Activity and Stillness

 Anaesthetic mediated stilling of brain activity versus non-anaesthetic mediated stillnes

 

The Prior - Consciousness expresses itself in and via dynamically functioning neurons.

The floor of a neuronal cell, consists of microtubules and actin filaments. The microtubules intercalate to form a dynamically functioning network, that expands and contracts according to cell activity. This is analogous to sarcomere filaments in contracting and expanding muscle.

The expansion and contraction of the microtubule filaments, lead to a rhythmic oscillation pattern, that manifests itself in a dynamically functioning neuronal cell, transmitting information via secreted neurotransmitters. In other words microtubules act upstream of nerve impulse transmission.

When anaesthesia is administered to a living organism, the anaesthetic treatment locks the intercalation, inhibiting nerve impulse transmission, resulting in progressive diminishment  of the rhythmic oscillation pattern of neuronal firing.

This anaesthesia mediated diminshment of neuronal firing, is different from stillness acquired through meditation. The anaesthetic treatment physically affects the neuronal network architecture, which leads to involuntary collapse of the brain. Meditation is the voluntary stilling of neuronal activity by affecting neurotransmitter mediated nerve firing, without affecting neuronal architecture.

The former leads to collapse of the living organism if administered in excess. The latter in the case of a human being, leads to illumination of mind activity in a still background, which in other words is called liberation of the mind via enlightenment

Bayesian Brain

 We humans possess a Bayesian brain, which implies that our prior memories/experiences/expectations determine our newer experience. It is a pre-conditioned brain that perceives.

This pre-conditioning is partly determined by the free energy principle which states that the difference in free energy between our prior brain states and brain states following the particular experience  that is the least, is the one that is selected and retained as an experience/memory. This difference in free energy could be alternatively termed, "minimize surprise". 

For further reading:

https://www.youtube.com/watch?v=NIu_dJGyIQI&t=35s

 

Hologram of CD markers on cell surfaces

 The CD markers (Cluster of Differentiation) pertaining to cells of the immune system, that are on the cell surface are depicted in textbooks in a linear array.

But a cell has a 3-Dimensional geometry. Thus the arrangement of CD markers exhibits topological features, and it is a misnomer to name it as a cluster.Rather name them as differentiation markers, or more specifically, an Array of Differentiation markers (AD markers). This points to a matrix-like arrangement of cell surface markers as compared to a linear array.

Depending on the sequence of connecting the dots, a different network of markers emerge.  Similarly, a different set of CD markers on various cell types will have different 3D topological arrangements. This is simiar to a country with different cities lighted up. Cells to Cities ---> FRACTALS.

 

A Subjective Approach to the Scientific Method

 A Subjective Approach to the Scientific Method

This essay proposes a radical paradigm shift in thinking, from the traditionally practiced, hypothesis driven- research data collection-research data analysis driven scientific method, to a richer and more comprehensive subjective approach to the scientific method. The subjective approach is proposed to complement and advance the traditional objective approach, in order to drive scientific research in the direction of asking more insightful original research questions, develop innovative research methods and implement more in-depth research  data analyses. The subjective approach aims to address human researcher centered cognitive biases, in other words anthropocentric cognitive  biases.

 The premise of the subjective approach is based on the Indian philosophical inquiry  field of Advaita Vedanta (https://en.wikipedia.org/wiki/Advaita_Vedanta ), which in the collected text format is available as the Upanisads (https://en.wikipedia.org/wiki/Upanishads ),  and the psychological practice of Raja-Yoga ( https://en.wikipedia.org/wiki/R%C4%81ja_yoga ) which is based on Patanjali’s Yoga Sutras.

For this essay, the philosophical premise of Advaita Vedanta is taken to be the perspective that the world of objects is a world of appearance which is everchanging and impermanent and is superimposed on an underlying all-pervasive substratum, which is the subjective observer. The psychological practice of Raja-Yoga is the intuitive understanding based on yogic experience of the human being as consisting of five koshas i.e.sheaths( https://en.wikipedia.org/wiki/Kosha)superimposing on the individual self, the metaphysical I, which is a witness to the thought process. (Drg Drsya Viveka https://en.wikipedia.org/wiki/D%E1%B9%9Bg-D%E1%B9%9B%C5%9Bya-Viveka ). These sheaths from the outside to the inside are, annamayakosha (food-sheath), pranamayakosha (vital-energy sheath), manomayakosha (mind i.e. recorder of perceptions sheath), vigyanmayakosha (intellect sheath), and anandamayakosha (bliss sheath). The practice of Raja-Yoga which incudes regulation of the prana in the pranamayakosha or  vital-energy sheath, regulates the erratic energy flow in the human body where a pre-conditioned mind predominates. A human mind trained by Raja-Yoga practice has balanced energy flow throughout the body, and is going through progressive stages of de-conditioning of priors. Such a deconditioned mind is  highly concentrated and is able to provide clearer insights into the objects it gives its attention to. Practioners of Raja-Yoga, do not succumb to erratic and compulsive behaviours, and possess  a calm analytical mind as opposed to a reactive mind.

In the following passages I have provided practical examples of how the practioners of the above philosophical inquiry method and  yogic practice may advance  the field of scientific research investigation, in the areas of:  asking insightful research questions, developing innovative research methods, implementing in-depth research data analysis, as well as addressing confirmation bias.

Asking more in-depth original research questions: A traditional hypothesis and/or data-driven researcher may ask the question, what is the reason that the leaf of a tree is green. The given answer is the leaf is green due to the pigment chlorophyll, which drives the photosynthesis process that manufactures, sugars from carbon dioxide and water in the presence of sunlight. A scientific researcher well-versed in the Advaita vedantic philosophical inquiry would ask the question, why does the leaf of a tree appear green to humans, as opposed to a cat seeing a grey leaf. Does the subject i.e, human perceptive apparatus, play a role in the outcome of the observation of a leaf appearing green? Is the green leaf observation an anthropocentric observation?

Implementing more in-depth research methods: A  traditional hypothesis and/or data-driven researcher may  shed light on the mechanism of how a leaf exchanges energy with its surroundings via biochemical investigative methods and tools. A scientific researcher well-versed with Raja-Yoga practice may implement an innovative  research method based on the observation that since both the subject i.e. human observer and the object i.e. the tree, exchanges energy with the surroundings, why is it that the human subject can self-regulate its inner vital-energy flow, as well as exchange air with its surroundings via breath, while a tree is dependent on an outer clean environment to provide air, sunlight and water to it. An innovative method can be implemented by such a researcher, who designs  a panel of external and internal parameters that differentially compares energy exchange and flow with respect to the object i.e. the tree and its environment, the human subject and its environment, as well as energy flow in the subject-object system i.e. human-tree sub- system and the human-tree-environment system 

In-depth Research Data Analyses:  A  traditional hypothesis and/or data-driven researcher may compare the patterns of similarities and dissimilarities , during bioinformatic analyses of gene sequences of closely evolutionarily related organisms. A scientific researcher well-versed in  Advaita vedantic philosophical inquiry would ask whether the patterns of similarities and/or dissimilarities that  appear via bioinformatic data analyses, are fixed/static or changing as an organism, adapts to its environment ? If the patterns are changing over time, then what is the time-scale over which old patterns disappear and new patterns appear? Thus the research database does not become a fixed entity, but an evolving one.

Addressing human researcher cognitive biases: A scientific researcher well-versed in Raja-Yoga practice, may question their own conditioned priors leading to cognitive biases, such as confirmation bias (https://en.wikipedia.org/wiki/Confirmation_bias ). For example if the researcher reads an article that confirms data from their own laboratory or confirms their hypothesis, since the researchers have evolved priors via Raja-Yoga practice  resulting in a  clearer less conditioned mind, the researcher may develop in-depth insights into the confirmatory research data or article and ask insightful original questions which furthers the research field.

So, from the above examples we can see that a subjective approach to the scientific method complements the traditional object driven approach by  advancing  science from a static body of facts, to an evolving dynamic entity contingent  on contextual perspectives.

The case for a therapeutic cancer vaccine

The case for a therapeutic cancer vaccine

                              

                               Anti-Cancer drugs: A prelude

RAS proteins are important for normal development. Active RAS drives the growth, proliferation, and migration of cells. In normal cells RAS receives signals and obeys those signals to rapidly switch between the active (GTP) form and the inactive (GDP form) states. Mutated RAS* is stuck in the active state, ignores signals to the contrary, and drives cells to become cancerous. 

https://www.cancer.gov/research/key-initiatives/ras/about

Despite repeated attempts, researchers failed to develop a drug that could inhibit the activity of RAS proteins in cancers. They had hoped to find a small molecule that could preferentially bind the unique features of the RAS protein, but they couldn’t find a surface on the protein that would bind a drug.https://www.cancer.gov/research/key-initiatives/ras/about

It is being increasingly recognized that cell signaling is being carried out via phase separation of liquid compartments consisting of the signaling components.

https://pubmed.ncbi.nlm.nih.gov/31792379/

https://pubmed.ncbi.nlm.nih.gov/32203417/

 I hypothesize that  since, the mutant ras protein is stuck in an active signaling state, there should be a greater number of phase separated droplets in a cell carrying the mutant ras protein versus the wild-type ras protein. An effective drug should be able to inhibit the formation of these phase separated droplets.

In the 2010s, the Shokat Lab at the University of California San Francisco and the Fesik Lab at Vanderbilt University developed innovative drug screening and medicinal chemistry techniques that identified molecules that could bind mutated KRAS proteins. https://www.cancer.gov/research/key-initiatives/ras/about 

Rationally designed drugs, may be used to target, matrix metallo-proteinases and collagenases, which are "ENZYMES" that function, to degrade the extracellular substrate in the tumor micro-environment,so as to inhibit cancer cells, escaping from the primary tumor into circulation, to establish secondary metastases. However, such drugs are works in progress.

                                       The case..

Since many challenges exist toward developing effective anti-cancer drugs, another approach would be to develop a therapeutic anti-metastatic cancer vaccine, directed specifically toward the antigen profile of circulating tumor cells, that express altered levels and types of cell-surface biomarkers. The goal would be a multi-epitope anti-metastatic therapeutic cancer vaccine.

Such a vaccine would prevent secondary metastases, since data support the idea that the majority of deaths from solid tumors are caused by metastases. https://pubmed.ncbi.nlm.nih.gov/31397113/ 

When the drug fails to contain the primary tumor (anti-cancer drug resistance), the anti- metastatic cancer vaccine could prevent the spread of the primary tumor to secondary sites, by targeting tumor cells  in circulation.

Self, Mind in Biology and Yog-Vedanta explained mechanistically

 Self, Mind in Biology and Yog-Vedanta explained mechanistically

The emergent mind in biology, also called the embodied  mind, is  due to  interactions between and within cells in the living organism, in organs throughout the body such as brain, heart etc . This is the biological basis of thought which occurs in the embodied mind. The physics of an emergent mind involves mechanisms of phase transition, the chemistry involves interactions between and within cells, the biology involves organization of cells in tissues and organs,  and the math involves fractal (self-similar) patterns of interactions.

The underlying mind according to the psychological practical experience of  Yog, specifically Raja-Yog which encompasses techniques of meditation, involves manas (recorder of perceptions), chitta (memory bank), buddhi (the determinative faculty , deciding the pros and cons-is this a chair or not) and ahamkara (the individualization capacity). The underlying mind has three attributes i.e, sattva (balance/harmony), rajas (activity) and tamas (inertia), which collectively constitute prakriti or internal nature.

Both the emergent, embodied mind and the underlying mind which identifies with the body, are subtle matter. During meditation, such as object based   meditation where one repeatedly dwells on sound and the mantra (words with meaning), when the underlying mind vibrational activity is stilled, because the mind is focused on the mantra, away from thoughts, the mind state is termed “chitt vritti nirodh” or literally translated into  mind activity stopped, the witness to mind activity is revealed. This witness to the mind activity is termed Purusha in Yog or Atman in Vedanta , which is translated as Self. The mind activity is movement or moving energy, and since movement can only be relative to that which is unmoving, the self is inert or inert energy.

In the experience of  meditation  this self in context of an  individual human being, termed Atman, is equated to the selves in all living beings, and pervades the entire physical and mental universes, which is termed Brahman or the underlying universal self. Brahman/Atman is inert unmoving/still energy and thus cannot be quantified or measured, while mental activity or moving energy i.e. Prakriti or Shakti, can be quantified or measured. This equation of Atman =Brahman, is the conclusion of A-dvaita (Non-dual) Vedanta , and can be intuited by rational enquiry of clear minds. This philosophical rational enquiry is the process  or technique of Jnana-Yog also termed Advaita Vedanta.

 According to Sri Ramakrishna, through practice of meditation, Brahman and shakti are identical, and he uses the analogy of fire and its power to burn.

The various states of samadhi which are a culmination of Yogic practice are degrees  of revelation of the Purusha, via Raj-Yog practice. The chakras in the Raja-Yog systematic practice are areas of concentrated energy, which are experienced. The energy chakras dealing with food/eating, sexual activity and excretion of waste products are dense, like tied knots. With advanced and sustained Yogic meditation, the knotted energy gets progressivley  untied, and energy chakra becomes lighter, as in the heart or anahata chakra. With progressive sustained meditation, the person feels happier, lighter and cheerful.

Sat-Chit-Ananda literally translated into Truth/Being-Consciousness-Bliss, can be narrated as when, mind activity is stilled, the ground of truth  i.e being is experienced and manifested as bliss. People experiencing bliss, manifest transformative behaviours such as calmness, eveness of mind (Stithaprajna), humility etc. This is the reason Swami Vivekananda said “Religion is realization” not talk, theory or intellectual consent. Realization is the lived experience of brahman, (Knowing by Being), the underlying non-quantifiable stillness, and a realized or enlightened person, manifests transformed behaviour, exhibiting kindness, compassion etc. Realization can also be termed as liberation from mental activity or “mukti/moksha”.

The basis of oneness/unity or connectedness of physical and mental universes, is this underlying still continuity which is termed Brahman in Vedanta. This Brahman is termed God, and Atman or the individualized self, is termed Ishvara (inner controller) or antaryamin or (inner seer).

It is the practice that finally matters, so that stillness, which feels as bliss is a lived experience.

The following is speculation: In the concept of re-birth, at death  the body decomposes, while the mental activity remains as a set of vibrations or forms a vibratory footprint. At conception, when  the sperm  physically, fuses with the egg to form the zygote it provides the environment for the vibratory footprint to take a home, and interactions of this vibratory footprint with its zygotic environment , produces a conscious living organism. The living organisms, takes in food from its environment and develops systematically into an adult human. The tendencies developed by a human being are not ony inherited, but coming from previous births. A realized or enlightened human, who has transcended mental activity no longer takes re-birth.

The physicist David Bohm, talks about wholeness and fragmentation. The wholeness refers to Brahman/Unity and fragmentation to vibratory mental activity.   

 

Cancer Research in the Context of Organoid Biology

 One of the  goals of biology research is to simulate the native architecture of tissues, so that one can study cells in their "natural environments".

A step towards this goal is the development of organoid systems.

Organoid systems are the cultures of stem cells in a three-dimensional environment, i.e. a matrigel, which develop over time in the presence of requisite growth factors into tissue-like structures. 

Self-organization into tissue-like structures, is a crowning achievement of invitro cell biology. What remains to be included is the vasculature, which can be incorporated by mixing the matrigel and microfluidics systems, with various technological approaches.

In the cancer context the stem cells, maybe replaced by cancer stem cells (patient derived/cell line derived) for primary tumors and circulating tumor cells for metastatic cancer.

The above system, may then be utilized for testing anti-cancer compounds, or even used to determine cancer related signatures in their native microenvironments. This information may inform the development of therapeutic cancer vaccines, which can be applied to patients with early diagnosis (depending on the stage), to prevent full blown development to metastastic cancer  which is fatal.

Ref:https://pubmed.ncbi.nlm.nih.gov/31550983/