Biological Signalling Pathway - Order Emerging from Chaos

Biological signalling pathway is a set of chemical reactions leading to the generation of organic/inorganic molecules. It is also defined as a series of actions among different molecules in a cell that leads to the synthesis of certain products or a change in the cell structure and function. In other words, the end products of biological signalling pathways are either synthesis of new products, such as a fat, sugar or protein; or triggering of cellular changes such as cell duplication, cell shape change, spur a cell to move or to undergo cell death.

What's exciting about biological signalling pathways

Living cells have unique capability to respond to both mechanical (vibrations), biochemical (drugs) and electromagnetic signals (light) including ionized and gaseous molecules (anesthesia). In fact, the ability of cells to perceive and correctly respond to their immediate environment is the basis of development, tissue repair, immunity, homeostasis and well being. Any errors in signaling interactions and cellular information processing usually results in discomfort, diseases, compromise the quality of life, and in certain cases death. Therefore, figuring out the molecular underpinnings of cellular signalling pathways is absolutely necessary to uncover new opportunities for curing diseases, improving the quality of lives or creating new forms of life. The exciting thing about signalling mechanisms in living systems is that they do follow certain physical laws of nature that are universally applicable. 

Order emerging from Chaos

Many biologists would like to describe signalling pathways as the routes through which information flows in cells. For example information about extracellular cues flow from a particular receptor that gets activated by its ligand, all the way to the nucleus where the propagated signal might ultimately result in the expression of a particular gene or production of a particular product. This is a reductionist view of biological signalling pathway and comes with many limitations when one tries understand the workings of complex organization such as the brain or immune system. In my view signalling across cell membranes are more like the spontaneous order created out of chaos without violating the second law of thermodynamics. The second law of thermodynamics tells us that everything in the universe tends to disorder. In a reductionist view, one would expect chaos to be the norm in the complex systems. Yet, occasionally spontaneous order and pattern emerge out of synchronization. Everywhere we look, we see universe is full of such events, as if they follow certain universal laws of nature. For instance,

• Gravitational locking of the moon

• Simultaneous flashes of fireflies

• Spontaneous beating of heart cells

are few popular examples of regularly ordered consequences of chaotic events which seemingly appear to violate the second law of thermodynamics, but actually they don't. The spontaneous synchronization of inanimate objects was first observed by the famous physicist Christian Huygens in mid 1665. (Strange coincidence, in 1665 Robert Hook published his famous Micrographia). 

 

Of course the Dutch physicist of mid 17th century was not aware of the universality of this phenomenon. Today, we know that the spontaneous synchronization pervades nature. If you want to see this magical phenomenon of ordering or synchronization emerging out of disorderliness, right in front your eyes, try this interesting experiment out for yourself.

Credit: UCLA

 

The synchronization of metronomes works regardless of the number of metronomes placed on a moving platform. In the same way, a living cell is home to the chaos consisting of a hundreds and thousands of random molecular protein-protein interactions (akin to metronomes) in a non-stationary medium. And occasionally molecular events enter into spontaneous sychronization, depending on any new interaction partners introduced into the system.

By the same principle, the extracellular binding of a ligand to the surface of a living cell results in a phosphate transfer interaction events which synchronizes with intracellular phosphate transfer interaction events resulting in gene expression, protein synthesis or cell migration.

I therefore view biological signalling pathway as "wave patterns emerging from a synchronized interaction events". To get a perspective of how it emerges, consider the analogy with the Conway's Game of Life, nicely depicting how chaotic events generate orderly patterns.

 

Now look at the orderly waves generated by hundreds and thousands of fireflies, nicely illustrated by this simulation of firefly flash synchronization.

 

How biological signalling pathways actually emerge

Biological signalling pathways are created by the molecular interactions events governed by molecular forces of nature. The molecular composition of every individual is unique due to the genome which will ultimately dictate when, where, how much and what kind of protein molecules are going to made in the body. Consequently, molecular interactions orchestrated in every cells, tissues and organs in an individual has to follow the principle of synchronization in order to communicate and respond to the food and environment. Imagine a sub-cellular protein-protein interaction event takes place inside a living human cell. Now every interaction event inside the cytoplasm is doing their own thing. An event is only affected by its closest neighbors. If it sees another event close-by, say a phosphate transfer interaction, then it nudges its own interaction event a little bit, so it will grab a phosphate group for itself that it would have not otherwise. Now, what is remarkable about this small change at any moment in time is that even though the changes in interactions are small and close range, over time, you can see waves traveling through other interaction events inside the cell, and eventually, they all have coupled the exchanging of phosphate transfer interactions at one point in time (synchronized phosphate transfer). This may result in creation of a new product or a change in gene expression. To visualize the phosphorylation signalling pathway read the research paper (Hino et al Dev Cell 2020) from Michiyuki Matsuda's Laboratory of Bioimaging and Cell Signaling.

The phosphorylation signalling is not traveling like a domino effect. That's not what happens. It is sort of like the way water doesn't gradually freeze as you lower the temperature. It is liquid, liquid liquid as you are lowering the temperature. And then at a critical temperature, boom, the molecules suddenly start to change their state from liquid to solid. Similarly, the signalling pathway does not manifest itself when a ligand binds. Only at a critical amount, a ligand is able to induce spontaneous synchronization of phosphate transfer interaction events among the interaction events inside the cell. This synchronization event in time is what we call phosphorylation signalling pathway. It is more like a wave that resonates at one moment in time. For instance, look at this movie below showing waves of ERK signalling activity in response to extracellular cues. Can you notice the phenomenon of synchronization, like seen in firefly and Coneway's 'game of life' videos?

Credit: Pertz Lab

Credit: Developmental Cell

This phenomenon of synchronization is universal. We can witness it occurring at every scale of nature from subatomic to cosmic. It uses every communication channel that nature has ever devised, from electrical interactions, chemical interactions, mechanical interactions to gravitational interactions. Anywhere the two things can influence or communicate each other, nature uses this phenomenon to get things in sync. This is the secret of biological signalling pathway - an order emerging from the chaos of thousands of random molecular interactions.

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