For decades, researchers have attempted to unmask a shadowy receptor in our cells, known as sigma–2. They figured out that sigma–2 is present in the liver, kidneys and central nervous system, and they stumbled upon drugs that bind to it, but they couldn’t unlock its structure or function.

By taking an unconventional approach to the problem, the HMS scientists and their colleagues have at last discovered what sigma–2 really is: transmembrane protein (TMEM) 97, known to regulate cellular cholesterol levels.

The discovery, published May 30 in PNAS journal, solves a 30–year mystery that has “crippled” investigations into exactly how sigma–2 is involved in Alzheimer’s disease, schizophrenia and several types of cancer and how the receptor might be manipulated to treat those diseases, the study authors said.

“I hope our identification of sigma–2 will lead to a detailed molecular understanding of how this unusual receptor works and what happens when drugs act on it,” said Andrew Kruse, assistant professor of biological chemistry and molecular pharmacology at HMS and senior author of the paper. “In the long term, if we want to treat conditions that haven’t been effectively treated before, we need to understand their fundamental biology.”

The findings also may open new doors for understanding and devising treatments for Niemann–Pick disease type C, a fatal disorder in which a person’s cells can’t metabolize cholesterol and other fats. Studies suggest TMEM97 influences levels of a protein that causes the disease. With the revelation that TMEM97 is the same as sigma–2, the well–stocked toolbox scientists have built to study sigma–2 can now be applied to Niemann–Pick as well.

Sigma receptors were discovered in 1976. In the ensuing years, scientists lifted several layers of the shroud surrounding sigma–1, which has been linked to neurodegeneration, addiction and pain; in 2016, the Kruse lab uncovered its atomic structure. But despite its own compelling links to health and disease, sigma–2 remained stubbornly in the shadows.

Instead of treading the same fruitless paths others had attempted, Kruse took a step back and reevaluated assumptions the field had made.

First, those on the hunt to identify sigma–2 had been either culturing mammalian cell lines – a technique that is expensive to do in bulk – or studying rat livers, which are small and hard to acquire in sufficient quantities. Kruse decided to try a cheap and scalable alternative: calf livers.

His lab bought a dozen livers from a mail–order meat company for about $20. They were flash–frozen, so the tissue was well–preserved once thawed. Tests indicated the inexpensive organs were “at least as good, if not better” than what other scientists had been using, said Kruse.

The researchers optimized every step as they designed their recipe to extract, purify and identify sigma–2. Crucially, Kruse’s group partnered with synthetic chemists at the University of Texas at Austin to build a molecule that bound to sigma–2. That allowed them to capture enough sigma–2 molecules within the liver purée that a mass spectrometer – a device that separates particles by weight – could detect them along with the hundreds of other proteins in the sample.