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The language in the article is a bit overhyped. There are multiple examples of gradients being involved in pattern formation. It's just that electrical potentia

The language in the article is a bit overhyped. There are multiple examples of gradients being involved in pattern formation. It's just that electrical potentials are a bit of a newer area of study. There's the chemical gradient based on WNT signaling in fruitfly development, the SHH (sonic hedgehog) chemical gradient in limb pattern formation and body planning asymmetry. There's even auxin signaling in plant development. Heck, one of Alan Turing's (yes, THAT Turing) most famous papers from the 50s described reaction-diffusion mechanisms for pattern formation. Basically for evolution to invent some kind of reproducible pattern of something, you need to start with a gradient of something and tie that to gene transcription. In the fruit fly example it's a chemical trigger that reaches the nucleus via wnt signaling. In the flatworm example, it's a membrane polarization gradient that drives the gradient rather than a chemical one. I'd imagine the patterns you can create from electrical depolarization are simpler than the ones you can get from chemicals interacting as you lose many of the interesting interactions you get from reaction-diffusion

100ideas 2y ago
Ditto. The larger question is how does the linear sequence of DNA (primary sequence) ultimately drive the spatio-temporal development program that leads to mature differentiated cells working together at the organoid / organ / organism scale. How do cells know what to do in time and space as the organism grows? How is that logic encoded in the genome? Eric Davidson did a bunch of pioneering work meticulously "debugging" this spatiotemporal genomic logic in the sea urchin. Pretty amazing. Eukaryotes like us have control elements directly upstream of our genes (trans-acting aka close acting) and also 100,000's of base pairs distant (cis-acting). The region of DNA directly preceding the beginning of an open reading frame at the start of a gene usually has a sequence of DNA motifs that bind proteins that can increase or decrease expression of the gene. Davidson and others showed that the transcription factor proteins that bind to these control motifs actually have additional other proteins that bind to them, in literally a layer on top, and that the sequences of proteins in this second layer recruit a tertiary layer of proteins that conditionally cause more or less gene expression, depending on their identities. You could say the secondary and tertiary layers are a form of "abstraction" in a literal sense, since they encode a hierarchy of logical operations. Here's an open-access overview of Davidson's work which incidentally illuminates a lot of these concepts in more detail for a lay audience: "ERIC DAVIDSON: STEPS TO A GENE REGULATORY NETWORK FOR DEVELOPMENT" by Ellen Rothenberg, 2016; doi: 10.1016/j.ydbio.2016.01.020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828313/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828313/ to see the decoded logic in pseudocode and with a diagram, see "cis-Regulatory control circuits in development", Howard and Davidson, 2004, Developmental Biology, vol 271, https://doi.org/10.1016/j.ydbio.2004.03.031 https://doi.org/10.1016/j.ydbio.2004.03.031 (open access)
adrian_b 2y ago
Yes, I believe that the linked article oversimplifies when talking about a "bioelectric" state, perhaps because this sounds more appealing to those familiar with electrical and electronic technologies. The actual state that is described is determined by the chemical concentrations of various kinds of ions and molecules along and across the body of an animal. The distribution of electric potential that appears as a consequence of the chemical concentration variations, due to the fact that the atomic ions and also many of the molecules involved are electrically charged, is just a coupling mechanism between those chemical concentrations, so that when one of them is changed that tends to also change the concentrations of other atomic or molecular ions. The same "bioelectric" state (i.e. electric potential distribution) could appear as a consequence of distinct distributions of the ions and most certainly those seemingly identical "bioelectric" states would behave quite differently. This is similar with what happens in semiconductors, whose behavior cannot be simulated based on just the distribution of electric charge, but one must account separately the concentrations of all kinds of charge carriers, e.g. electrons, holes, fixed crystal defects etc.
- LarsDu88 2y ago
  I think I want to clamp down on the hyperbole a bit here, and I think its obvious the author is targeting the software engineer folks who might not be familiar with developmental biology or evolution. The planaria has evolved a mechanism by which its body plan can be recapitulated from the distribution of electric potential. When it gets cut in half, the electric potential changes, but this is still enough information for the vivisected halves to redifferentiate. The trade off is, of course, there is only so much information in an electric potential with regard to the patterning of a complex organism, so its hard to imagine a cheetah or a pig pulling off this same kind of trick. The idea of some subdivision of an animal having its own prerogatives is not some sort of new idea. It goes all the way back to Richard Dawkin's 1970s book "The Selfish Gene" which lays out exactly where the "incentives" are for cells, genes/cistrons, cancer, transposons, etc... Just because there's some example now of something vaguely reminiscent of semiconductors (which is cool for sure!) does not mean we're gonna start rethinking everything in biology.
  - 2y ago
authorfly 2y ago
Your response has fascinated me. Listening to podcasts, I have always so dearly wanted to know what Michael or others meant specifically by "Voltage gradient". These have given me great topics to further conduct research into, with my currently fundamental neuroscience knowledge rooted in understanding of memory, learning and Action Potentials. I have tried to further this understanding with LLMs but am ofcourse not sure if what they are saying is correct (given the understudied and sparse nature of this research). If you had a moment to help me understand what exactly these voltage gradients are, how they differ from action potentials, and to tie these to the processes at the cellular level to the larger system, I would be so grateful (for example, is SSH used in limb regeneratio nas well as pattern formation? How? Is it dormant in normal limbs? Which cells, in the limb or in the brain? Which research articles found this? I am fascinated!). In the meantime, here is what Claude told me. I am not sure if it is accurate, I get a sense of "sweeping under the rug": "Specific ion channels and gradients: During limb regeneration in amphibians like salamanders, one of the key ion channels involved is the V-gated proton channel (Hv1). The wound epidermis cells at the amputation site become depolarized due to the influx of protons (H+) through the Hv1 channels, creating a localized region of elevated intracellular pH. This pH gradient, or proton gradient, is believed to be a crucial signal that initiates and guides the regenerative process. Other ion gradients, such as calcium (Ca2+) and sodium (Na+), have also been implicated in regulating various stages of limb regeneration, but the proton gradient is particularly well-studied. Reaching and influencing cells: The voltage gradients or ion gradients can propagate through tissues and reach distant cells due to a phenomenon called bioelectric signal propagation. Cells are electrically coupled through gap junctions, which allow for the passive spread of ions and small molecules between cells. This electrical coupling enables the voltage or ion gradients to be transmitted from the source cells (e.g., wound epidermis) to the target cells (e.g., blastema) over long distances. The gradients can influence gene expression, cell proliferation, and cell migration in the target cells, guiding the regenerative process. Pattern effects and limb regeneration processes: The specific patterns of voltage or ion gradients are crucial for determining the outcomes of regeneration, such as the completeness and proper patterning of the regenerated limb. For example, manipulating the proton gradient can lead to the formation of supernumerary (extra) limbs or alteration of the limb pattern. The voltage gradients are involved in various stages of limb regeneration, including wound healing, blastema formation, patterning, and differentiation of cells into specific tissue types (e.g., bone, muscle, nerves). Gradient vs. specific voltage measurement: The term "voltage gradient" or "bioelectric field" refers to a spatial pattern of voltage differences, rather than a singular voltage measurement at a specific point. It's similar to a topographic map, where the voltage (or ion concentration) varies across different regions, creating a gradient or slope. In contrast, an action potential or membrane potential refers to a specific voltage difference across the cell membrane at a given point in time. The voltage gradient is a long-range signal that provides positional information and guides cellular behaviors during regeneration, while action potentials are localized electrical signals involved in neuronal communication and muscle contraction. The voltage gradient, or bioelectric field, is a spatially distributed pattern of voltage differences that serves as a long-range instructive signal for coordinating cellular activities during regeneration. It is distinct from a singular voltage measurement or an action potential, as it represents a gradient or slope of voltage across different regions, providing positional cues and guiding the regenerative process."

100ideas 2y ago

Ditto. The larger question is how does the linear sequence of DNA (primary sequence) ultimately drive the spatio-temporal development program that leads to mature differentiated cells working together at the organoid / organ / organism scale. How do cells know what to do in time and space as the organism grows? How is that logic encoded in the genome? Eric Davidson did a bunch of pioneering work meticulously "debugging" this spatiotemporal genomic logic in the sea urchin. Pretty amazing. Eukaryotes like us have control elements directly upstream of our genes (trans-acting aka close acting) and also 100,000's of base pairs distant (cis-acting). The region of DNA directly preceding the beginning of an open reading frame at the start of a gene usually has a sequence of DNA motifs that bind proteins that can increase or decrease expression of the gene. Davidson and others showed that the transcription factor proteins that bind to these control motifs actually have additional other proteins that bind to them, in literally a layer on top, and that the sequences of proteins in this second layer recruit a tertiary layer of proteins that conditionally cause more or less gene expression, depending on their identities. You could say the secondary and tertiary layers are a form of "abstraction" in a literal sense, since they encode a hierarchy of logical operations. Here's an open-access overview of Davidson's work which incidentally illuminates a lot of these concepts in more detail for a lay audience: "ERIC DAVIDSON: STEPS TO A GENE REGULATORY NETWORK FOR DEVELOPMENT" by Ellen Rothenberg, 2016; doi: 10.1016/j.ydbio.2016.01.020 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828313/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828313/ to see the decoded logic in pseudocode and with a diagram, see "cis-Regulatory control circuits in development", Howard and Davidson, 2004, Developmental Biology, vol 271, https://doi.org/10.1016/j.ydbio.2004.03.031 https://doi.org/10.1016/j.ydbio.2004.03.031 (open access)

adrian_b 2y ago

Yes, I believe that the linked article oversimplifies when talking about a "bioelectric" state, perhaps because this sounds more appealing to those familiar with electrical and electronic technologies. The actual state that is described is determined by the chemical concentrations of various kinds of ions and molecules along and across the body of an animal. The distribution of electric potential that appears as a consequence of the chemical concentration variations, due to the fact that the atomic ions and also many of the molecules involved are electrically charged, is just a coupling mechanism between those chemical concentrations, so that when one of them is changed that tends to also change the concentrations of other atomic or molecular ions. The same "bioelectric" state (i.e. electric potential distribution) could appear as a consequence of distinct distributions of the ions and most certainly those seemingly identical "bioelectric" states would behave quite differently. This is similar with what happens in semiconductors, whose behavior cannot be simulated based on just the distribution of electric charge, but one must account separately the concentrations of all kinds of charge carriers, e.g. electrons, holes, fixed crystal defects etc.

LarsDu88 2y ago
I think I want to clamp down on the hyperbole a bit here, and I think its obvious the author is targeting the software engineer folks who might not be familiar with developmental biology or evolution. The planaria has evolved a mechanism by which its body plan can be recapitulated from the distribution of electric potential. When it gets cut in half, the electric potential changes, but this is still enough information for the vivisected halves to redifferentiate. The trade off is, of course, there is only so much information in an electric potential with regard to the patterning of a complex organism, so its hard to imagine a cheetah or a pig pulling off this same kind of trick. The idea of some subdivision of an animal having its own prerogatives is not some sort of new idea. It goes all the way back to Richard Dawkin's 1970s book "The Selfish Gene" which lays out exactly where the "incentives" are for cells, genes/cistrons, cancer, transposons, etc... Just because there's some example now of something vaguely reminiscent of semiconductors (which is cool for sure!) does not mean we're gonna start rethinking everything in biology.
- 2y ago

authorfly 2y ago

Your response has fascinated me. Listening to podcasts, I have always so dearly wanted to know what Michael or others meant specifically by "Voltage gradient". These have given me great topics to further conduct research into, with my currently fundamental neuroscience knowledge rooted in understanding of memory, learning and Action Potentials. I have tried to further this understanding with LLMs but am ofcourse not sure if what they are saying is correct (given the understudied and sparse nature of this research). If you had a moment to help me understand what exactly these voltage gradients are, how they differ from action potentials, and to tie these to the processes at the cellular level to the larger system, I would be so grateful (for example, is SSH used in limb regeneratio nas well as pattern formation? How? Is it dormant in normal limbs? Which cells, in the limb or in the brain? Which research articles found this? I am fascinated!). In the meantime, here is what Claude told me. I am not sure if it is accurate, I get a sense of "sweeping under the rug": "Specific ion channels and gradients: During limb regeneration in amphibians like salamanders, one of the key ion channels involved is the V-gated proton channel (Hv1). The wound epidermis cells at the amputation site become depolarized due to the influx of protons (H+) through the Hv1 channels, creating a localized region of elevated intracellular pH. This pH gradient, or proton gradient, is believed to be a crucial signal that initiates and guides the regenerative process. Other ion gradients, such as calcium (Ca2+) and sodium (Na+), have also been implicated in regulating various stages of limb regeneration, but the proton gradient is particularly well-studied. Reaching and influencing cells: The voltage gradients or ion gradients can propagate through tissues and reach distant cells due to a phenomenon called bioelectric signal propagation. Cells are electrically coupled through gap junctions, which allow for the passive spread of ions and small molecules between cells. This electrical coupling enables the voltage or ion gradients to be transmitted from the source cells (e.g., wound epidermis) to the target cells (e.g., blastema) over long distances. The gradients can influence gene expression, cell proliferation, and cell migration in the target cells, guiding the regenerative process. Pattern effects and limb regeneration processes: The specific patterns of voltage or ion gradients are crucial for determining the outcomes of regeneration, such as the completeness and proper patterning of the regenerated limb. For example, manipulating the proton gradient can lead to the formation of supernumerary (extra) limbs or alteration of the limb pattern. The voltage gradients are involved in various stages of limb regeneration, including wound healing, blastema formation, patterning, and differentiation of cells into specific tissue types (e.g., bone, muscle, nerves). Gradient vs. specific voltage measurement: The term "voltage gradient" or "bioelectric field" refers to a spatial pattern of voltage differences, rather than a singular voltage measurement at a specific point. It's similar to a topographic map, where the voltage (or ion concentration) varies across different regions, creating a gradient or slope. In contrast, an action potential or membrane potential refers to a specific voltage difference across the cell membrane at a given point in time. The voltage gradient is a long-range signal that provides positional information and guides cellular behaviors during regeneration, while action potentials are localized electrical signals involved in neuronal communication and muscle contraction. The voltage gradient, or bioelectric field, is a spatially distributed pattern of voltage differences that serves as a long-range instructive signal for coordinating cellular activities during regeneration. It is distinct from a singular voltage measurement or an action potential, as it represents a gradient or slope of voltage across different regions, providing positional cues and guiding the regenerative process."