Fats can warn of danger in our bodies

For years, some diseases have resisted easy answers, including autoimmune conditions where the body attacks itself, and neurodegenerative disorders that destroy memory, hearing, movement and even sight.

Together, these illnesses affect millions of people.

The body does release warnings for such conditions, but those first whispers of trouble have remained largely unheard, undetected or even poorly understood. Until now.

Scientists from Indian Institute of Science Education and Research (IISER), Pune, have uncovered enough clues to believe some of the strongest warnings may be coming from a group of molecules long ignored: fats.

Also known as lipids, fats have never enjoyed good PR. They are blamed for clogged arteries, bad cholesterol and weight gain. But biochemist Siddhesh Kamat, who runs the IISER lab, said fats may be among the body’s most subtle communicators — and among its most vital defenders.

“There’s an entire class of fats that don’t store energy or make up cell membranes,” he told TOI. “They send hormone-like signals, and it has been just a few years since we’ve begun to understand how they really work.”

These “signalling lipids” are rare and elusive. They exist in the body in minuscule quantities, dissolve poorly in water and vanish easily in lab settings. Many scientists didn’t even know they existed until 20 years ago.

Today, though, researchers like Kamat and his team are tracking them in the brain, through the immune system, and even inside organs, to answer some fundamental questions: When are these lipids made? What do they actually do in the body? And what happens when they’re troubled? The IISER team focused on one class inparticular — Lysophosphatidylserine, or LysoPS. It was barely a topic when Kamat started up his lab in 2016, but LysoPS was showing associations to autoimmune and neurological disorders.

“We saw patients had different levels of LysoPS than healthy individuals,” Kamat said. “Problem was nobody really knew how to measure them accurately.” That became the IISER lab’s first big challenge. Unlike proteins or DNA, lipids are extremely hard to isolate.

It took Kamat and team two years to develop a method to detect LysoPS in blood and tissue. “We probably failed 90% of the time,” Kamat said. “And we needed expensive mass spectrometers, hard to come by in most Indian labs.”

Then there was the molecule itself. Labs can procure molecules to work with, but LysoPS was rare in the market too. Only one US firm sold it, at an exorbitant price.

So, the IISER lab took on another Herculean task: synthesizing the molecule from scratch.

“After that, we could introduce it into animal models, into cell cultures, into their brains,” Kamat said. What they found was astonishing. LysoPS was like a “biological flare gun”. When tissues were injured, it helped summon immune cells to the site of damage. It regulated inflammation, and then — critically — it helped shut it off. Too little LysoPS, and the immune system didn’t react to threats. Too much, the body spiralled into chronic inflammation. “They have to be at optimum levels,” Kamat said.

One disorder caught the IISER lab’s attention: a genetic condition called PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). Those with PHARC often get symptoms in early adulthood, from cataract, hearing loss and in severe cases brain shrinking.

“We know of at least six families in India that harbour this disease. There is currently no cure,” Kamat added.

His team found that mutations in an enzyme, which breaks down LysoPS, were leading to dangerously high lipid levels in the brain.

“Immune cells in the brain, called microglia, went into overdrive to regulate the levels,” he explained. “They started attacking neurons, just chewing them up.”

After this finding, the lab worked on mouse models of PHARC to test new therapies. One is to block the receptor that LysoPS binds to, another attempts to slow the enzyme that makes the lipid in the first place.

Both approaches are still experimental but promising, Kamat said.

His team is also working on a test to detect abnormal LysoPS levels in blood and cerebrospinal fluid, with hopes to catch the disease early — before it can cause irreversible brain damage.

Another breakthrough emerged in allergy research. The IISER lab showed LysoPS’ key role in release of histamines from mast cells — the culprits behind allergic reactions.

“If we can regulate lipid release instead of suppressing the full immune response, as is the case now in most allergy drugs, we can make allergy treatments more precise — antihistamines that don’t make you drowsy,” Kamat said.