In this assay, I describe reflections on biological systems and the nature of life. If you do not know it, the title is an obvious reference to the famous Schrodinger’s assay that motivated many physicists to create the branch of science that is Biophysics. In its current stage, these words are not written with the intent to be precise or complete, but to guide my own thoughts in the understanding – however superficial – of which are the general principles, opposite to specific molecular mechanisms, that drive biological processes and that are more likely to help us in the understanding of human physiology and pathological states. I will often express trivial observations from which, perhaps, less trivial considerations may be built upon.
From disorder to self
A living organism is an active chemical system, one that is constituted by an identifiable ensemble of molecules that manifest cooperative behaviour. For life to be observed, it has to be identifiable. As trivial as this observation is, identity is a founding character of the chemical systems we call life.
Life, as we know it, is based on the basic chemical unit that we call ‘cell’. The boundary of the cell is defined by lipids, amphipathic molecules that are made of a portion that likes water and another portion that does not. A basic characteristic of amphipathic molecules is their capability of spontaneous self-assembly. The polar, water-liking, head of lipids will try to contact water molecules, whilst the water-repelling tails will associate with each other trying to exclude water molecules, like oil in a glass of water.
Local reduction of disorder (or entropy as often we call it) is a feature of living systems. Reduction of entropy can occur only as consequence of irreversible chemical reactions that convert energy to order the local environment, like a person burning calories to tidy up their home, that in the process generate waste that they dump into the external environment. However, self-assembling systems are spontaneous and reversible processes that increase order at no entropic cost to the environment. The best example for this are colloidal suspensions. If large spheres are mixed with smaller spheres, large spheres will start to organize in ordered structures. In fact, around the large sphere, there is a volume of solvent that is inaccessible to the small sphere (because of steric hindrance). The entropy of a system of a mixture of large and small sphere is higher when there is a level of organization in the large spheres. Another example of such process is the spontaneous ordering of polymers. Even without amphipathic properties, there are molecules such as polymers that can interfere with the internal bonding of water (water molecules like each other) and are therefore driven into ordered structures. The net effect of this process, driven by so called entropic forces, is to maximize the entropy overall, primarily increasing the entropy of the solvent by maximizing the number of states available to water molecules; at the same time, polymers or other macromolecules are driven into ordered, low entropy, structures.
Therefore, given the right conditions of solvent and molecules, a spontaneous process of self-organization will drive compartmentalization of chemical systems. It is very important to stress that one of the first fundamental steps that initiate life, i.e. establishing an identity through a boundary between the self and the environment, is a thermodynamically favoured process that occurs at no entropic cost to the environment. This step results in the maximization of the internal entropy but, counter-intuitively at first impression, generates order and define a self at the same time.
Such compartmentalized systems do give raise to special environments where chemical reactions can occur at high efficiencies. Furthermore, the constant supply of energy provided by the sun, can readily start catalysis in these compartmentalized systems and drive these systems far from the equilibrium. Of the many compartmentalized systems that can naturally and spontaneously occur, however, only those that will be stable in time will be able to evolve into nowadays ‘living systems’.
From transient to stable
What we call a living cell requires the preservation of its own identity for long enough to give birth to life as we recognize it—a living organism must exhibits mechanisms to ensure its own integrity over time: the integrity of its boundary and the integrity of an active internal chemical system. Both require the existence of favourable conditions such as suitable operational windows of temperature, pressure, pH, etc. All systems incapable of maintaining integrity within a range of conditions that may occur in time extinguish themselves as soon as environmental factors change even slightly. It appears, therefore, that the maintenance of integrity over time necessitate that a primordial biochemical system exhibits some sort of “thermodynamic resilience”, i.e. its chemistry can operate and its identity maintained in face of environmental challenges. We can easily postulate that any primordial biochemical system was simple in nature and manifested comparatively little resilience to environmental changes. Reversible processes of self-organization would be constantly counter-acted by more energetic stochastic events inducing a relentless process of creation and destruction of such thermodynamic systems. Natural selection forged life from the very beginning, enabling only those systems capable of increased “thermodynamic resilience” to survive.
There is experimental evidence that simple self-assembling systems such as lipid vesicles can grow by uptake of other lipids from the environment and trigger fission in smaller vesicles spontaneously. The propensity to fusion and fission events of the early proto-cell may have represented both a challenge and an opportunity to the evolution towards an early system. Fission and fusion can be seen as a challenge to thermodynamic resilience as the identity and composition of this proto-cell is extinguished when fusion and fission occurs unregulated. At the same time, simple mechanisms that would minimize fusion and regulate fission, for instance specific composition of proto-cellular membranes, under the empowering thrust of natural selection would lead to the emergence of a ‘replicator phenotype’. This replicator phenotype could be thermodynamically favoured in specific environmental conditions and, hypothetically, better supported by simple internal chemistry that would favour a stable process of fission.
During this phase, inheritance of characters could be only of one kind, structural inheritance. Composition of amphipathic chains of specific types may favour self-assembly with other chains of the same type and stochastically divide into multiple “daughter” entities that constituted by the same elements, different ever so slightly by chance, would be still favouring the same self-assembly processing to occur, but randomly accommodating variation in the composition of the boundary and inner content. At the same time, irreversible reactions stabilizing this process may emerge by increasing efficiency in the utilization of energy to maintain structural integrity.
Once that the cycle of relentless creation and destruction is replaced by a cycle of relentless replication, natural selection will favour the optimal “thermodynamic resilience” for a given environment.
From random to self-governed
In face of environmental changes a primordial system to survive into a life form will require adaptation of its active chemistry supporting different chemistry active on different operational windows. Gains in thermodynamic resilience may occur by: i) stabilizing thermodynamic variables (e.g., temperature, pressure, volume) within optimal windows (homeostasis), ii) migrating to a different environment (taxis) or iii) adapting the internal chemistry to the different conditions (through evolution or, on shorter time scales, by allostasis).
Homeostasis is defined as the capability of a system to maintain certain parameters nearly constant. For instance, the human body is kept at around 37°C where cell biochemistry operates optimally. Homeostasis is the incarnation of thermodynamic resilience, where this is ensured by an active process of self-government, another founding property of life. There are many different terms to define this property of biological systems (e.g., homeorhesis and allostasis), but homeostasis is the one encompassing all of them. For instance, allostasis is the process by which a system maintain its homeostasis through a change. Let’s consider a simple biochemical system where its internal chemistry depends on pH. In order to be thermodynamically resilient, this system will require the capability to buffer pH either by chemical composition or by utilizing regulated proton pumps that will ensure a stable pH. However, when these mechanisms are insufficient to guarantee pH stability, a system can shut down those internal machineries that generate variations of pH as a by-product. A partial loss of efficiency (read as fitness) in such a system will however guarantee maintenance of other fundamental reactions and, therefore, overall fitness.
Another possibility is to engage in taxis, the active movement towards a more permissive environment, for instance searching for those conditions of nutrients, temperature, pH, etcetera where a system operates optimally. Taxis is another property shared by all animate being. Either plants trough growth, or other organisms through migration, all organisms are capable to sense the environment and trigger movements to seek for their optimal environment where their metabolism will operate more efficiently. For instance, a plant will adapt its growth to seek for sunlight, bacteria sense gradients of chemicals to find food and higher organisms migrates to places where abundance of food and water, and environmental conditions are suitable for them.
Homeostasis and taxis are manifestations of self-government that can be established only once that a biochemical system acquires the capability to process information from its internal and the external environments to execute specific actions to ensure thermodynamic resilience.
I am no expert in any of the topic I discussed here. However, I have the impression that thermodynamics aspects of life are often far too emphasized. The question is not if life contradicts the second law of thermodynamics (it does not), the question is how much the second law can teach us about living beings. Often, a connection with entropy, its evolution towards higher values, is seen as a necessary link to justify the spontaneous occurrence of life. Even if this was true, does it matter, if a much simpler justification is available in the process of natural selection as a fundamental law of Nature? And even if natural selection could be justified with a thermodynamics description, would this help us to understand life, or to resolve the many afflictions that living beings are cursed with?
I firmly believe that research in thermodynamics of self-assembly systems and the role of entropic forces in biology are essential to a better understanding of life. However, the question about why life has evolved and if this conflicts with thermodynamics has been already addressed. It seems, sometimes, there is a conflict between the laws of physics and biological mechanisms, but – of course – there is none. Life is a complex phenomenon, the emergent property of a highly compartmentalized ensemble of chemically active molecules that abide (again, obviously) the basic laws of physics, but which description as a system, may not be properly described by thermodynamics. This is why systems biology is branch of biophysics that was born for this purpose exactly.
The most elemental aspects of life are identity as an active biochemical system (i.e., its compartmentalized metabolism), its capability to maintain integrity (i.e., its homeostasis, its capability to replicate) in face of environmental pressures and to be autonomous (i.e., the capability to process information and undertake decision).
For those of us working on a disease such as cancer, it is thus unsurprising that cancer is intimately linked to deregulation of all of these fundamental characteristics of life.
I’ve written this assay in different periods reading literature beyond the scope of my own research. Therefore, I cannot reference my text properly, but these are the material I’ve read and may be of interest to you.
Devies et al. (2013) “Self-organization and entropy reduction in a living cell” Biosystems
Spanner (1953) “Biological systems and the principle of minimum entropy production” Nature
Prigogine (1971) “Biological order, structure and instabilities” Quarterly Reviews of Biophysics
England (2015) “Dissipative adaptation in driven self-assembly” Nature Nanotechnology
Frenkel (2014) “Order through entropy” Nature Materials
Schrodinger (1944) “What is life?”
Yodh et al. (2001) “Entropically driven self-assembly and interaction in suspension” Phil. Trans. R. Soc. Lond. A
Bray (1990) “lntracellular Signalling as a Parallel Distributed Process” J Theor Biol
Bray (1995) “Protein molecules as computational elements in living cells” Nature
Bray (2003) “Molecular Networks: The Top-Down View” Science
Mc Ewen and Wingfield (2003) “The concept of allostasis in biology and biomedicine” Hormones and Behaviour
Ray and Phoha “Homeostasis and Homeorhesis: Sustaining Order and Normalcy in Human-engineered Complex Systems”
Sterling “Principles of allostasis: optimal design, predictive regulation, pathophysiology and rational therapeutics” in “Allostasis, Homeostasis, and the Costs of Adaptation” by J. Schulkin
Berclaz et al. (2001) “Growth and Transformation of Vesicles Studied by Ferritin Labeling and Cryotransmission Electron Microscopy” J Phys Chem B
Markvoort et al. (2007) “Lipid-Based Mechanisms for Vesicle Fission” J Phys Chem B
Mostafavi et al. (2016) “Entropic forces drive self-organization and membrane fusion by SNARE proteins” PNAS
Stachoviak et al. (2013) “A cost–benefit analysis of the physical mechanisms of membrane curvature” Nature Cell Biology
Although I never found the time to read it, the following book seems to cover exactly the topics I discussed. Having browsed through its pages now and then, it is likely I have been influenced by it:
Radu Popa “Between necessity and probability: searching for the definition and origin of life”