast, Lee and Wong’s research on autistic children was far more limited in scope. Although they tapped more than 80 Hawaii youth to participate in the study, only 15 of the kids were willing and able to complete a strict, three-month ketogenic diet.

Low in carbohydrates and absent of sugar, the ketogenic diet can be laborious to prepare.

It’s a high-fat diet of butter, cream, coconut, avocado, nuts and other luxurious fats, as well as chicken, steak, bacon and eggs. While delicious in many ways, it can be impractical for busy parents to prepare three meals per day, plus snacks, without relying on store-bought staples like bread, rice, pasta and breakfast cereal.

Also forbidden are most grains, starchy vegetables, fruit and legumes.

The goal of the diet is to shift the body into ketosis, a natural metabolic state in which the body begins to derive energy from fat rather than carbohydrates.

A modified version of the so-called “keto” diet that incorporates a “cheat day” has become a fad among some athletes who praise its energy-boosting and weight loss effects.

But there’s no cheating — not even for a piece of Halloween candy or your own birthday cake — for people who adopt the ketogenic diet as a medical treatment.

“We eat tons of rice in Hawaii and we drink a lot of soda,” Wong said. “There’s sugar everywhere. Processed foods are everywhere. And these are all foods that will prevent you from going into ketosis.”

Feeding cave fish a ketogenic diet, on the other hand, is a far simpler task.Yoshizawa is finding that his cave fish respond to the ketogenic diet in the same way that autistic children do — both species become better socialized.

“Families often want another alternative,” Wong said. “We hear a lot of, ‘Do I have to put my child on medicine?’ and right now that’s the only treatment. So we’re trying to find more options.”

The diet was not, however, effective in reducing the restrictive, repetitive movements (such as hand-flapping or body rocking) present in the fish and in some of the children.

“With the children, the first thing that changed, usually on day two or three of the diet once their bodies went into ketosis, is that they started demonstrating eye contact and interest in other people,” Wong said. “The same thing is happening with the fish. There’s a real difference in their social behavior.”

These findings add to early evidence that some symptoms of autism could be effectively managed through diet. Treatment options are currently limited to cognitive behavioral therapy and medication.

Evolved from the surface fish, top, Mexico’s blind cave fish, bottom, have developed new physical and behavioral traits in response to their shadowy ecosystem in deep, freshwater caves. The fish are the same species, but differentiated by striking genetic differences.

Masato Yoshizawa

The ketogenic diet is already long-established as a viable treatment option for drug-resistant epilepsy.

In addition to his dietary studies, Yoshizawa is examining the effects on cave fish of the antipsychotic drug Abilify, a medication commonly prescribed for autistic children with anxiety.

He’s also probing a genetic mutation found in some particularly voracious cave fish that is linked to obesity in humans.

His biggest hope is that the cave fish trials will shed light on how autism forms in humans and help establish new remedies.

“I hope we can find a supplemental treatment for these suffering kids,” Yoshizawa said. “If you think about kids 4 or 5 or 6 years old and they can’t have cake on their birthday, that’s sad. But now we start realizing that sugar is a kind of drug because your brain always wants it because it’s quick energy.”

Bridging The Gap Between Fish And Humans

There are, of course, limitations when attempting to translate the results of a fish study to humans.

Cave fish are blind, for example, so there’s a striking difference in biology. Fish also have different social behavior patterns than humans.

Despite these disparities, the results of Yoshizawa’s work with cave fish are helping researchers like Lee and Wong who work with autistic children to craft more meaningful research.

The cave fish studies also help to further establish the connection between the gut and the brain, and the role of food as a valid form of treatment for developmental disorders.

Wong said the fish might also inform the parameters of a future research project she wants to conduct in which autistic children adhere to a regular diet but receive a daily dose of ketones in medicine form.

“I’m excited about what fish can teach us about human behavior,” said Lee, who led a neurodevelopmental clinic at Shriners Hospital for Children in Honolulu before becoming a founding member of Milestones.

“While it’s exciting and we try to draw a correlation between social behavior in the fish and in our children, there’s something unique about humans and our ability and desire to communicate socially that’s very different than anything we see in the animal kingdom. We’re still trying to bridge that human and fish divide to understand autism better.”

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