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March 15, 2016

Simple Mechanism Lets Primitive Cells Grow, Avoid Washed-Out Feeling

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    Fatty acid vesicles containing split fragments of an RNA enzyme (black) and high concentrations of short pieces of RNA (red) exhibit no enzyme activity because the short pieces bind to complementary sequences in the RNA enzyme (upper left). When vesicles comprised of membranes containing a simple fatty acid derivative and more complex molecules called phospholipids are mixed with those not containing phospholipids (lower images), the phospholipid-containing vesicles expand by taking up membrane components from the simpler vesicles. This growth dilutes the contents of the phospholipid-containing vesicles, separating the short pieces of RNA from the enzyme fragments, allowing the fragments to assemble and activating the enzyme (upper right). [Katarzyna Adamala, Ph.D., MGH]

    If the origins of life are to be recapitulated, any number of natural cellular innovations will have to be reenacted in the artificial cells built by scientists. One of these innovations, an enzyme activation mechanism, appears to have been brought to the fore by scientists based at Massachusetts General Hospital. With this mechanism, primitive cells suppress enzyme activity when they are small and their contents are concentrated and enhance enzyme activity while they grow and their contents become increasingly dilute.

    The mechanism, report the scientists, provides a simple explanation of how the first cells, the ones that evolved at the origin of life, may have picked up the trick of maintaining homeostasis. Details of the mechanism appeared March 14 in the journal Nature Genetics, in an article entitled, “A Simple Physical Mechanism Enables Homeostasis in Primitive Cells.”

    “[We] show that concentration-dependent reversible binding of short oligonucleotides, of both specific and random sequence, can modulate ribozyme activity,” wrote the article’s authors. “In both cases, catalysis is inhibited at high concentrations, and dilution activates the ribozyme via inhibitor dissociation, thus maintaining near-constant ribozyme specific activity throughout protocell growth.”

    This work was accomplished in the laboratory of Jack Szostak, Ph.D., a co-recipient of the 2009 Nobel Prize in Physiology or Medicine for his contribution to the discovery of the enzyme telomerase. In the current study, Dr. Szostak’s team examined how the concentration of a protocell’s contents might affect the activity of RNA enzymes called ribozymes. The researchers hypothesized that high levels of small nucleic acid strands within a cell might bind to corresponding sequences on a ribozyme, suppressing its activity. They first tested this in free solution—not within vesicles—and found that short RNA strands could totally shut down ribozyme activity at high concentrations but had little effect at low concentrations.

    Experiments with vesicles containing both ribozymes and short strands of RNA specifically designed to bind to the ribozymes showed that enzymatic activity remained steady as the vesicles expanded; but in vesicles containing the enzymes alone, activity dropped as the vesicles grew. The researchers also observed this regulatory effect when the short strands of RNA contained random sequences.

    “This simple physical system enables a primitive homeostatic behavior: the maintenance of constant ribozyme activity per unit volume during protocell volume changes,” the researchers added. “We suggest that such systems, wherein short oligonucleotides reversibly inhibit functional RNAs, could have preceded sophisticated modern RNA regulatory mechanisms, such as those involving miRNAs.”

    Previous studies had shown that simple membranes comprised of fatty acids and lacking the complex molecular components of modern cells would still be permeable to small nutrient molecules, including those needed to assemble nucleic acids, such as RNA or DNA. Also, a 2013 study showed that it was possible to copy molecules of RNA—which many believe was the genetic blueprint of the first cells—without the complex enzymes used by today's cells, even within small sacs or vesicles formed from fatty acid membranes. Finally, Dr. Szostak's team also found that such vesicles will expand under certain conditions, raising the question of how vesicles' internal environment can be maintained, since their contents would become diluted as the enclosing membranes expand.

    "Without some sort of regulatory mechanism like we've shown here, cellular growth would be accompanied by some loss of function, since active enzymes would be present at a lower concentration in larger cells," said Aaron Engelhart, Ph.D., a postdoctoral fellow in Dr. Szostak’s laboratory and the first author of the Nature Genetics article. "We haven't extended this work to dividing vesicles yet, but a key long-term goal of the lab is developing a full, chemically based primitive cell cycle, including both growth and replication. A number of people in the lab are working on the next step towards that—systems that will allow us to make many copies of a single strand of RNA—and it will be very exciting to see how systems like the one we've explored in this paper work in such a cycle."

    "Modern cells are constantly regulating what they are doing—synthesizing, degrading, and exporting a whole suite of RNAs and proteins—depending on the cell's particular needs at the time," Dr. Engelhart explained. "One would expect that the earliest cells weren't nearly as complex as today's cells, but they still had the need to regulate their internal environment. The sort of regulation we've shown here—switching on enzymes during growth—is perhaps the simplest form of the internal regulation that a primitive cell might have needed."

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