Inside a cell there are tiny droplets that have no membrane yet behave like separate compartments. One such droplet, made of identical short RNA fragments, resembles fresh aspic: it is transparent, springy, and easily changes shape. But if you watch it long enough, something resembling a sponge begins to grow inside it. At first this is noticeable only in that molecules in the center move more slowly than those at the edge. Then the droplet stops merging with its neighbors, and its core becomes almost solid. It is this process, which scientists call aging, that has now been reproduced in a computer model and dissected in detail.
The cause turned out to lie not in the composition but in the order of the letters. Each RNA strand with CAG repeats can form pairs with neighboring strands, the way a hook-and-loop fastener catches on itself. When there are many such fasteners, the strands interweave, and the droplet from the inside begins to look like a ball of yarn with loose ends sticking out. In the center of this ball, molecules barely move, because each one is pinned by its neighbors. At the edge, however, there is more freedom, and there the droplet remains fluid for a long time. This is how spatial heterogeneity arises: the core ages faster than the shell.
To test how important the order of the letters really is, the researchers compared two droplets. The first contained CAG repeats, the second the same letters but in random order. The composition is identical, yet the behavior is different. The random sequence aged four to five times more slowly, because its strands less often formed strong pairs with one another. So it is not what the droplet is made of that matters, but how the instruction for its molecules is written.
This work answers a question that had remained open. It was unclear whether the aging of RNA droplets could arise spontaneously, solely from interactions encoded in the sequence. Now it is clear: yes, it can. And the heterogeneity of aging is explained by a gradient of base pairing. In the center of the droplet there are more pairs, the strands are more tangled, so everything freezes faster there. This mechanism resembles a feedback loop: pairing extends the strands, extension increases entanglement, entanglement slows motion, and slow motion reinforces the network.
Practical benefits may emerge in medicine. In certain hereditary diseases associated with CAG repeats, RNA foci form in cells and over time harden, interfering with normal function. If the irreversible hardening of these droplets can be prevented, it may be possible to slow the progression of the disease. For now this is only a direction for future research, but scientists now have a specific molecular target.
In the core of the droplet, relaxation times are six times longer than at the periphery, and the density of entanglement nodes is five times higher. Yet both sequences have the same nucleotide composition but a different order, and that alone is enough for one to age five times faster than the other.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.