Cancer-Free energy principle

The free energy principle tries to explain how (biological) systems maintain their order (non-equilibrium steady-state) by restricting themselves to a limited number of states.^[1] It says that biological systems minimise a free energy functional of their internal states, which entail beliefs about hidden states in their environment. (source wikipedia).

Is it possible that in cancer, during the process of tumorigenesis and metastases the free energy is maximised leading from order to disorder ?

Cancer

I have written the following blog post and pinned it so that cancer researchers  who may come across this blog post can get ideas about why cancer occurs, how to think about cellular states in tumor formation and how they relate to the driver mutations and the tumor microenvironment. Hope it is useful.

The risk of developing cancer increases with age. The probabilities of errors in replication resulting in cancer causing mutation  occur because of the second law of thermodynamics . Error in DNA replication implies lack of  precision/accuracy in replication and an increase in randomness. This is exactly what the second law of thermodynamics predicts- an increase in entropy i.e randomness of the universe. With age the human dies, loss of physical organization of the human body occurs, matter gets converted to energy, and energy is returned back to the universe.

So for treatment of cancer local entropy has to be decreased to regain back organization/precision accuracy. This means drugs have to be discovered/designed /invented that decrease entropy/randomness/disorganization of the system in this case the malignant tumor.

Humans are only following the laws of physics. Elephants do not get cancer. They have multiple copies of the tumor suppressor p53. Their metabolism is slow  resulting in large body size, and very long life spans. Lower metabolic rates means slower reactions and lower entropy. Humans unlike elephants have high rates of metabolism and accumulate toxic by-products. These contribute to errors in DNA replication which results in diseases such as cancer and the   aging process.

Probably high metabolism rates  is related to advanced cognitive capacities. Elephants may live longer , do not have cancer but they lack cognitive capacity comparable to humans . It is this cognitive capacity  which has allowed humans to adapt themselves to the surroundings and influence their environment including climate. Maybe this advanced cognitive capacity will help design useful anti cancer drugs.

Tumor heterogeneity hypothesis-Different tumor cells possess altered ratios of tumor suppressing to tumor promoting activity, resulting in altered  signaling networks in different cells.

Cancer occurs when there is impairement in restoration of homeostasis due to 2nd hit which is microenvironment related,  in primary mutational hit (tumor suppressor inhibiting/oncogene activating) cells.

Sequence of events-Ist mutational hit. Cells starts dividing and at the same time  retains homeostatic balance, so they form a benign tumor. Second hit occurs (tumor microenvironment interactions in which cells in the microenvironment lacking the mutation i.e. the soil fails to  contain the dividing cells as they lack the primary mutation, and give insufficient inhibitory signals to the dividing cells) -Homeostasis breaks down, malignant Tumorigenesis results.

Visualization-Oscillating pendulum

Cellular states preceding and following tumorigenesis are  like- an oscillating pendulum that  overshoots mean position once (equivalent to cellular state i.e benign tumor after primary mutational hit). The pendulum tries to  come back to mean balance position (equivalent to restoring homeostasis in cell after primary mutational hit). Due to  loss of elasticity of pendulum string (equivalent to secondary hit due to tumor microenvironment interactions) status quo of extreme position maintained, (which is  equivalent to malignant tumor ).

Proposed Mechanism for the above:

What if the default mode of single cells is replication and differentiation/ maturation is secondary. Depending upon the interaction of replicating cells with the microenvironment, adjacent cells release inhibitory molecules which make a replicating cell differentiate/mature. This is because competition for food resources as a whole will wipe out cells, so for survival cells divide to a certain number and differentiate, so that the tissue survives as a whole.

 In cancer the default replication of cells carrying driver mutations for tumorigenesis  is not inhibited sufficiently by the surrounding cells so uncontrolled cell proliferation occurs. It is possible that driver mutations arise all the time in cells due to replication errors, but then such cells do not survive and proliferate because inhibitory signals by  surrounding cells  impedes their survival to allow tissue/organ/host  formation to occur. This results in a benign tumor.

In malignant tumorigenesis the tumor survives at the expense of a host, because the cells in the neighbouring microenvironment of the cell carrying the driver mutation are not able to give out sufficient inhibitory  signals to inhibit proliferation of cells carrying the driver mutation. One reason could be that a sufficient number of neighbouring cells lacking the driver mutation is needed to give out sufficient signals to inhibit proliferation of cells lacking the driver mutation. If cells lacking the driver mutation divide at a slower rate than cells with the driver mutation, then they will not be able to provide sufficient inhibitory signal against the cell carrying the driver mutation, resulting in  a malignant tumor.

Activating a tumor suppressor/inhibiting an oncogene within a tumor by a drug may alter tumor cellular state. Tumor cells may adapt and give survival cues to the tumor microenvironment. So drug has to target signaling by tumor microenvironment to tumor cells. So not one drug but two, targeting tumor cell +tumor microenvironment.

I found the following articles particularly useful:
http://www.pnas.org/content/111/48/17188.full
http://www.physiology.org/doi/full/10.1152/ajpcell.00145.2015
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1891444/

What if:

Each particle is a vibration in a field. Particles interact with each other to give rise to higher orders of emergence.

 What if consciousness/sentience  is the vibration at each level, and interactions of vibrations at higher orders of emergence form complicated structures giving rise to consciousness as manifested through the living brain.

A plant is living and is different from a table made of wood, because the arrangement of atoms is different in a plant versus wood and plant/life interacts with the environment whereas wood does not.

Talking about memories : if they are encoded in the synaptic connections in the brain or within a neuron when the neuron dies the memory dies as structure is lost. But the atoms remain as combinations of vibrations in a field .

What if consciousness is  the vibratory energies at each level of emergence. In higher orders of emergence, vibrations/particles  interact with each other and through phase transition give rise to the brain and mind.

Phase transition and the Phenomenal Self

Even a baby has a notion of self. It cries and laughs when the "other" touches it, makes sounds towards it. This implies the self is a constant from infancy.

What is this self ?

I think the phenomenal self to be an emergent phenomenon of physiological process that govern interoception/proprioception and that remains throughout life and even during processes such as sleeping and dreaming.

Everything is connected to everthing else in some way. A simple explanation is as follows:
At every level of emergence the superimposing layer is resonating with the underlying layer at the same frequency , but the amplitude of each layer is different. Each layer of emergence consists of resonating frequencies with differing amplitudes that branch to form a fractal like pattern, giving rise to complexity.

Concepts of entanglement at the quantum level are beginning to be discovered which support the above.

When the complexity of vibrations/oscillatory motion reaches a certain critical threshold, phase transition occurs and there is emergence of a new physical form, in the following way:

For e.g. consider a uniform energy field with positive pushing forces being cancelled by negative pulling forces. The net field value is  zero and the field is at equilibrium with no net vibrational force. Now suppose the amplitude of the positive forces exceed that of the negative forces, the net force being positive, the field has a net vibration, then a certain kind of particle (type I) comes into existence. Now in another copy of the same field which intersects with the previous field the amplitude of the negative forces exceed that of the positive forces, and another kind of  particle (type II) comes into existence. Now suppose the positive interacts with the negative in myriads of ways to form more complex structures. For e.g. one particle I(arising from net positive forces) interacts with two particles type II (from net negative forces) to form a larger particle (particle A) with net negative force. This larger particle A (with net negative force) then interacts with other larger particles [larger particles with net negative force (A) and net positive force (B)]  in a fractal manner . Repeat this, even  a hundred  times and "complexity " arises. May be at 1000 repeats there is a phase transition and a new physical form arises. Maybe at 1500 another phase transition occurs and there is a new physical form . Such permutations and combinations are governed by probablities of interactions which in turn are governed by factors such as proximity etc. Nearer particles have a greater degree of entanglement than faraway particles.

So coming back to the emergent self, it could be a phenomenon arising from phase transition due to interacting physical parts of the nervous system involved in interoception/proprioception.   In other words, the atoms, molecules, nerve cells , synaptic connections , and other physical stuff emerging from phase transition could give rise to the self which is an emergent phenomenon /process of being.

This phenomenal self/mind that perceives, dissolves most probably when the part of the nervous system involved in propioception  gets damaged. However it  seems to remain intact in patients with traumatic brain injury because such patients  respond to proprioceptive stimulation.

Sands of time-Predictive search for cures\treatments

What if the diagnosis of a disease is a particular state : (Snapshot). If time is emergent and the diagnosis comprises of snapshots of  diseased states, the earlier diseased states erodes with time (since the snapshot is an observation-in emergent time, time is a series of states stitched together by mental processes of the brain). So the treatment has to be based on prediction of the future diseased states.

CLOCKS

Energy Alignment= Clocks at different speeds (Markov Blankets)-InSYNC.

Consciousness

Substratum Consciousness-Single Wave (Scalar) I Observation-Particles-Markov Blankets I Emergent Consciousness Multiple Waves (Vector)