New research offers a potential explanation for the formation of early Earth protocells.

Few questions have captivated humankind more than the mystery of life's origins on Earth. How did the first living cells emerge? How did these early protocells develop the structural membranes essential for thriving and eventually assembling into complex organisms?

New research from the lab of University of California San Diego Professor of Chemistry and Biochemistry Neal Devaraj has uncovered a plausible explanation involving the reaction between two simple molecules. This work appears in Nature Chemistry.

The Role of Lipid Membranes in Life

Life on Earth requires lipid membranes – the structure of a cell that houses its interior mechanics and acts as a scaffold for many biological reactions. Lipids are made from long chains of fatty acids, but before the existence of complex life, how did these first cell membranes form from the simple molecules present on Earth billions of years ago?

Scientists believe that simple molecules of short fatty chains of fewer than 10 carbon-carbon bonds (complex fatty chains can have nearly twice that many bonds) were abundant on early Earth. However, molecules with longer chain lengths are necessary to form vesicles, the compartments that house a cell's complicated machinery.

Time-lapse fluorescence microscopy video showing vesicle formation (images were taken every 2 minutes for 4 hours). Credit: Neal Devaraj lab / UC San Diego

While it may have been possible for some simple fatty molecules to form lipid compartments on their own, the molecules would be needed in very high concentrations that likely did not exist on a prebiotic Earth – a time when conditions on Earth may have been hospitable to life but none yet existed.

"On the surface, it may not seem novel because lipid production happens in the presence of enzymes all the time," stated Devaraj, who is also the Murray Goodman Endowed Chair in Chemistry and Biochemistry. "But over four billion years ago, there were no enzymes. Yet somehow these first protocell structures were formed. How? That's the question we were trying to answer."

A Groundbreaking Discovery: Lipid Formation Without Enzymes

To uncover an explanation for these first lipid membranes, Devaraj's team started with two simple molecules: an amino acid named cysteine and a short-chain choline thioester, similar to molecules involved in the biochemical formation and degradation of fatty acids.

The researchers used silica glass as a mineral catalyst because the negatively charged silica was attracted to the positively charged thioester. On the silica surface, the cysteine and thioesters spontaneously reacted to form lipids, generating protocell-like membrane vesicles stable enough to sustain biochemical reactions. This happened at lower concentrations than what would be needed in the absence of a catalyst.

"Part of the work we're doing is trying to understand how life can emerge in the absence of life. How did that matter-to-life transition initially occur?" said Devaraj. "Here we have provided one possible explanation of what could have happened."

Reference: "Protocells by spontaneous reaction of cysteine with short-chain thioesters" by Christy J. Cho, Taeyang An, Yei-Chen Lai, Alberto Vázquez-Salazar, Alessandro Fracassi, Roberto J. Brea, Irene A. Chen and Neal K. Devaraj, 30 October 2024, Nature Chemistry.
DOI: 10.1038/s41557-024-01666-y

This research was supported, in part, by National Science Foundation (EF-1935372) and the National Institutes of Health (R35-GM141939).

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