We may need a fourth law of thermodynamics for living systems

The physics of thermodynamics, which involves quantities such as heat and entropy, offers well-established tools for determining how far from equilibrium an idealized system of particles is. But when it comes to life, with its complex, interconnected cells, it’s not clear that our current set of thermodynamic laws is enough — and a set of experiments involving human cells could be a first step toward creating a new one.

Thermodynamics is important to life because disequilibrium is one of its key properties. But because cells are filled with molecules that actively consume energy, their state is different from, say, a group of beads floating in a liquid. For example, biological cells have what is called a set point, meaning they behave as if they are following an internal thermostat. There is a feedback mechanism that brings them back to set point, allowing them to continue operating. It is this type of behavior that is perhaps not easily captured by classical thermodynamics.

N Narinder and Elisabeth Fischer-Friedrich from Dresden University of Technology in Germany wanted to understand in detail how imbalance in living systems differs from the state of imbalance in a non-living system. They did this with human HeLa cells – a line of cancer cells commonly used in scientific research that were taken without consent from an African-American woman called Henrietta Lacks in the 1950s.

First, the researchers used chemicals to stop cells midway through cell division, then probed their outer membranes with the tip of an atomic force microscope, which can precisely interact with objects as wide as a fraction of a nanometer. This made it easier to assess how each cell’s membrane fluctuated (how much the tip of the microscope moved) and how those fluctuations changed when researchers interfered with certain cellular processes, such as stopping the processing of certain molecules or the movement of certain proteins.

They discovered that, for these fluctuations, a standard thermodynamic “recipe” that would explain the behavior of a non-living system was no longer completely accurate. More precisely, the notion of “effective temperature” has proven to be imprecise. This is an idea intended to capture something similar to our understanding of how temperature rises when we unbalance a system like a pot of water by heating it.

But the researchers concluded that a quantity more useful for capturing the degree of imbalance in life is a property called “time reversal asymmetry.” This explores how much a given biological process – for example, molecules repeatedly connecting to larger molecules before splitting again – would differ if it occurred backwards rather than forwards in time. The presence of time reversal asymmetry could be directly linked to whether biological processes serve a purpose such as survival and proliferation, says Fischer-Friedrich.

“We know in biology that there are many processes that really depend on whether a system is out of balance, but it’s actually important to know how out of balance a system is,” says Chase Broedersz of Vrije Universiteit Amsterdam in the Netherlands. The new study identifies valuable new tools for pinpointing this problem, he says.

This is an important step toward improving our understanding of active biological systems, says Yair Shokef of Tel Aviv University in Israel. He says that the fact that the team was able to experimentally measure not only time reversal asymmetry, but also several other non-equilibrium measures at once, is both novel and useful.

However, we may need to take many additional steps if we want to understand life through thermodynamic principles. Fischer-Friedrich says that ultimately the team wants to derive something akin to a fourth law of thermodynamics that only applies to living matter where processes have a set point. They are already working to identify physiological observables – specific elements to measure in cells – from which the development of such a law could begin.