An elegant ballet of proteins enables modern cells to replicate themselves. During cell division, structural proteins and enzymes coordinate the duplication of DNA, the division of a cell’s cytoplasmic contents, and the cinching of the membrane that cleaves the cell. Getting these processes right is crucial because errors can lead to daughter cells that are abnormal or unviable.
Billions of years ago, the same challenge must have faced the first self-organizing membranous bundles of chemicals arising spontaneously from inanimate materials. But these protocells almost certainly had to replicate without relying on large proteins. How they did it is a key question for astrobiologists and biochemists studying the origins of life.
“If you delete all enzymes in the cell, nothing happens. They’re just inert sacks,” said Anna Wang, an astrobiologist at the University of New South Wales in Sydney. “They’re really stable, and that’s kind of the point.”
However, in a recent paper in Biophysical Journal, Romain Attal, a physicist at the City of Science and Industry in France, and the cancer biologist Laurent Schwartz of the Paris Public Hospitals developed a series of mathematical equations that model how heat alone could have been enough to drive one important part of the replication process: the fission of one protocell into two.
Attal thinks that that the chemical and physical processes active in early life were probably quite simple, and that thermodynamics alone could therefore have played a significant role in how life began. He said that the kinds of basic equations he has been working on could spell out some of the rules that governed how life first emerged.
“Temperature gradients are important to life,” Attal said. “If you understand a subject, you need to be able to write down its principles.”
Flipping for Fission
For primitive cells to divide themselves without complex protein machinery, the process would have needed a physical or chemical driver. “It’s really about stripping a cell down to its basic functions and thinking, ‘What are the basic physical and chemical principles, and how can we mimic that without proteins?’” Wang said.
Figuring out these processes becomes more challenging when you consider that scientists still can’t agree on a definition of life in general, and of protocells specifically.
What scientists do agree on is that protocells must have had some kind of heritable information they could pass down to daughter cells, a metabolism that carried out chemical reactions, and a lipid membrane isolating the metabolism and heritable information from the randomness in the rest of Earth’s primordial soup. Whereas the outside chemical world was inherently random, the partitioning provided by the lipid membrane could create an area of lower entropy.
For a protocell to grow before it divides, it would have to increase not only the volume inside the cell but also the surface area of the surrounding membrane. To create two smaller daughter cells with the same total volume as the parent cell would require additional lipids for their membranes, because their surface area would be larger relative to their volume. The chemical reactions needed to fuel the synthesis of these lipids would give off energy in the form of heat.
As Attal discussed these ideas with Schwartz, he began to wonder whether this energy was enough to drive early cell division. A search of the research literature revealed a study finding that mitochondria (the cell’s energy center, which began as a symbiotic bacterium billions of years ago) have a slightly higher temperature than the surrounding cell. Attal wanted to know whether that energy difference could be generated in protocells, and whether it was adequate to drive fission.
He began sketching out a series of equations to model what might be happening. He started with a series of assumptions, such as that the protocell would be rod-shaped and that it had a double-layered membrane allowing nutrients to diffuse in and wastes to diffuse out.
“It’s a very, very rough model,” he said. “I was surprised that it could be reduced to a single differential equation.”
Attal realized that the energy produced by the primitive cellular metabolism would heat up the lipids on the inside of the membrane more quickly than those on the outside. Thermodynamics would then force the energetic inner lipids to “flip” to the outside, causing the outer membrane layer to expand at the expense of the inner layer. One easy solution to this imbalance would be for the cell to pinch together into two daughter cells. This pinching would occur at the middle of the parent cell, where it was hottest and the lipid movements were most pronounced.
Too Small to Get Hot?
The work is purely theoretical, but Attal said it can be tested experimentally by creating similar vesicles in the lab and measuring whether the temperature inside is different from the temperature outside.
Wang says the work is important as a reminder that the asymmetry in lipid membranes could play a role in primitive life. However, both she and the biophysicist Paul Higgs of McMaster University are skeptical of some of the assumptions Attal made. They both pointed out that because cells and protocells are small, only minimal heat could be generated, and they questioned whether that temperature difference would be large enough to drive fission before the heat diffused across the membrane.
Wang also has doubts about the proposed movement of the lipids between the inner and outer membrane. In modern membranes, lipids don’t flip-flop readily between the inside and the outside because their molecules have complex structures. That may not be the case for the simpler lipids that early life is thought to have used. When scientists create vesicles from these compounds in the lab, “they move around like crazy. You can’t stop it from happening,” she said.
Higgs questioned Attal’s assumption that the cells would be rods. That shape requires specific proteins to stiffen the membrane, which protocells almost certainly lacked. As a result, they would be spherical, not rod-shaped.
“I don’t see how you can maintain a rod shape without a hard wall,” he said.
Neither of these issues means that heat didn’t play a role in early cell division, only that Attal’s mathematical model may not be the most accurate, Wang says. Still, Claudia Bonfio, a biochemist at the University of Strasbourg in France, says that the paper adds to the literature on early life because “it’s a nice starting point for experiments. We too often forget that reactions consume and produce heat, which could have an effect on things like fission.”