Thursday, July 21, 2022

What humans can learn from the sea cucumber’s toxic arsenal

While ordinary vegetable cucumbers cost $3 per kilo, sea cucumbers can cost over $3,000 per kilo. These animals are prized as a delicacy in Asia, and are used by pharmaceutical companies to treat diseases like cancer.
Unfortunately, over-harvesting now threatens many sea cucumber populations.

From Wired by Maggie Chen

Sea cucumbers are squishy and soft.
They also employ lethal strategies to protect themselves.

A SEA CUCUMBER, lying innocently on a bed of sand, looks kind of like a blob, and feels almost plushy.
But although the creatures seem squishy and defenseless, they have evolved fascinating strategies to keep themselves safe.
Anne Osbourn, a biologist at the John Innes Center in England, recently published a paper in Nature Chemical Biology that uncovered chemical compounds through which sea cucumbers protect themselves from attack—and themselves from being destroyed by their own poison.
Her team believes that understanding how to synthesize these valuable compounds can allow for the design and mass production of molecules that might be useful for human health.

Despite their unassuming demeanor, sea cucumbers are equipped with clever chemical tricks.
When threatened by predators, one of the strategies these animals can use is to expel their thread-like internal organs—known as Cuvierian tubules—through their anus.
These tubules immobilize the predator in a sticky, toxic embrace.
The toxicity comes from saponins: chemical compounds that are known for their antioxidant and anti-inflammatory properties.
Saponins are commonly found in plants as an antimicrobial defense mechanism, and they are used to fend off pathogens such as fungi.
Their antifungal activity comes from their ability to bind with cholesterol­—a key component of the cell membrane­—and poke holes in it, causing cell death.

But saponins are much less common in animals.
Having originally studied these compounds in plants, Osbourn was intrigued to find that they existed in sea cucumbers—specifically a variety of saponins that are built from terpenoids, organic ring-like scaffolds.
(These triterpenoid saponins differ chemically from other classes, due to the attachment of methyl groups at specific carbon positions. And, as Osbourn puts it, “They look a bit like chicken wire.”)

To figure out exactly which saponins the sea cucumber makes, the scientists extracted chemical compounds from stores of dried sea cucumber as well as from the tissues of live sea cucumbers (P.
parvimensis and A.
japonicus) at various stages of development.
Reconstituting a dried sea cucumber was relatively simple: “You just put one sea cucumber in a petri dish, put some water, come back a day later, and it becomes a real sea cucumber,” says coauthor Ramesha Thimmappa, formerly a postdoctoral scholar in Osbourn’s lab.
“It swells!”

Then, the scientists used liquid chromatography mass spectrometry, where individual compounds in the extracts are separated into charged particles and shot into a mass spectrometer.
The instrument measures the speed at which the particles travel to determine each one’s weight, which can then be used to identify each compound’s molecular composition.

They discovered several saponin compounds, some of which, Osbourn says, “tend to be in the outer walls of the sea cucumber: in the tentacles, the body wall, the feet. In the outer tissues, it’s the right place to provide protection.”
They found others that were primarily present in the early growth stages of the sea cucumbers.
“We think that they may protect the eggs against predators—fish and various other grazing creatures,” she says.

But this chemical defense creates a big problem for sea cucumbers: They need to avoid killing themselves with their own toxins.
And that means their own cells can’t contain cholesterol, the target that the saponins bind to and pierce.
Instead, they have evolved two kinds of cholesterol alternatives: lathosterol and 9(11) sterols, which probably fulfill the same function of maintaining cell membrane stability.
The scientists believe that the sea cucumbers’ ability to make saponins—and these saponin-resistant sterols—evolved concurrently.
“We think it’s a self-defense strategy,” Osbourn says.
“If you can produce these toxic compounds, you have to be able to not poison yourself.”

As it turns out, these unique evolutionary capabilities hinged upon a single point.
Sea cucumbers are part of the echinoderm family, along with sea stars and sea urchins.
They all share a common ancestor, but sea urchins don’t have the same saponin defense superpowers.
So to figure out how the sea cucumbers had diverged genetically from the rest of the group, Osbourn and Thimmappa (now an assistant professor of genome engineering at Amity University) compared their genomes to those of their echinoderm counterparts.
Specifically, the researchers were interested in studying lanosterol synthase, a highly evolutionarily conserved enzyme that is critical for sterol and saponin biosynthesis.
It folds their precursor molecules into intricate origami-like shapes.

The team discovered that sea cucumbers just don’t have it.
Instead, they have two enzymes that are from the same family but are drastically different in biological function: One gives rise to the saponins found in juvenile sea cucumbers, the other creates their cholesterol alternative and also generates saponins found in their outer walls.
One change from the traditional lanosterol synthase sequence in the amino acid chain was all it took to create these two sea cucumber-specific enzymes with completely different functions—an evolutionary adaptation that was “simple, but very elegant,” says Thimmappa.

This work of characterizing and determining the functions of single chemical compounds in sea cucumbers is “super cool,” says Leah Dann, a PhD student at the University of Queensland who studies island conservation and was unaffiliated with the study.
For sea cucumbers, which don’t have adaptive immunity (the ability to generate antibodies that can prevent future diseases), these saponins might help protect against harmful microbes or fungi.
And, since they don’t have a spiny outer shell, these chemical defenses may explain why many organisms leave them alone.
“They look so yummy,” Dann says.
“But most fish will not touch them.”
“They explained why sea cucumbers have triterpenoid saponins,” says Lina Sun, a professor at the Institute of Oceanology at the Chinese Academy of Sciences.
(Sun is unaffiliated with the study, and her comments have been translated from Chinese.) Discovering and characterizing the two synthase pathways that generate these saponins and special sterols is “very important,” she adds.
From this work, Sun is interested to see how, in other echinoderm species, the genes associated with saponin biosynthesis might differ from those in sea cucumbers.

A compound that attacks cholesterol has some intriguing implications for human health care.
“Sea cucumbers are highly valued both for food and for health,” Osbourn says.
“Sea cucumber extracts, which are rich in saponins, are very valuable.”

They have long been harvested as a culinary delicacy—and revered for their antioxidant and anti-inflammatory health benefits.
(The saponin dosage in certain sea cucumbers, while sometimes lethal for fish and other small critters, can be edible and even beneficial for humans.)
Studies have previously found that sea cucumber saponins can reduce cholesterol and inhibit inflammation to alleviate atherosclerotic plaques in mice, and have been connected with anti-tumor activity against cancer.

Saponins also have other uses for home and personal care, like for making soap.
Originally named after their presence in the roots of the soapwort plant (Saponaria), saponins can dissolve in water to create a frothy broth.
“Nature is so good at making chemicals,” Osbourn says admiringly.

In the future, she and her team are interested in learning how to synthesize more of these naturally derived compounds—to recreate them on a larger scale without having to harm any sea cucumbers, and to “harness all of the triterpene diversity that’s out there in nature.”
Ultimately, she thinks, such molecules could be designed and made on demand, to be used as medicines, or commercialized as foaming agents or emulsifiers.

In the meantime, though, one of the most likely places you’ll find sea cucumbers and their compounds is in soup—something Osbourn was once served for lunch when attending a conference in China.
“It was quite chewy,” she says.
“I’m sure it was good for me.”
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