Potential versus Actualization

What is the difference between a cancer stem cell and stemness in cancer. Actually a lot. A cancer stem cell is a cell with a realized/actualized potential, while stemness is determined by unrealized potential. Its like a tree versus a seed. The plant is an intermediate stage. So a change from unrealized potential to actualizations passes through different stages of growth.

The idea of my blog is to trigger your thinking

Why do you even need to read my blog.

Firstly it is not about news or updates. Its about topics which I forsee as important and my musings on it. On reading it , the articles/one liners should be able to trigger your thought process for newer ideas, ways of approaching science related problems, basically be inspirational, all without budging from your computer. I am interested in humans all over the world.

 Briefly the interests  in this blog are:

1. Life as in Biology including emergence, adaptation
2. Cancer-because a lot is unknown
3. A layman's musings regarding Physics-as it forms the fundamentals of science
4. Meditation-Many people are practising it and I am curious about the mechanisms involved
5. Philosophy in the Indian context

The whole idea is about speculating and stimulating cogitation. My ideas may not be true, but they are there to stimulate yours. Agree, Disagee, Question -I have achieved my goal.

Adaptation

Are humans sculpting their environment leading to adaptation and inheritance of adapted traits ? 

Emergent Properties in Biology-Interactions

I am writing this blog post to connect the ideas of emergence with what we know in biology.

"Interactions" leading to emergent properties, such as the phenotype of an organism, which emerges from the genotype of the organism is where biology research is heading to.

The genotype is encoded in the DNA of the organism which through the transcriptional and translational machinery gets converted into proteins. These proteins interact with each other in signal transduction networks which consist of positive and negative feedback loops. It is these signaling networks that convey the signal from outside a cell to the functionality of the cell. 

On the other hand, the proteins interact with the DNA and can regulate switching on/off of genes via epigenetic mechanisms.

 So in a cell, there are  "layers of interactions", where each layer instructs the subsequent layer, and the functional property of the cell emerges from the genotype. The layers of  cellular processes  are epigenetic regulation--->transcription--->translation--->signaling networks --->feedback loops thus forming a complete circuit. 

The cells interact with each other forming tissue and with increasing scales of interactions the organ emerges, followed by the organ system and then the whole body. Thus phenotype emerges from genotype.

 The body of the living organism then interacts with the environment and what emerges is the ecosystem of complex interactions which form a part of the biosphere on earth. Each emergent layer consists of a multitude of interactions, which when increased on the scale gives rise to the next emergent layer which is more complex than the previous layer.

 Thus interactions are fundamental to emergence and form the glue of the living world.

Cancer , Entropy , Pendulum model of 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,"wrong bases", imprecisely inserted in the DNA resulting in many alternate ways of structural re-organization. This is exactly what the second law of thermodynamics predicts- an increase in entropyof 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, in other words there has to be a constrain on structural organization, 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/