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How can we apply bioelectric signals in medicine and regeneration to facilitate longevity?

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Subash Chapagain
Subash Chapagain Jul 31, 2022
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Come up with the best possible applications to use bioelectric signals for clinical and therapeutic solutions.
Why?
Since Watson and Crick’s (and more rightfully Rosalind Franklin’s) groundbreaking elucidation of the structure of DNA in the 1950s, the field of biology and medicine has almost entirely been developed on the central dogma that DNA codes for RNA and RNA codes for proteins. Given all the evidence from modern molecular biology and advances in biochemistry and computation, this central principle of the biological world has to be the most successful model - from the first principles of biological assembly to therapeutics and drug design.
Like any other sub-field within biology, the central dogma of biology has so far dominated the field of developmental biology, which makes the basis for regenerative medicine. How, after meiotic recombination, an embryo forms and how that embryo develops into a full-fledged adult organism through time has been only viewed from the lens of central dogma: the DNA has all the information encoded in it, and throughout the process of an organism’s development the information is differentially utilised (as a controlled biased expression) to form proteins such that differently specialised cells are formed which form the anatomical apparatus that we call as the ‘body’ of the organism. This way of understanding the development of biological organisms has worked well so far, yet, hasn’t been useful, especially in tackling the medical problems/questions related to organ/tissue regeneration.
Some background:
However, the beauty of science lies in the pursuit of alternative hypotheses. In what seems (at least to me) the most non-canonical approach to explaining the developmental process is Professor Michael Levin’s idea of bioelectric signalling as the basis for anatomy. This idea is so fascinating, both in the fundamental philosophy and its potential, that it might be the most important idea in biology since Darwin. Professor Levin and his lab have used the planarian—a type of flatworm about two centimetres long- to effectively demonstrate that evolution has not hard-coded a set of specified movements that turn tadpoles into standard frogs; rather, the electric potential and the gradient across the cellular microenvironment guides as a signal for differentiation and organ formation. The same has been described when salamanders regrow amputated limbs back. This notion directly challenges the existing idea that the information for the growth of organs and anatomical fate effectively comes from the blueprint in DNA. They have evidently proved this by using different models of planarians: for example, when these tiny organisms are perturbed in their early developmental stage, not at the genetic level but just at the protein level, by expressing ion gates ( ion-gates are proteins that pump ions in/out of the cells, also called voltage channels), the bioelectric pattern created by this alteration decides where each organ forms. In other words, copy the natural pattern of bioelectric signals for, say, ‘eye development’ and express ion channels to the abdomen: voila! You get eyes in the abdomen. This is extremely interesting and mind-boggling!
Scaled up to higher organisms, this idea has the potential to revolutionize regenerative research and accompanying medical fields. This might be exactly what the human race has needed to meet its dream of longevity.
Read in detail the ideas:| Bioelectric signaling: Reprogrammable circuits underlying embryogenesis, regeneration, and cancer
H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induce Xenopus tail regeneration
Watch Professor Levin's talks:
Standing on these ideas, what do you think would be the best uses of bioelectric signalling in biology, medicine and health?

[1]https://journals.biologists.com/dev/article/134/7/1323/53047/H-pump-dependent-changes-in-membrane-voltage-are

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Related research & Research Ideas

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Tuber Dao
Tuber Dao Sep 12, 2022
( Gathered some related research & a few questions)
Research confirms a single human cell frequency can be measured (in Hertz)
https://www.pnas.org/doi/10.1073/pnas.1713395115
Research confirms DNA vibration/frequency can be measured:
https://www.nature.com/articles/s41598-020-60105-3 (albeit retracted)
Recent research concludes a frequency of 10 Mz transforms stem cells into bone tissue (potentially speeding up bone fracture healing).
https://www.rmit.edu.au/news/all-news/2022/feb/sound-waves-stem-cells
Research from 2006 concludes sound waves can detect DNA damage:
https://pubs.rsc.org/en/content/articlelanding/2006/AN/b605648m
Research from 1977 measured a specific electrical current near regenerating newt limbs. Indicating a particular current strength & sodium ions were required during the limb regeneration process.
https://ncbi.nlm.nih.gov/pmc/articles/PMC431978/
Research also indicates that nerves may be responsible for the release of growth factors or chemotactic agents necessary for the regenerative process in newts. (Would be interesting to know if a specific frequency or electrical current induces the nerves to release such agents.).
https://www.scientificamerican.com/article/how-do-chameleons-regener/
RESEARCH IDEAS
  1. Measurement of healthy cells and DNA (both vibrational frequencies and electric current.) Testing different sound frequencies and electric currents on stem cells and DNA strands to see whether any sort of regeneration takes place (similar to the 10mhz bone tissue research listed above)
  2. Emitting specific frequencies or electric currents on nerves or even the brain to attempt to induce “chemotactic agents” necessary for regeneration.
(PS You may find this interesting - Using specific frequencies that induced specific cell apoptosis https://www.youtube.com/watch?v=1w0_kazbb_U (its a little slow so I suggest 1.25x speed !)
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Subash Chapagain
Subash Chapagain2 months ago
Hi, thank you for your valuable input. Sorry for being a bit late to reply. The papers you have mentioned are really helpful in building insights into one common convergence: it is possible to use non-biological or biophysical features of the cellular organisation to discriminate healthy vs disease conditions, or to enhance some selective properties of the cells. I have a few comments on these methods: a) How instructive is the 'vibrational' frequency in terms of cell growth, migration, differentiation and proliferation? b) How reproducible are all of these experiments? Can they be verified? I am concerned that one of the research (detecting DNA damage with sound waves) was published almost 16 years ago, but we have not seen much progress in the field. I wonder if the results are really reproducible. The idea of vibrational frequencies is an alluring one, but what I feel lacking is its universality and the proof of concept. It could be the fault of the experimenters themself and doesn't necessarily mean that the idea is wrong. Compared to bioelectric signalling (bioelectric signalling is already very well established even with the technical limitations of measurement), there seems to be a need for more rigorous framing of the experimental design for using sound frequencies as diagnostic and curative agents. The idea of combining sound frequencies in tandem with bioelectric signalling is really interesting. It would be awesome if some labs pick up on this idea and test the hypothesis.
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Tuber Dao
Tuber Dao5 days ago
Subash Chapagain Thaks for the review and comment ! I'm a layman in the space and fascinated by it all; will be keeping an eye on Mr Levins work and research in general.
All the best,
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Bioelectric signalling for cancer detection and therapy

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Subash Chapagain
Subash Chapagain Oct 12, 2022
Classically, the electric potential across the cell membrane was only thought of as a property of excitable cells like neurons. However, now it has been established that cells, even the non-excitable ones, are able to generate and receive bioelectric signals .
The net electrochemical gradient across a membrane produces the membrane potential, denoted by Vmem. When the cytoplasm becomes more positively charged than the extracellular space, the cell is said to be depolarized, and it will have a less negative Vmem. When the cytoplasm becomes more negatively charged than the extracellular matrix, the cell is hyperpolarized, and it will have a more negative Vmem. In normal physiological conditions, the average Vmem of the cells ranges from -90 to -10 mV (milliVolts) depending on the cell type .
The expression of ion channels in the cells influences the membrane potential along with the presence of bioelectric gradients like electric fields and ionic composition of extracellular space in the tissue. The ion and voltage gradients have a functional role in the control of cell differentiation, migration and proliferation during embryogenesis and regeneration .
This property of cells to be regulated by bioelectric signals is important because it helps us differentiate a range of signals that is ‘normal’ from any other ‘abnormal’ pattern of signalling. Indeed, it has been observed that isolated cancer cells have a more positive resting membrane potential than other somatic cells, in the range of -30 to -20 mV. This bioelectric potential is similar to the proliferative cell types like embryonic and stem cells which are phenotypically very different from healthy, differentiated somatic cells. Considering the fact that ion channels are abnormally expressed in cancer cells and that blocking ion channels can inhibit cancer cell proliferation, bioelectric signalling can be considered as one salient hallmark of cancer .
Since electric fields are important instructional cues for cell migration and tissue organization, the signals can be used to first detect and then to modulate the cell behavior. The general idea is that a group of cells that assume cancer-like phenotypes can be expected to deviate from the normal range of, and will enable us to detect the risk for tumor development. Subsequently, since bioelectric signals are also instructive, manipulating the signals might allow us to revert the phenotype to non-cancerous type.
Proof of concept for cancer diagnosis and treatment
A study published in 2019 by researchers at the University of Bath offers a genuine proof of concept that bioelectric signalling can indeed be used as an alternative method to predict and diagnose the risks for cancer development. The team built a platform that can record the electrical activity of cell populations over time. Using rat glioma and human prostate cancer cells, they showed that the system can be used as a non-toxic, non-exhaustive detection of early cancer progression .
Another study showed that the electrical signalling pattern derived from the intracellular potassium (K+) can be used to modulate T cell-based immunotherapy against cancer. The levels of K+ are raised in the tumour microenvironment as a result of cell death, and it can be used as a target for treatments that enhance T-cell-based cancer therapy. The introduction of an activator of the K+ channel in the T-cells allows these cells to overcome the suppression exerted by K+. The bioelectric property of the T-cells involving the K+ activity have been found to be a secondary checkpoint in cancer regulation, and hence can be exploited in designing the therapy. Specially since traditional immunotherapies are associated with adverse side effects, the K+ modulator used as in this study can be coupled with conventional therapy to lower the required dosages and minimize side effects .

[1]https://www.frontiersin.org/articles/10.3389/fphys.2015.00143/full

[2]https://ieeexplore.ieee.org/abstract/document/8351948

[3]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4244194/

[4]https://pubmed.ncbi.nlm.nih.gov/29291972/

[5]https://pubmed.ncbi.nlm.nih.gov/16061851/

[6]https://www.liebertpub.com/doi/10.1089/bioe.2019.0020

[7]https://www.liebertpub.com/doi/10.1089/bioe.2019.0016

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Wearable bioreactors for tissue/organ regeneration

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Subash Chapagain
Subash Chapagain Nov 03, 2022
Bioelectric signalling patterns have been used (in conjunction with other multiple drugs) to demonstrate that it is possible to regenerate otherwise amputated limbs in model organisms.
The approach uses a wearable bioreactor that was specifically designed for a holistic application of electric signals and different drugs so as to facilitate the regeneration of the limb in Xenopus laevis. The research team has named this device BioDome. The device is composed of a soft silicon that houses silk hydrogels used for controlled-release of drugs. The BioDome provides an in-utero type of environment that can facilitate regenerative events in the tissue (hind limbs in this case). Controlled state of hydration, electrical stimulation at the wound site, and pharmaceutical cocktails were some parameters that could be handled by the BioDome, and were essential for the recruitment and dedifferentiation of cells. The data suggest that the nonregenerative adult Xenopus system can be reprogrammed toward a sustained regenerative state by a brief targeted chemical trigger, aided by electrical stimulation.
Implications of this type of wearable bioreactor for regeneration:
  1. No need for ‘genetic’ intervention
The system triggers endogenous, but latent regenerative competency to restore and regrow the amputated tissue/organ. No genetic engineering is required. The induction does not need any gene therapy or stem cell implants, nevertheless produces molecular, cellular and tissue-level changes that can restore limb morphology and sensorimotor function.
2. Highly useful for amputees and survivors of catastrophic injuries
This system, if well developed, can be life-changing for people who have lost their limbs/digits due to accidents and injuries. This has usage for post-war veterans and survivors who suffer organ/tissue loss due to various diseases and physical hazards.
3. Useful for organ transplantation/ xenografting
Another usage would be to facilitate tissue growth after organ transplantation and xenograft treatment. Electrical signal mimicry is particularly helpful as there is ample evidence that it enhances regrowth and stimulates the morphogenesis of tissue/organ under question. Coupled with advances in biological signal processing, this can be even applied to ensure optimal tissue growth without any risk for graft rejection.

[1]https://www.science.org/doi/10.1126/sciadv.abj2164

[2]ncbi.nlm.nih.gov/pmc/articles/PMC2967604/

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Bioelectronic devices for autoimmune diseases and inflammation

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Subash Chapagain
Subash Chapagain Nov 15, 2022
Yet another exciting application of bioelectric signalling for the medical world comes in the domain of autoimmune diseases and neuroinflammation, for example, rheumatoid arthritis. A group of researchers from New York have pioneered this field, and they have developed a bioelectric device precisely for this purpose. Bioelectronic medicine adopts a new approach to treating and diagnosing diseases by using device technology to read and modulate electrical activity within a given system in the body. Feinstein Institute scientists have developed a device to control the electrical signal used by the nervous system with significant results for autoimmune diseases like rheumatoid arthritis.
Also known as the longest neuron in the body, the vagus nerve is highly involved in rheumatoid arthritis. In a very well-characterized neuronal reflex circuit called the ‘inflammatory circuit’, signals travelling in the vagus nerve are found to inhibit the production of cytokines like tumour necrosis factor (TNF) by immune cells like the monocyte and macrophages.
The inflammatory reflex signalling can be greatly enhanced by electrical stimulation of the vagus nerve, and researchers have found that such stimulation can be used to modulate the level of cytokine production and attenuate disease severity in inflammatory syndromes. This observation has been validated and reproduced in experimental models of inflammatory diseases like endotoxemia, sepsis, and colitis.
Based on this experimental evidence, the bioelectronic device is designed by these researchers. The device is minute in size: just as big as the fingernail, and it can be implanted with a small incision in the neck. The device delivers electrical current to the whole of the vagus nerve which contains approximately 100,000 fibres. The preliminary data from the group shows that it takes only of
Is this new therapy better than the existing ones?
The present-day go-to remedy for autoimmune disease is immunosuppressive drugs that block cytokines like TNF-alpha, IL-1 and IL-6. However, the drugs do not work for everyone, and sometimes can be toxic and expensive. Hence, in these special cases, electric stimulation therapies can be the better, non-invasive, non-toxic and cheaper alternatives.
Further reading suggested:
  1. Literature summary https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258775/
  2. Mice experimental study https://www.frontiersin.org/articles/10.3389/fnins.2019.00877/full
  3. Proof of concept study in humans https://www.frontiersin.org/articles/10.3389/fnins.2019.00877/full

[1]https://pubmed.ncbi.nlm.nih.gov/22665702/

[2]https://pubmed.ncbi.nlm.nih.gov/21071287/

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General comments

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Michaela D
Michaela D3 months ago
This is the most eye-opening information I have probably had in years! Thank you so much for sharing.
Applications are endless, as mentioned in the video: birth defects, cancer, degenerative diseases, ageing. First, I am looking forward to experiments with mammal cells, and seeing how strong these bioelectric signals are for humans. I’m curious how the information is maintained when you genetically reprogram cells (iPSCs) and make organoids. Understanding the role of the bioelectrical signals would help overcome some challenges (we still cannot make perfect organ models) and accelerate this technology. Exciting!
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Subash Chapagain
Subash Chapagain3 months ago
Michaela D It gives me joy that what I found profoundly interesting, you too found it interesting. I learned about Dr Levin's ideas a few months back, and I couldn't stop myself from going through all of his papers and lectures. Soon in the future, I plan to do a categorical post (linked to this challenge) with the best upcoming applications that can in the near future be applied for medicine and therapeutics.
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