Tuesday, 12 September 2017

Cancer-Laws of thermodynamics-Oscillating between states -Involvement of Driver Mutations/Tumor Microenvironment

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.

Cancer accelerates extended life span to death and therefore its frequency arises 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.

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/



Monday, 11 September 2017

Meditation-Sankhya Yoga-Yoga Psychology Based on Experience

The Rishis (Sages) of the past meditated. They included both men (eg Kapila) and women (eg Gargi).
By meditate I mean concentrated focus/observation of their own psychical system.
Meditation is a systems approach.  The rishis went from the surface layers of the mind to probe into deeper levels.  The body is multicellular , including the brain (consisting of the sensory input processing system). Under normal circumstances, in a conditioned human, the physical predominates i.e data arriving from the sense organs (eyes, ears etc) .The  4 components i.e.buddhi-intellect ahamkara-identity/individualization capacity, manas - memory bank , chitta-(awareness at the mental level)are a  prakriti (psychical nature) according to sankhya psychology. The 3 attributes of sattva(balance/equilibrium/harmony),rajas (activity) and tamas (inertia) are present in various combination in each individual human. The observable universe is when the self/atman/purusha/subject/observer/ is superimposed by prakriti.During meditation, the self /atman/purusha/observer loses superimposition of  prakriti in the following manner.  When prakriti is stilled by various techniques like mantra repitition, meditative techniques of raja yoga/patanjali yoga  the observing part (subject/atman) has no more object to observe. Subject-object become one. When the atman/self/purusha/subject/observer  loses identification with the object, (distinct energy fields lose their individual vibrations=detachment in gita where kshetra=field and kshetrajna=knower of the field) the self/atman merges (unite/integrate=yoga) into the underlying unified energy field (brahman) . Thus tat tvam asi. Atman (Individual self-You-tvam) =Brahman (universal-Tat). Emergent consciousness is lost i.e vibrating energy fields is lost and equilibriated/bliss energy fields remain. This is the result of meditation.
Terminology in Advaita(Non-dual)=Atman (Individual Self), Brahman (Universal Self).
Terminology in Sankhya =Buddhi (Intellect), Ahankara (identity), Chitta (mental awareness), Manas (memory bank), Sattva (Balance), Rajas (Activity), Tamas (Inertia).
Terminology in Gita =Kshetra (Field), Kshetragna (Knower of the Field)
Deities-Anthropomorphic representation of abstract attributes.
The various deities of "hinduism" represent various abstract mental states during subject object split. For eg. Shiva represents destruction (Tamas), Vishnu-preservation (Sattva)-Brahma-projection/creation (Rajas) of the universe .This is because prakriti engages in creative, maintaining and destructive activities.
4 experience based paths to the above:Bhakti-Yoga(Love of Self-subject object separation followed by subject object unity), Karma -Yoga (Work /Activity based, Removing focus from fruits of activity but focusing on the activity itself, love of work and work for the sake of work and not for the gains or losses/side effects that accrues with it  ), Raja-Yoga( Patanjali's Ashtanga Yoga System-involves dhyana,dharana,samadhi), Jnana-Yoga(Knower of Self/Advaita based).
Christ who experienced unity is quoted as -do unto others as you would like others to do unto yourself was a bhakta (lover of the self). Buddha was a jnani (knowledge seeker) (meditated on the self).
Loss of  organization  at the physical level/structure =death of the body.
Aging = loss of structure/physical organization.
"God" in "Hinduism"=Atman/IndividualizedSelf which merges into Universal self"Brahman".
Good (Sattv-ic)/Evil (Tamas-ic)=Creative/Destructive mental energy states.
Self knowledge= Atman knowledge

Questions -Research Gate

https://www.researchgate.net/profile/Sonali_Sengupta8/questions