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Intelligent Design, the best explanation of Origins » Molecular biology of the cell » Development biology » The recent groundbreaking scientific research which explains the real mechanisms of biodiversity

The recent groundbreaking scientific research which explains the real mechanisms of biodiversity

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The recent groundbreaking scientific research which explains the real mechanisms of biodiversity

http://reasonandscience.heavenforum.org/t2293-the-recent-groundbreaking-scientific-research-which-explains-the-real-mechanisms-of-biodiversity

The assertion that evolution is a fact, is repeated like a mantra by proponents of evolution and naturalism, which try in that way to justify their unbelief in a intelligent creator. One of the most frequent claims is that microevolution and macroevolution are the same on a different timescale. And that there is no mechanism that prevents micro to become macro. The ones that are better informed, imho, know that the mechanism that provokes change and evolutionary novelties above species level, that is, the change from bacteria do man, is UNKNOWN. In order to explain the origin of biodiversity , body shape, body plans, organ development, and ultimately, if the the claim of macro-evolution from luca to homo sapiens is true, we need first to understand how organs, limbs, and creatures arise, what mechanism determines what size and shape they should be when they are growing. What mechanism programs the cell to "know" how and where to form an organ? How does the creature know how to rebuild a severed limb to the correct size, shape, and orientation? Once this is elucidated, we can ask if the same mechanisms explain biodiversity.  It seems that groundbreaking scientific research is starting to unravel this longstanding mistery, and its far from being explained through neodarwiniam predictions and claims, but epigenetic mechanisms, which will elucidated below. 

A great deal is now known about morphogen gradients in the developing embryo—how cells know where to go and what types of cells to become. Recent research shows that electric potentials in non brain cells are a signal for creating patterns during development and during re building of organs. This information of different field potentials surrounding individual cells can give information for the developing organ. Now, research from the laboratory of Dr. Michael Levin is demonstrating new ways that cells signal with electricity and the great importance of electrical properties for individual cells and tissues. He describes how electrical gradients and fields are critical in the 3D function and shape of cells and organs. 
 A prominent aspect of multi cellular creatures is that they have organs of a particular size and shape. When regeneration occurs in reptiles the same exact shape is grown. Information for the cellular activity appears to exist in the space that will make up the specifically shaped organ. Levin notes that “cancer can be seen as an error of geometry, because tumor cells grow, migrate, and function without regard for the orderly structure within which they occur.”
 Each cell has specific electrical gradients and properties that together form a large electric field of information. This field of information can show individual cells in the embryo how to behave. This is analogous to the fact that electrical flow between cells in the early embryo  forms the basic network that is then built into a formal structure with elaborate chemical synapses. This, also, occurs during rebuilding of tissue. Somehow, the information of the electrical flow through the electric gap junction synapses determines the future structure. Electrical signals now appear to be critical in forming the shape of organs, the very function and identity of organs, and the creation of new limbs on animals that regenerate. In these animals, stem cell behavior is directed by currents created with potassium, sodium, chloride, and protons that affect the genetic networks of cells at a distance. Recent research shows that limbs can be influenced by proton and sodium alterations. New types of ion channels, pumps and electrical connections have now been found in a variety of different organs.


This is remarkable. If electric gap junction synapses determine cell shape, then  macro change atributed commonly to macroevolution  and structural biological novelties should also depend on these. 

Electrical signaling is key for cells to properly interpret their environment, and when this process goes awry, the cells default to a cancer program. 4
While ion flows control cell-level behaviors such as migration, differentiation, and proliferation, bioelectric signals also function as master regulators of large-scale shape in many contexts: a simple signal can induce complex, highly orchestrated, self-limiting downstream morphogenetic cascades. For example, an unmodulated flux of protons can cause the formation of a complete tail of the right rise and tissue composition. 


Our data suggest that the mechanism by which blastema cells polls the rest of the host (to determine where the wound is located and what other tissues already exist in the fragment and thus don't need to be recreated) is mediated by physiological signals passing through nerves and long-range gap junctional paths.

 A significant component of morphogenetic cues are ionic in nature. Remarkably however, this effect is non-local in nature - it is the transmembrane potential of other, quite distant cells that determines the metastasis-like effect.
Many critical questions remain about how cellular polarity is synchronized and amplified across embryonic fields to allow cells to ascertain their position with respect to the midline. We identified a dependence of asymmetric gene expression on early communication between left and right sides in the chick and frog. For example, expression of left-sided markers depends on events occurring on the right side, during very early stages, suggesting that the two sides need to coordinate their decision with respect to the L-R identity of each. One mechanism for communicating between cells and tissues involves gap junctions: multimers of connexin proteins form channels between cells and pass small molecules, subject to complex regulation by various signals.


So it seems within gap junctions that action happens, but the action per se is REGULATION AND COMMUNICATION THROUGH VARIOUS SIGNALS. THATS THE KEY. 

We showed that gap junctions are crucially involved in L-R patterning in early embryos of Xenopus and chick. gap junctions are a bioelectric patterning element that sets up domains of isopotential cell fields during morphogenesis.
Serotonin signaling is used in information exchange between cells in processes such as L-R patterning and control of timing and cell movement during gastrulation. We have shown that serotonin is utilized by both chick and frog embryos, at very early stages, as a small molecule signal which is transported in a left-right gradient and regulates the development of laterality. Indeed, we now know that the early frog embryo is literally an electrophoresis chamber, which uses voltage potentials to generate consistently biased left-right gradients in serotonin in an epigenetic process not dependent on zygotic gene expression. We have modeled this process quantitatively, and characterized novel intracellular serotonin-binding proteins which directly activate asymmetric gene expression after their rightward movement, linking an early biophysical process to transcriptional regulation via chromatin modification pathways. Serotonin is also a key mediator for bioelectric control of neuronal outgrowth from transplants. 



Electrical Fields Guiding 3D Shape of Cells and Organs

How does the cell know what size and shape it should be? Many cells alter their shape to provide different functions, like microglia. Even more complex is the question as to how organs, limbs, and creatures know what size and shape they should be when they are growing. How do the cells know how and where to form an organ? How does the creature know how to rebuild a severed limb to the correct size, shape, and orientation?

There are thousands of these same questions, including how astrocytes and neurons know the exact networks they should form. How immune cells know how to travel through very complex differing 3D environments? An equally difficult question has been addressed in previous posts as to how the

cell knows exactly what shape a coded sequence in a protein will take. Both cells and microbes alter the codes of their protein toxins that require extremely detailed and accurate shapes. In fact, modern science cannot calculate what shape a 400 amino acid coded sequence will be when it folds into a protein. It would take all the supercomputers together two thousand years to calculate the folding of one average protein. Yet, proteins assemble into the exact shape in a millisecond, helped by very complex chaperone molecules. Cells routinely edit their messenger RNA with alternative splicing to make a whole variety of shapes. How do they know how to do this?

Research shows that: If a cell of a two cell embryo is removed it still becomes the full creature.

Starved flatworms shrink keeping perfect proportions among the organs
Planaria can reproduce the entire body from a small piece
Amphibians can grow a perfectly proportioned limb
Many structures need nerve-mediated information in order to maintain shape and function


For all of these questions, it is hard to imagine the information of the 3D shape being inside one cell, or even a group of cells. It seems more likely that a field of information somehow guides these processes. Is this evidence for an electrical field of information forming 3D shapes of cells, organs and creatures, also, related to the influence of mind?

Electrical Gradients and Fields In and Around Cells





Previous posts have demonstrated the critical part that electrical synapses play in forming the structure of the neuronal network that uses chemical synapses. Also, a previous post showed that field potentials in and around brain cells, while poorly understood, are important for specific functions. Multiple posts have documented the elaborate communication that occurs between cells through signaling including neurotransmitters, brain factors, cytokines and hormones.

A significant amount of research shows the importance of various gradients in the space between cells for communication. This was noted in the posts on the movement of platelets that attract and signal to other immune cells. Another post showed the elaborate travels of leukocytes. A great deal is now known about morphogen gradients in the developing embryo—how cells know where to go and what types of cells to become.

Recent research shows that electric potentials in non brain cells are a signal for creating patterns during development and during re building of organs. This information of different field potentials surrounding individual cells can give information for the developing organ. Now, research from the laboratory of Dr. Michael Levin is demonstrating new ways that cells signal with electricity and the great importance of electrical properties for individual cells and tissues. He describes how electrical gradients and fields are critical in the 3D function and shape of cells and organs. Professor Levin notes that cancer cells use electric gradients for many purposes. In fact, aberrations in electrical processes can lead to cancer. Differences in electrical potential in cells are important in determining whether a cancer metastasizes and electrical states in one cell can have effects on distant cells, triggering metastasis. These electrical potentials in one cell can signal other cells that trigger genetic networks and epigenetic effects.

Electrical State of Cells




From Magnus Manske
The electric state of a cell is determined by many complex factors. One is the opening and closing of ion channel proteins, which control the movement of charged particles (ions) across the cell membrane. Changes of the cells’ electrical potential via the activity of ion channels are shown to be able to suppress or trigger cancer. Another factor is electrical synapses that transfer electricity from one cell to another.
Different electrical properties of cells affect what type of cells are made from stem cells, how much reproduction goes on, where cells travel to and their shape and orientation. Electrical gradients and fields certainly affect travelling immune cells, stem cells, and all brain cells. They also exert profound effects on other somatic cell types during embryonic development and regenerative repair. Electrical properties are simultaneous with chemical metabolism using genetic network processing. They are critical for healing wounds and responding to infections. They determine the symmetry and shape of organs.
Differential ion channel activity in the body sets up specific patterns of voltage potential throughout tissues. During development, these electrical properties of cells determine what types of cells they become. For example, two specific groups of cells in the embryo have increased electrical potential and these become the two eyes. Research shows that by changing the electrical potential of cells at a critical time when eyes are being made, eyes can be induced to form elsewhere, effectively reprogramming other cell types into a complete visual organ.

While electrical activity can drive downstream genetic changes, just changing the electrical gradient can dramatically change the cell’s behavior. After an amputation, controlling the voltage potentials of wound cells causes the regrowth of a limb. The specification of the details appears to exist in the electrical field. At specific regions of the animal’s body, either a tail or limb grow due to the electrical signaling, which kickstarts a “build whatever goes here” program.
Electrical fields that are being discovered with multiple influences could contain this 3D information. Altering the electric field alters the information and the biological results.


Signaling with Chemicals and Electricity


Quite a number of previous posts reveal the elaborate signaling of microbes and immune cells such as T cells and platelets. The critical intestinal epithelial cells and skin cells are involved in very elaborate signaling between large numbers of microbes on one side and many immune cells on the others. Of course, brains are known to use elaborate signaling.

A previous post noted that cancer is like a microbe colony in that they work together for their ends. This view of cancer is that many cells in an environment trigger the actions of the community of cancer cells. Another view of cancer is as a defection of individual cells from the goals of the organism; this can occur by cells’ being isolated from, or mis-interpreting, the patterning cues that normally orchestrate cell behavior into complex anatomy. The new research by Levin adds a very large new dimension in the way electrical signals between cells might be critical in this cancer development.



A prominent aspect of multi cellular creatures is that they have organs of a particular size and shape. When regeneration occurs in reptiles the same exact shape is grown. Information for the cellular activity appears to exist in the space that will make up the specifically shaped organ. Levin notes that “cancer can be seen as an error of geometry, because tumor cells grow, migrate, and function without regard for the orderly structure within which they occur.”

This can occur through each cell having specific electrical gradients and properties that together form a large electric field of information. This field of information can show individual cells in the embryo how to behave. This is analogous to the fact that electrical flow between cells in the early embryo (see post on electrical synapses) forms the basic network that is then built into a formal structure with elaborate chemical synapses. This, also, occurs during rebuilding of tissue. Somehow, the information of the electrical flow through the electric gap junction synapses determines the future structure.
Electrical signals now appear to be critical in forming the shape of organs, the very function and identity of organs, and the creation of new limbs on animals that regenerate. In these animals, stem cell behavior is directed by currents created with potassium, sodium, chloride, and protons that affect the genetic networks of cells at a distance. Recent research shows that limbs can be influenced by proton and sodium alterations. New types of ion channels, pumps and electrical connections have now been found in a variety of different organs.

This is remarkable. If electric gap junction synapses determine cell shape, then  macro change attributed commonly to macroevolution  and structural biological novelties should also depend on these. 

Voltage Gradients in Non Brain Cells


Cells not in the brain, also, use ion channels that create an electrical potential between the inside and outside of the cell. These do not send a signal down a long axon wire as neurons do, but the electrical potentials are critical for the cell’s behavior. In a previous post, calcium cyclic signaling was noted to be the crucial signal between plants and microbes when forming nitrogen factories.

Whole tissues and sheets of cells, also, have flows of electricity through electrical synapses called gap junctions (just like neurons). When the skin is broken the electrical gradients and fields are disrupted and these are a signal for immune cells to repair the tissue. An even larger field exists over an entire organ, and this field has crucial information regarding the shape and function of the organ.
It is very difficult to study, but even inside the cell, many membranes exist for the nucleus, the mitochondria and other organelles such as the critical information center of the endoplasmic reticulum. Electrical potentials and information fields exist in these, also.


Cancer and Electrical Gradients


Cancer cells’ behavior is very tied to electrical signals. They use them as clues to avenues of travel. Electrical fields determine shape changes in the cells. The electrical potential, also, affects what type of cell is produced from stem cells. 


Cancer cells have altered electrical activity and use different ion channels and pumps. They have different transporter molecules that affect how the ions travel and, therefore, the electrical gradients. It now appears that these alterations in ion channels are signatures of different cancers and are critical to their formation. Many differences in the effects of cytokines and neurotransmitter signals, also, appear to be tied to these electrical differences. These ion channels influence all aspects of metastasis. In fact, oncogenes (special genes that cause a cell to become cancerous) are related to various different ion channels.

Research in cancer has been increasingly difficult because of the many different mutations that are found in types of cancers, and, more recently, in individuals. The studies have shown that there is a wide range of different mutations that don’t fall into any noticeable patterns.

Dr. Levin’s work points in a different direction entirely. He notes that the gradients and fields of electrical information may be a more important way to understand this process. It is the very space that the cells are living in that appears to be aberrant and causing the cancers. Electrical signaling is key for cells to properly interpret their environment, and when this process goes awry, the cells default to a cancer program.

Studies show that cancer cells can be differentiated from other cells by their electrical properties. The overall electrical status of the cancer cell is determined by the sum of all the ions and pumps. There are a vast amount of different possible genetic scenarios in this basic measurement of electrical status.


But, in fact, the simple electrical status appears to identify cancer cells. Dr. Levin likens this to “pressure” in physics – a group property that can be implemented with a wide variety of underlying molecular details (e.g., different ion channel genes). He notes that the statistical electrical study of cancer electric gradients might be the most information. He notes that the extremely complex analysis of all of the ion channels might not even reveal the critical information (this type of research is currently not even feasible).


Just analyzing messenger RNA and specific proteins made will not determine all the factors altering the global electrical fields because electrical state is a function of the 3D open/closed states of the channels, not merely their presence at the mRNA and protein levels.

The large electrical fields themselves appear to create the regulation that occurs. A study showed that by increasing the electric potential in cancer cells, metastatic activity can be suppressed, despite specific proteins being present that are known to be involved in metastatic activity.

Information Fields and Geometry


All of the signals that affect a cell, together, are called the morphogenic field. It includes all of the instructions that come from all secreted cellular signals, including cytokines and the effects of all the molecules in the extra cellular space (see post on Extracellular Space and Neuroplasticity). This includes many gradients that are used by immune cells to gather information and attract other cells. An unusual feature recently discovered as a cause of cancer is special proteins that produce cells in particular orientations—called planar cell polarity. When this polarity is altered it can cause cancer.

Electrical gradients are now shown to be critical as well. When the usual gradient or field information is somehow altered it can cause cancer. Each embryo has its own innate field. It has been observed that cells in the midst of a live organ are not as susceptible to the same chemical influences to become cancerous. They are much more able to become cancer when isolated from the influences of other cells. When the region’s electrical properties are different, they are less likely to become cancerous.

Signals from neurons are, also, a factor in causing cancer. When nerves are cut, then cancers occur more frequently. These neuron signals appear to be contributing to the field information in local regions.

A striking example of the field is when shunts are needed between the abdomen and the blood. These shunts send large amounts of cancer cells to many regions, but they do not become metastatic in some areas, but do in others. Another is when the shape of a region is altered by surgery it is more likely to become cancerous, possibly by altering the field.
Cancer cells turn away from the community aspect of the entire organism and become involved in individual behavior and their own new community (see post on Cancer – The Emperor of Cells.) The cancer cells either aren’t given appropriate information in the field about the creature, can’t extract the information or don’t care anymore. Cancers form their own organs and fields. The cancer cells, also, form their own information fields and communicate and cooperate using them. They reproduce and evolve to be stronger as a community. They signal each other to fight microbes and immune attacks. Cancer cells eliminate communication to the body and tissues of the body. But, they maintain the same junctions and communications among this smaller community.


Where is the Information


The study of electric fields brings up the problem of orders of magnitude of effect and the question of emergent properties. While at the level of genetic network activity, each cell in the field has definite behaviors—they are all influenced by the overall information fields. All levels are at play—the genetic, epigenetic, individual cells and networks of cells.

Having information in morphogenic fields including electrical gradients is similar to the notion that mental events occur in neuronal electric networks. Dr. Levin speculates that the same way that information is contained in neural networks, information could be maintained in electrical fields of cells, organs and creatures.
All of this, raises the question, of course, about its relation to cellular intelligence in particular and mind in nature in general.


Which Comes First – Electric Fields or Biochemistry


The genetic networks are very critical in electric signaling because cells use protein ion channels imbedded in the membrane. These proteins affect distant actions and are very involved in creating the overall gradients.

In one of many circular genetic processes, the actions of the genetic machinery are controlled by electrical gradients and the elaborate signaling of the genetic networks create the electrical gradient

Nices Catch22 situation. 

Patterning occurs by a continuous interplay of genetics and physics.
This conundrum indicates that there is a more global regulation of the entire process. In fact, research shows that the electrical influences cannot be reduced to simple chemistry inside of a cell. Electrical gradients of individual cells and many cells contribute to the creation of the 3D shapes and functions of organs and creatures. Examples of this include the creation of the embryonic eye, the head, and the regeneration of limbs exactly to size. For movement of cells, when electrical and chemical gradients are in competition, the electrical gradient wins.
The example of the eye is instructive. Dr. Levin notes that it shows the electrical information is more crucial. It is the electrical properties of the regions forming the two eyes that determine where the eyes will go. When this electrical property is altered, the eye forms in different places. This effect cannot be replicated outside of the head by any of the known “master” eye genes.


What Signals Could Describe 3 Dimensions?


How does a cell first create a shape of an organ in the fetus and then maintain it throughout life, with many new cells being generated? Signals can let a cell know about position, size and polarity and orientation. It is either cell-to-cell communication, which is basically the current research goal, or a pre formed field or organizing template. The 3D process in the fetus is called morphogenesis. Each cell in the embryo has to know its position relative to others and differentiates into the appropriate type of cell for that position.

Field structures in physics are similar to the concept of morphogenetic field. A field includes information at each location. It includes regulation at a distance. The gradient is a concept already used in studies of development. Current research shows that electrical potentials and gradients in the space between cells are an important source of information for cells, and control the movement of chemical signals such as serotonin and butyrate.


Electrical Fields Guiding 3D Shape of Cells and Organs


While both chemical and electrical factors are clearly relevant to determining the three dimensional function and shapes of cells, organs and creatures, it appears that an information field of some kind would be necessary for the level of information needed. Recent research shows the importance of the electrical potentials, gradients and fields.
Among theories of what mind could be (see post), information fields have been proposed. Perhaps this current research furthers such a view.

1) http://reasonandscience.heavenforum.org/t1826-how-does-evolution-supposedly-work
2) http://reasonandscience.heavenforum.org/t2279-what-prevents-the-transition-from-micro-to-macro-evolution
3) http://jonlieffmd.com/blog/electrical-fields-guiding-3d-shape-of-cells-and-organs
4) http://www.drmichaellevin.org/research.html
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413735/



Last edited by Admin on Sun Feb 21, 2016 1:49 pm; edited 13 times in total

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2 Morphogenetic Systems as cognitive agents on Sun Feb 07, 2016 2:51 pm

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Morphogenetic Systems as cognitive agents

Orchestration of the activity of billions of cells into the formation of tissues, organs, and whole bodies does not stop at embryogenesis. In adulthood, even though all cells eventually get replaced, the whole structure keeps a coherent shape for up to 2 centuries (e.g., tortoises). Moreover, some creatures are able to regenerate large parts of their body; for example, salamanders can re-grow entire lost limbs. Thus, living systems constantly monitor their shape for deviations and often can initiate processes to correct the damage and thus restore their "target morphology". These properties are not only of central importance to the fundamental understanding of embryogenesis, regeneration, cancer, and evolution, but are also crucial outside of biology: cybernetics, complexity theory, control theory, and engineering would benefit greatly from an understanding of how such complex, robust, and self-regulating machines can be designed and built. Robots that sensed (and repaired) damage would have immense scientific impact in space exploration, nanotechnology, and other areas where highly adaptive, massively parallel control algorithms are needed. Interestingly, although we are learning ever more about molecular pathways, we still know very little about how living systems regulate and remodel large-scale shape.


Current efforts are largely dominated by the molecular genetic approach. We are rapidly acquiring an immense amount of detail about which gene products interact with which other gene products. We also have functional experiments (inactivate gene A, or introduce gene product B in some region, and see a change in patterning of some organ); from these biologists derive models of control signals propagated among cells that direct their behavior and thus control patterning. While data grow exponentially, true insight into shape generation and repair is significantly impaired because bioinformatics is focused on gene sequences but not applicable to analyses of shape. Thus, several fields are stymied by a lack of conceptual and computerized tools to link mechanistic understanding of molecular signals with behavior of the patterning systems they encode. The field is missing (1) convenient symbolic mathematical tools with which to formalize shape and changes in shape, such that the outcomes of patterning experiments can be stored in a searchable database (like Entrez at NCBI, but for morphogenesis instead of gene expression), (2) generally-accessible agent-based virtual environments within which mechanistic models of patterning can be simulated in silico and integrated with existing data for testing and derivation of key regulatory properties, and (3) accessible artificial intelligence tools to help discover models consistent with experimental results in fields where the data are so abundant and complex that scientists cannot invent models consistent with empirical data.

We are using the data on genetic and bioelectrical mechanisms of regeneration in planarian flatworms (a very popular model system for molecular genetics work) as a proof-of-principle to 1) create a prototype for a symbolic mathematical formalism for encoding knowledge about shape, 2) implement a computing platform (expert system on planarian regeneration) so that anyone can query the existing literature for information about functional experiments that modify morphology, 3) produce a flexible and easy-to-use system for modeling the patterning consequences of control networks including both biochemical and physiological mechanisms, 4) create an Artificial Intelligence tool to assist users to discover mechanistic, constructivist models of signaling among components that match sets of functional data on patterning pathways, 5) use this system to identify a model explaining some of the remarkable regenerative abilities of planarian worms, which can regenerate any part of their body regardless of how they are cut, and 6) experimentally test new predictions of the models we identify in this way. Our work is yielding conceptual modeling and automated mining tools to revolutionize the building of algorithmic, understandable models directly from functional data that are too difficult to discover manually, thus impacting many fields of biology and engineering.
Using techniques from artificial intelligence, computational neuroscience, and cognitive science to make models of morphogenesis - treating patterning systems as primitive cognitive agents

Modeling pattern formation and cell regulation as neural-like circuits with plasticity, memory, and goal satisfaction circuits; using modulation of global neurotransmitter and electrical synapse properties to write pattern memories and behavioral repertoires into living tissue
Constructing quantitative models of patterning using extremal (least-action) principles

http://ase.tufts.edu/biology/labs/levin/research/newdirections.htm

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Research on the Dynamics of Information Processing in Biological Structures

Biological information comes in (at least) 2 flavors: 

spatial information (3-dimensional structure or topology of tissues, organs, and whole organisms),

and temporal information (perceived patterns within environmental stimuli that occur in time).

Both of these kinds of information need to be detected, remembered, and processed by cells and tissues to guide their function. Our lab uses a convergence of molecular biophysics and computational modeling to understand how this occurs at multiple levels of organization. The results of this effort will not only shed light on the fundamental nature of real living creatures but also will provide important clues to the capabilities of "life-as-it-could-be" in synthetic biology or hybrid cybernetic systems. The former ties our work to the biomedicine of birth defects, traumatic injury, and cancer. The latter has implications for the design of artificial life and the engineering of robust, adaptive devices and novel computational media. Altogether, we view this as a branch of information or computer science as much as it is biology.

Our lab current mind-map can be schematized this way:



Temporal Information

Biological structures have remarkable abilities to perceive patterns in the signals which impinge upon them, which manifest as learning, plasticity, and adaptive behavior. Although traditionally this is studied by neurobiology and behavior science, it is not exclusively a property of neural networks. We are interested in signal processing and pattern inference by somatic tissues that detect and organize information during pattern formation and homeostatic physiology. This includes questions of memory storage outside the CNS, adaptive plasticity in the brain, neural control of growth and form, and the mapping of cognitive programs on radically altered body structures. 

Spatial Information

Most of the interesting questions in biology boil down to the control of shape. We all start life as a single cell – the egg, which somehow self-assembles into an incredibly complex organism (whether it be an oak tree, rabbit, or snail). The question of how it is able to achieve its intended pattern (or "morphology") is the main issue of developmental biology. However, this problem is relevant throughout the life-span: as the body's cells age and die, they are replaced so that the organism remains intact. Moreover, some organisms are good at repairing damage – salamanders re-grow limbs, hearts, eyes, and jaws if they are amputated. Thus, the body has to know when it is damaged, and decide precisely which growth programs to activate to get back to the original shape (and know when to stop growing). Even cancer is part of this puzzle, because tumors are, in an important sense, a disease of geometry – cancer results when cells stop attending to the normally tight patterning controls of the organism, and can sometimes be tamed by the strong patterning influence of regenerative or developmental processes. Thus, developmental, regeneration, and cancer biology all share a fundamental set of questions: how do cellular systems know what shape to build, and through what molecular mechanisms do they build that shape? We are interested in the information processing, communication, and computations that go on as cell groups perceive current patterning states of the host and change their behavior towards specific morphogenetic goals.

http://ase.tufts.edu/biology/labs/levin/research/index.htm

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4 Temporal Information on Sun Feb 07, 2016 3:38 pm

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Temporal Information


The Properties of Memory Storage and Transmission in Tissue:

Flatworms can learn in a variety of behavioral paradigms and are a unique model system in which regeneration and memory can be studied in the same animal. We are asking how and where information is encoded and how it can be imprinted upon the regenerating brain by other tissues. 

The ability to manipulate large-scale anatomy using our unique bioelectric reagents offers an excellent opportunity to study the plasticity and dynamic properties of the brain-body interface. In organisms with ectopic sense organs or limbs, how does the brain recognize the presence of these extraneous (and evolutionarily unexpected) structures, and how does it incorporate their data and abilities into functional behavioral programs? We are currently pursuing this question using behavioral and neurophysiological analysis of tadpoles with extra eyes in the flank and other regions. Understanding the means by which the CNS recognizes tissues in aberrant locations will enrich fields such as sensory augmentation, regenerative repair of injury, brain plasticity, morphogenetic surveillance during pattern formation, and synthetic biology/bioengineering.

Spatial Information


The capacity to generate a complex organism from the single cell of a fertilized egg is one of the most amazing qualities of multicellular creatures. The processes involved in laying out a basic body plan and defining the structures that will ultimately be formed depend upon a constant flow of information between cells and tissues. The Levin laboratory studies the molecular mechanisms that cells use to communicate with one another in the 4-dimensional dynamical system known as the developing embryo. We also study the flow of information necessary for an injured system to recognize what structures must be rebuilt, and the algorithms that coordinate individual cell activity towards specific patterning outcomes during remodeling and cancer suppression. Through experimental approaches and mathematical modeling, we examine the processes governing large-scale pattern formation and biological information storage during animal embryogenesis and regeneration. Our investigations are directed toward understanding the mechanisms of signaling between cells and tissues that allows a biological system to reliably generate, maintain, and repair a complex morphology. We study these processes in the context of embryonic development, regeneration and cancer, with a particular emphasis on the biophysics of cell behavior. In complement to other groups focusing on gene expression networks and biochemical signaling factors, we are pursuing, at a molecular level, the roles of endogenous voltages, and bioelectric gradients as epigenetic carriers of morphological information. Using gain- and loss-of-function techniques to specifically modulate cells' ion flow we have the ability to regulate large-scale morphogenetic events relevant to limb formation, eye induction, craniofacial and neural patterning, limb regeneration, head remodeling, etc. While our focus is on the fundamental mechanisms of pattern regulation, this information will also result in important clinical advances through harnessing bioelectrical controls of cell behavior for regenerative medicine.


Bioelectrical controls of vertebrate appendage regeneration





Regeneration is a fascinating example of pattern regulation, and has important biomedical implications. A regenerating system must not only recognize damage, but also pursue a goal-directed process of restoring the missing structures (and crucially, know to stop when this process is complete, thus avoiding cancerous overgrowth). Interestingly, systems with high regenerative ability have low susceptibility to neoplasm, contrary to the simple view in which cellular plasticity and propensity for proliferation should go together in cancer and regeneration. Instead, data suggest that the morphogenetic controls imposed during regeneration can prevent cells from ignoring the patterning cues of the host (as occurs in many cancers). What is the mechanistic nature of these controls? Our lab studies the role of voltage gradients, and how these biophysical controls couple to genetic and epigenetic pathways in the induction of regeneration and the imposition of correct morphology on the restored tissue. We mainly use two model systems to understand these processes: Xenopus laevistadpoles and planarian flatworms. 

While vertebrate regeneration is considered to be limited, the Xenopus tadpole is able to regenerate its tail - a complex appendage containing spinal neurons, muscle, skin, and vasculature. We identified three electrogenic proteins whose activity is required for the production of a depolarization zone that underlies regeneration in the blastema and demonstrated that a proton flux from the wound epithelium is necessary and sufficient to drive the downstream events of regeneration, including cell proliferation, innervation, and expression of regeneration-specific markers. We are currently working on inducing regeneration of limbs, eyes, tails, and craniofacial structures in normally non-regenerating species by providing the appropriate bioelectric signals to the cells at the wound site. While ion flows control cell-level behaviors such as migration, differentiation, and proliferation, bioelectric signals also function as master regulators of large-scale shape in many contexts: a simple signal can induce complex, highly orchestrated, self-limiting downstream morphogenetic cascades. For example, an unmodulated flux of protons can cause the formation of a complete tail of the right rise and tissue composition. Inducing the host to form structures it already knows how to make is a very desirable property for regenerative medicine approaches since avoids the inevitable complexity explosion of having to micromanage (directly bioengineer) the creation of complex organs and appendages. We are also pursuing novel long-range sources of patterning information for regeneration, such as the body-wide bioelectric cues that regulate formation of the nascent brain and suppression of tumorigenesis.


Bioelectrical, non-local controls of regenerative polarity in planaria




Planarian flatworms have an impressive capacity for regeneration. They are able to regenerate large parts of the body, and are continuously maintained by a well-characterized resident population of adult stem cells. Upon cutting, these organisms are able to regenerate the head and tail at their appropriate locations. What mechanisms determine the polarity and allow tissue re-patterning to take place? Consider: after bisection, cells on one side of the cut (in the head fragment's posterior end) will form a tail, while cells which were their immediate neighbors before the cut will make a head (the tail fragment's anterior half). Our data suggest that the mechanism by which blastema cells polls the rest of the host (to determine where the wound is located and what other tissues already exist in the fragment and thus don't need to be recreated) is mediated by physiological signals passing through nerves and long-range gap junctional paths. We have identified endogenous ion fluxes and voltage gradients maintained by specific ion pumps which are crucial for the determination of anterior-posterior polarity during regeneration; manipulating these signals allows us to specify tissue identity and thus control the anatomical structure of regenerating worms. Through studying the roles of electrical polarity (maintained by ion channel and gap junction systems) in planarian regeneration we are gaining insight into the control of regeneration and morphogenesis by endogenous ion fluxes and into the mechanisms by which stem cell differentiation is integrated into functional organ/tissue systems within the organism. Most importantly, we've recently shown that a rapid, transient alteration of the physiological signals underlying morphostasis and regeneration is maintained in perpetuity! That is, worms forming 2 heads (one at each end) because of a 2-day disruption of gap junctional signals will continue to form 2 heads through subsequent months of amputation or fission in normal conditions. These data illustrate how information embedded in physiological networks can be solidified into permanent alteration of the large-scale structure bodyplan. More broadly, this work identifies a molecular glimpse of how the "target morphology" of an animal (the form towards which regeneration regulates) can be permanently reset, and reveals that a drastic change in body structure and behavior can be maintained across a complex metazoan's organism's normal mode of reproduction without any change in DNA sequence.


Cancer as a problem of morphogenetic disorganization





One view of cancer (distinct from the current paradigm of intrinsically "cancerous" cells resulting from specific DNA modifications) is as a problem of organization within a "society of cells". Cancer is, in some sense, a disease of geometry - a failure of cells to attend to the signals that normally organize their behavior towards the patterning needs of the host. This view is supported by classical and recent data showing that aggressive cancer cells can be normalized by regenerative and embryonic environments - context is crucial, and environments in which tight morphogenetic cues are being imposed have the ability to reverse or reboot cancer phenotypes. The converse is also true: we have found a bioelectrical property that imposes a neoplastic-like phenotype upon pigment cells in vivo. This is not surprising, given that a significant component of morphogenetic cues are ionic in nature. Remarkably however, this effect is non-local in nature - it is the transmembrane potential of other, quite distant cells that determines the metastasis-like effect. We are pursuing several lines of inquiry including 1) developing methods for tracking bioelectrical signatures of pre-tumor cells as a non-invasive diagnostic modality, 2) understanding how voltage properties of distant cells can be a cancer-triggering event in the body, and 3) learning to control transmembrane potential of key cell types to normalize existing tumors.


Left-Right Asymmetry




The vertebrate body plan is basically bilaterally-symmetrical; however, consistent and well-conserved asymmetries of the brain and visceral organs are superimposed upon the fundamental structure. Asymmetries in the left-right axis present a number of deep puzzles which link evolutionary biology, clinical medicine, biochemistry, embryology, cognitive science, and perhaps even quantum parity violations. Strikingly, it is now known that even single mammalian cells in culture maintain a consistent left-right axis. We are working to understand the mechanisms by which the embryo aligns the left-right axis with respect to the other two axes, and imposes this spatial information on macroscopic cell fields prior to the morphogenesis of the asymmetric organs. In contrast to popular models of asymmetry initiation by extracellular fluid flow during gastrulation, our lab studies much earlier, intracellular events that break symmetry and establish consistent asymmetry as a form of planar cell polarity, using physiological mechanisms to amplify cytoskeletal chirality across cell fields.


Gap Junctions in Pattern Formation:
While asymmetrically expressed genes have been identified in several vertebrate systems, many critical questions remain about how cellular polarity is synchronized and amplified across embryonic fields to allow cells to ascertain their position with respect to the midline. We identified a dependence of asymmetric gene expression on early communication between left and right sides in the chick and frog. For example, expression of left-sided markers depends on events occurring on the right side, during very early stages, suggesting that the two sides need to coordinate their decision with respect to the L-R identity of each. One mechanism for communicating between cells and tissues involves gap junctions: multimers of connexin proteins form channels between cells and pass small molecules, subject to complex regulation by various signals.


So it seems within gap junctions that action happens, but the action per se is REGULATION AND COMMUNICATION THROUGH VARIOUS SIGNALS. THATS THE KEY. 


Using misexpression of Connexin proteins and their mutants to disrupt and induce long-range gap junctional paths in early chick and frog embryos, we showed that gap junctions are crucially involved in L-R patterning in early embryos of Xenopus and chick. The data suggest the presence of a unidirectional circumferential flow of small molecules through gap junctions across the whole embryonic field during blastula/early gastrula stages. Our research focuses on understanding the mechanisms upstream and downstream of specific gap junction communications (GJC) in embryos, as they relate to pattern formation and growth control, and on identifying the small molecule morphogens that traverse junctions. More broadly, we focus on gap junctions as a bioelectric patterning element that sets up domains of isopotential cell fields during morphogenesis. More recently, we have identified roles for the electrical synapses known as gap junctions in mediating bioelectric regulation of tumorigenesisbrain patterning, and neural pathfinding.


Bioelectric Aspects of Very Early Left-Right Patterning

L-R asymmetry can only be derived from gap-junctional movement of determinants that is directionally biased. In frog and chick embryos, we have identified a set of four ion transporters which reliably establish a voltage gradient along the midline. This gradient is required for normal asymmetry, and our current quantitative models suggest that it is sufficient to redistribute small molecule morphogens from left to right through the gap junctional paths. These transporters establish a battery across the midline, and in Xenopus, this occurs by the second cell cleavage. Molecular localization of ion channel/pump proteins, and direct detection of asymmetric ion flows (H+ and K+ ions) reveal that these embryos know their left from their right within about 2 hours of fertilization. What establishes the right-sided ion flow? Our latest work has focused on the cytoskeleton, and we showed that the early protein localization machinery is consistently right-biased, allowing intracellular kinesin and dynein motors to deliver maternal ion transporter cargo to the right ventral blastomere (thus establishing the battery and electromotive force for the trans-junctional morphogen(s)). We are currently characterizing the intracellular microtubule organizing center whose chirality is likely to be the ultimate origin of asymmetry, as its orientation with the other two axes is established during fertilization. Remarkably, the role of cytoskeletal proteins in directing asymmetry is conserved even across independent origins of multicellularity, as we were able to show that the same tubulin mutations randomize asymmetry in frog, human cells, and C. elegans as do in plants.We have also pursued roles for planar cell polarity in spreading LR information across a blastoderm.



The Role of Serotonin in Embryogenesis:

The importance of serotonin in neuronal function is well established. Interestingly, it also has roles in early embryogenesis, long before nerve systems appear. This is probably indicative of evolutionarily early systems of cell signaling which became co-opted by neurons when they arose. Taking advantage of the well-characterized pharmacology and genetics of many steps in the serotonin signaling pathway, we are studying how serotonin signaling is used in information exchange between cells in processes such as L-R patterning and control of timing and cell movement during gastrulation. We have shown that serotonin is utilized by both chick and frog embryos, at very early stages, as a small molecule signal which is transported in a left-right gradient and regulates the development of laterality. Indeed, we now know that the early frog embryo is literally an electrophoresis chamber, which uses voltage potentials to generate consistently biased left-right gradients in serotonin in an epigenetic process not dependent on zygotic gene expression. We have modeled this process quantitatively, and characterized novel intracellular serotonin-binding proteins which directly activate asymmetric gene expression after their rightward movement, linking an early biophysical process to transcriptional regulation via chromatin modification pathways. Serotonin is also a key mediator for bioelectric control of neuronal outgrowth from transplants


Mathematical Modeling and Physiomics:




Molecular biology and genomics are revealing a constantly expanding amount of information about genes, their products, and the way they interact. It is notoriously difficult to control or make predictions about systems involving mutual interactions of even a few components because of feedback loops and the basic results of dynamical systems theory. Indeed, looking at a high-resolution mechanistic pathway, such as painstakingly elucidated in many recent studies, is insufficient for knowing what biological pattern this transcriptional network results in. It is essential to develop constructive, synthetic models of morphogenesis which integrate 3-dimensional shape from the function of molecular components and pathways. To fully understand the implications of information coming from genome projects and biochemical analyses of gene activities for morphogenesis, a synthesis is needed. We are attempting to use the mathematical and computer modeling tools of chaos, information, and complexity theories to understand large-scale patterning and control properties of bioelectrical mechanisms and small molecule transport among cell groups. Our main efforts along these lines are directed towards 


(1) development of a formalization for morphogenetic processes (bioinformatics of shape, beyond gene/protein sequence, and automated model discovery), 
(2) testing the hypothesis that cell behavior can be understood as the segregation and movement of cell states through a multi-dimensional state space with axes defined by bioelectrical parameters such as membrane voltage, K+ content, pH, nuclear membrane potential, etc., and 
(3) developing quantitative models integrating physiology and genetics of ion transporter function during early left-right asymmetry.


Computational Approaches to Pattern Formation:



Bioinformatics has revolutionized molecular biology, but the field still largely lacks necessary computational tools to crack the problem of pattern regulation and control. With each new functional or high-resolution genomic dataset, it becomes ever more difficult to come up with constructive models that explain how complex pattern arises, and what steps could be taken to induce the kinds of patterning changes required for regenerative medicine and the repair of birth defects. Thus, we are working towards a set of software tools that utilize the principles of machine learning and artificial intelligence to establish a bioinformatics of shape. Our goal is to understand the fundamental rules that allow complex patterns to be formed and to repair themselves after damage, and to discover models of these processes that are not merely lists of necessary gene products but algorithms that clearly reveal the regulation of shape, size, topology, and anatomical arrangement. To this end, we have produced novel formalisms for describing functional experiments and resulting anatomical outcomes, and a genetic algorithm-based platform for discovery of mechanistic models that explain complex patterning results in the published literature. This resulted in the first quantitative model of planarian regeneration explaining numerous experimental datasets, and the first regenerative model discovered by a non-human intelligence (a machine learning platform). Importantly, our goal is not only to understand specifics of real model organisms (e.g., planarian regeneration) but to uncover broad general principles useful for synthetic morphology applications - an Artificial Life perspective. Another aspect of this work is the study of computation in biological tissues (which process information in order to regulate and remodel their shape). Thus for example, we are not simply trying to make computational models to explain planarian regeneration, but rather, we see the planarian itself as a model of the kind of computation we want to understand. Additional projects include computational models of emergent signaling dynamics that explain stochastic behavior and pattern dysregulation in cancer.

http://ase.tufts.edu/biology/labs/levin/research/temporal.htm



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Left-right patterning in Xenopus conjoined twin embryos requires serotonin signaling and gap junctions 1

Xenopus is a clawed frog is a genus of highly aquatic frogs native to sub-Saharan Africa.

We show that serotonergic and gap-junctional signaling, but not proton or potassium flows, are required for the secondary organizer to appropriately pattern its LR axis in a multicellular context. After fertilization, one of the key milestones of embryogenesis is the establishment of the primary body axes. Developmental biologists have long been intrigued by the mechanisms responsible for orienting the left-right (LR) axis, which is defined with respect to the anterior-posterior and dorsal-ventral axes. Although the vast majority of vertebrate species display LR-symmetrical external body plans, these animals have consistent asymmetries in the position and shape of the internal organs including the heart, stomach, gall bladder, spleen, and brain. Birth defects that disrupt LR patterning affect about 1 in 6000 live births, but are often accompanied by severe medical consequences, particularly when LR placement of individual organs in the body is randomized, a condition referred to as heterotaxia. The establishment and orientation of the LR axis requires 3 distinct steps that take place at progressively later stages of development: symmetry breaking, when the two sides of the embryo first become different and the nascent LR axis is consistently aligned with respect to the other 2 body axes; the conversion of these asymmetries to LR-biased expression of genes such as the Nodal-Lefty-Pitx cassette; and the translation of this asymmetric gene expression into asymmetric morphology and position of organs. Although the last two phases are fairly well understood and are generally considered not controversial, there remain many questions about the earliest steps in symmetry breaking. 


[size=30]Gap junctions: versatile mediators of long-range developmental signals[/size] 2


My lab works on developmental bioelectricity, studying how cells communicate via endogenous gradients of plasma membrane resting potential (Vmem) in order to coordinate their activity during pattern regulation . It is well-known that resting potential is an important regulatory parameter for individual cells’ proliferation, differentiation, and oncogenic potential . Voltage itself is an important “master control knob” because the same morphogenetic phenotype (e.g., inducing eye formation or metastatic conversion) can be induced by using sodium, potassium, chloride, or even proton flows to achieve a particular Vmem level. The chemical nature of the ion (and the genetic identity of the channel) often does not matter, as long as the voltage gradient is established correctly for a particular downstream outcome. In this Node post, I wanted to briefly mention a few of our recent studies which highlight an exciting new aspect of this field: long-range signaling via gap junctions.
Gap junctions (GJs) are electrical synapses – direct conduits for small molecules between cells, which can be used to form isoelectric compartments in vivo; they have numerous roles in normal development and disease. Most importantly, they are extremely versatile signaling elements , because they both regulate cellular resting potential and are themselves voltage-gated.  GJs are able to function as a kind of transistor, allowing voltage to control current flow. Because they are ideally-suited to process information in physiological cell networks, is no surprise that gap junctional communication is a key regulator of brain activity, developmental patterning, and carcinogenesis. One of our recent studies investigated the role of endogenous bioelectric gradients in brain formation in the Xenopus lae



vis embryo. Early frog embryos exhibit a characteristic hyperpolarization of cells lining the neural tube; disruption of this spatial gradient of the transmembrane potential (Vmem ), using misexpression of depolarizing channels, diminishes or eliminates the expression of early brain markers, and causes anatomical mispatterning of the brain. Conversely, forced establishment of the brain-specific voltage pattern (using expression of select ion channels) was able to rescue brain defects induced by mutant Notch protein (a potent regulator of neurogenesis), and even induce ectopic brain tissue in posterior regions of the tadpole.

In addition to cell-autonomous effects, we showed that hyperpolarization of transmembrane potential (Vmem ) in ventral cells, well-outside the brain, induced upregulation of neural cell proliferation. These long-range effects were mediated by gap junctional communication, and another recent paper extended such long-range regulation of cell division to similar non-local control of apoptosis (Pai, 2015). We suggested a model in which brain cells coordinate growth and sculpting decisions with the remaining tissues (to determine appropriate location, size, and boundaries of the nascent brain) via electrical signals mediated by GJ paths.


Interestingly, a similar story was found for tumorigenesis in Xenopus (Chernet et al., 2014). mRNA encoding mutant KRAS induces tumors in a zebrafish cancer model (Le et al., 2007). We showed that the same thing happens in Xenopus (complete with induced angiogenesis, overproliferation, expression of tumor markers, and immune response); remarkably, a specific bioelectric state of cells at a considerable distance (on the other side of the body) can suppress tumor formation, despite strong expression of the oncogene. The effect is mediated by butyrate signaling (Chernet and Levin, 2014), which links voltage regulation to chromatin modification, and – GJs. These data are part of a growing body of evidence (Bizzarri and Cucina, 2014Chernet and Levin, 2013Soto and Sonnenschein, 2011Tarin, 2011) highlighting aspects of cancer as a “disease of geometry” – a disorder of patterning cues and cell:cell communication that normally harnesses cell activity towards specific morphogenetic goals and away from tumorigenesis.

It appears that in diverse contexts, such as embryonic establishment of pattern and tumor suppression, GJs link bioelectric and biochemical pathways to regulate events at considerable distance. Thus, future work must focus not only on ever-more detailed dissection of biophysical signaling events within single cells, but also address group dynamics and large-scale emergent properties of physiological networks linked by electrical synapses (Donnell et al., 2009Levin, 2014aSaraga et al., 2006Schiffmann, 2008Steyn-Ross et al., 2007). Multicellular models of GJ signaling will surely contribute to the understanding of patterning and deviations from normal growth and form.

1) file:///E:/Downloads/ft799.pdf
2) http://thenode.biologists.com/gap-junctions-versatile-mediators-of-long-range-developmental-signals/research/

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Darwin's doubt, page 211:

Ion Channels and Electromagnetic Fields


Membrane patterns can also provide epigenetic information by the precise arrangement of ion channels—openings in the cell wall through which charged electrical particles pass in both directions. For example, one type of channel uses a pump powered by the energy-rich molecule ATP to transport three sodium ions out of the cell for every two potassium ions that enter the cell. Since both ions have a charge of plus one (Na+, K+), the net difference sets up an electromagnetic field across the cell membrane. 1 Experiments have shown that electromagnetic fields have “morphogenetic” effects—in other words, effects that influence the form of a developing organism. In particular, some experiments have shown that the targeted disturbance of these electric fields disrupts normal development in ways that suggest the fields are controlling morphogenesis.2 Artificially applied electric fields can induce and guide cell migration. There is also evidence that direct current can affect gene expression, meaning internally generated electric fields can provide spatial coordinates that guide embryogenesis.3 Although the ion channels that generate the fields consist of proteins that may be encoded by DNA (just as microtubules consist of subunits encoded by DNA), their pattern in the membrane is not. Thus, in addition to the information in DNA that encodes morphogenetic proteins, the spatial arrangement and distribution of these ion channels influences the development of the animal.

1) http://web.as.uky.edu/Biology/faculty/cooper/Bio450-AS300/K%20and%20Na%20lab/Nobel%20prize%20Na-K%20pump.pdf
2)  Bioelectromagnetics in Morphogenesis Michael Levin*
https://www.researchgate.net/profile/Michael_Levin2/publication/10696851_Levin_M_Bioelectromagnetics_in_morphogenesis_Bioelectromagnetics_24_295-315/links/0c96052e6a8c9ae0c6000000.pdf
3) Three-Dimensional Gradients of Voltage During Development of the Nervous System as Invisible Coordinates for the Establishment of Embryonic Pattern
http://onlinelibrary.wiley.com/doi/10.1002/aja.1002020202/pdf

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