We may need a fourth law of thermodynamics for living systems

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

Thermodynamics is important for life, because being out of equilibrium is one of its key properties. But because cells are filled with molecules that actively consume energy, a cell’s state is different from, say, a bunch of beads floating in a liquid. For instance, biological cells have what’s called a set point, which means they behave as if they are following an internal thermostat. There is a feedback mechanism that brings them back to the set point, which lets them keep functioning. It is this kind of behaviour that may not be easily captured by classical thermodynamics.

N Narinder and Elisabeth Fischer-Friedrich at the Dresden University of Technology in Germany wanted to get a detailed understanding of how disequilibrium in living systems differs from the state of disequilibrium in a non-living system. They did so with HeLa human 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 the cells midway through cell division, then probed their outer membranes with the tip of an atomic force microscope, which can precisely interact with objects only a fraction of a nanometre wide. This made it easier to assess the ways in which each cell’s membrane fluctuated – how much the microscope’s tip jiggled – and how those fluctuations changed when the researchers interfered with some of the cell’s processes, such as interrupting the morphing of some molecules or the movement of certain proteins.

They discovered that, for these fluctuations, one standard thermodynamic “recipe” that would explain the behaviour of a non-living system wasn’t fully accurate anymore. Specifically, the idea of “effective temperature” proved imprecise. This is an idea meant to capture something similar to our understanding of how temperature increases when we take a system like a pot of water out of equilibrium by heating it.

But the researchers concluded that a more useful quantity for capturing the degree of life’s disequilibrium is a property called “time reversal asymmetry”. This explores the extent to which a given biological process – for instance, molecules repeatedly connecting into bigger molecules before splitting up again – would differ if it ran backwards instead of forwards in time. The presence of time reversal asymmetry might be directly related to the fact that biological processes serve a purpose such as survival and proliferation, says Fischer-Friedrich.

“We know in biology that there’s a lot of processes that really rely on a system being out of equilibrium, but it is actually important to know how far a system is out of equilibrium,” says Chase Broedersz at Vrije Universiteit Amsterdam in the Netherlands. The new study identifies valuable new tools for pinning that down, he says.

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

However, we may need to take many more 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 is only applicable to living matter where processes have a set point. They are already working on identifying physiological observables – particular things to measure in cells – where deriving such a law could begin.