Velcro — what would we do without it? We can attach and detach fabric with it as often as we wish, yet it can hold together quite firmly. Like so many inventions, Velcro was an imitation of nature. An engineer and inventor named George de Mestral one day noticed how easily and effectively cockle-burs stuck to his pants and even the hairs of his dog. Rather than simply pulling them off and going about his day, he took some and examined them under a microscope. He discovered an ingenious hook and loop arrangement which he then sought to reproduce. It took him two decades to get the right combination of material and machine fabrication to create a marketable product. The hook material had to have just the right firmness and flexibility to hold strongly but release when pulled at the right angle. It was quite a challenge to make Velcro, but he stuck to it.
What makes Velcro so useful, compared to snaps or clips, which also grab well but require sharp, hard pressure to release? If you need to detach Velcro, you pull up a section of it and the rest comes along readily, yet Velcro holds an object very solidly. Velcro has a lot of individual hooks and loops that adhere to each other when pressed together. Each hook and loop has only a little adhesion and can be pulled away with little force. However, with all of the hooks and loops of a section of Velcro added together, the total adhesion is quite strong. They all work together to hold the object firmly, but to release it you just pull a few hooks away from their loops and then keep going, so the release is not that hard, unlike a snap or clip. The secret of Velcro is the additive effect of many tiny adhesions.
Cockle-burs are not the only place in nature where ingenious attach-and-release systems occur. Your cells depend on something similar — they are not just floating around in colonies like a big blob, but they have “infrastructure” to which they attach themselves. Each cell has tiny, delicate connectors that they use to attach, but they have many of them, so the total adhesion is significant. To release, these connectors can individually unbind until all detach and the cell is released. Each cell is an amazing feat of engineering, and the ways that cells work together to make up our bodies is quite incredible. Understanding their design helps us understand more about what promotes health and disease.
Your cells are in a bind…
Cells in your bloodstream and immune system cells are migratory, but most of your cells stay in place. We know that integrins, the antennas of a cell, catch signals from their environment by attracting and binding specific proteins, causing a change in the molecular shape of the entire integrin — and since the integrin extends through the cell membrane, those changes affect the cell’s function. The binding process, if attaching to a free-floating molecule, does not anchor the cell. But what if the binding occurs to a protein that is part of a larger structure? When that happens, as is the case for many of your cells, those cells are bound to something more stationary. That means that they are “stuck” to that structure. This is how cells attach and stay in their proper place. The integrins of the cell attach in a manner similar to hooks of Velcro.
Just inside the cell membrane are strong fibers called actin filaments, making up the “actin cytoskeleton”, which is a strong fibrous region to which the integrins can bind. This provides a stronger connection than simply attaching to the pliable cell membrane. This is the interior anchor for the integrin.
Most cells anchor externally to the “extracellular matrix” (ECM), which is a non-cellular mass of proteins and carbohydrates. The ECM fills the space between cells and is formed from components secreted by the cells. The extracellular matrix is strong but dynamic — the body changes it by breaking down portions of it with enzymes and secreting more components to build it up. The ECM contains special proteins that match certain integrins, allowing cells with those integrins to bind with the ECM. So we have strong actin filaments tied with the “antenna” integrins which are tied to the ECM. The number and location of the integrin bindings add up to a Velcro-like set of connections, with the cumulative binding being quite strong.
Have you ever made a telephone out of paper cups and string? The string is attached to two paper cups, pulled tight, with one cup for each person. The tight string transmits sound waves, and it also connects the two people using the telephone. If one moves, the other one had better follow, or else the connection is broken. This is a picture of how an integrin “antenna” can both pass signals and tie cells physically to a structure.
How does the integrin function? An integrin first binds to a “ligand”. A ligand is a molecule the receptor is designed to bind to. Cells can have various types of integrins, tuned to receive specific ligands. Some integrins are meant for attachment and others for receiving or passing signals. An integrin performs a rich array of functions, which can be controlled by ligands at either end of the integrin.
We see that certain integrins are meant to tie together the actin cytoskeleton structure of the cell to the ECM scaffolding outside of the cell, with the soft, pliable cell membrane adjusting its shape as it is pressed by stronger structures on each side of the membrane. When the integrin binds to a ligand, its complex protein molecule’s 3-dimensional shape makes a “conformational change” which influences the entire molecule’s shape from one end to the other. This shape change is the signal or the “sense” that tells the inside of the cell what is happening on the outside. It can’t directly sense the outside environment, but it gets an interpreted, encoded understanding of the environment through the conformational shape-shifting of the integrin. That then may cause a reaction, such as activating an ion pump, it could cause the genetic expression of the cell to change as the cell reacts to what it is sensing, or it could cause the integrin to bind to the ECM.
The conformational change in the integrin protein isn’t the end of the story, because if it is attached to the outside infrastructure, it will pick up waves or stress that travel along that structure. Simple mechanics, where the ECM pulls on the integrin and that stress is transferred to the inside of the cell, can occur. More molecular shape-shifting may happen in response to mechanical stress, resulting in a biochemical signal. And sometimes disassociation, where the binding is broken, happens under sufficiently strong force.
The integrin protein molecule, made up of amino acids, is so complex that its molecular shape combinations, in three dimensions, can be almost limitless. Equally limitless are the signaling and functioning of the integrin. Getting mechanical signals from the environment (mechanosensing) is a concert of many such functions. The American Society for Cell Biology published a description in Molecular Biology of the Cell (MBoC) which describes four steps of mechanosensing:
- Mechanopresentation: force or EMF (Electromagnetic Field) is presented to the ligand that is bound to the integrin.
- Mechanoreception: the receptor, such as an integrin, is pulled or moved by EMFs. It may react with a conformational shape change.
- Mechanotransmission: the force propagates along the integrin, either physically or with a molecular change.
- Mechanotransduction: the integrin’s response becomes a biochemical signal, causing a reaction in the cytoplasm of the cell.
Further, “mechanosensitive” proteins can adjust by deformation, relative displacement, hinge movement, unfolding/unmasking, translocation/rotation, and cluster rearrangement. Simply put: there are many ways the integrin proteins can be influenced in response to environmental stress.
Mechanosensing is often cumulative, where the number of “tuned-in” integrins can add up to a major signal if the numbers are high. If the cell has a high number of integrins that can react to a signal, then the cell is ultra-sensitive. If there is a large quantity of a certain ligand around the cell, then more integrins are activated. So the tuned-in integrin quantity and the number of ligands affect how strongly the cell “hears” the signal.
Long term effects
Have you ever seen pictures of a gourd that grew up inside a mold? The gourd growth adjusts to fill the entire inside of the mold, shaping the resulting gourd into the exact shape of the mold. Similarly, cells react directly to the mechanical nature and frequency of the environment that they bind with to find the best way to react to and deal with that environment. Vibration is noticed by cells. Physical stress, such as when exercising or taking a physical injury travels through the ECM and is noticed by the cells. The cells will adapt through epigenetic changes to react quite differently if the stress is significant and prolonged. This is key to both health and disease: the cell is not striving towards either one of these — it is just trying to find the best way to handle its current environment.
In a study published in Molecular Biology and Evolution, researchers at Texas A&M University used artificial biomaterials to which laboratory-grown cells could bind, and altered those materials to present different levels of pressure, viscosity, and stiffness. The cells responded to the different stiffness with new genetic expressions which they passed along to the next generation of cells. In other words, the changes were inherited when the cell reproduced. Some scientists call this “evolution”, because the adaptations to the environment pass down through generations of cells. More precisely, it is a stable new configuration that cells pass along. The good and bad news here is that environmental stresses can bring about longer term changes. Of course, the process can lead to positive as easily as negative adaptations.
The cAMP (adenosine 3’,5’-monophosphate) signaling pathway regulates cell growth and differentiation, gene transcription, and protein expression. cAMP is an important signaling molecule in the body. In a study published in Nature Cell Biology, researchers used a magnetic twisting cytometer, which applied mechanical stress to integrins by using microscopic magnetic beads coated with specific ligands (so that only one type of integrin (?1) was affected), and were able to enhance the cAMP signaling when mechanical stress was applied. Since only the ?1 integrin was experiencing mechanical force, researchers proved that the change was due to mechanical force applied to that integrin. That force was impacting a major metabolic pathway!
Your extracellular matrix ties you together, and many of your cells are attached to it. What affects the ECM impacts a lot of cells. Some of the reactions are short term, and some have longer term impacts.
Dr. Nemec’s Comments:
Movement sends information from outside of the cell to inside the cell. If the cell experiences movement from outside itself by being anchored to the ECM, then that movement from outside will cause a ripple effect and these ripples convey information. This is one form of communication. The integrin is like a hand that has fingers that can form its own sign language for the rest of the cell to read and understand. Since proteins are molecules that have so many conformational possibilities it becomes quite an extensive sign language indeed. Just imagine every cell tied together in a network — all sensing and communicating information through movement, signaling molecules and electromagnetic fields, and all are sending information along a 50 trillion cell network. This is how the body works in such harmony. Just like a school of fish moving as one, instantly changing in direction as needed. So the integrin is like an antenna that can received information from surrounding electromagnetic fields, from movement of the environment around it, and most importantly from frequencies originating from either the mind or the heart. If from the mind of stress (conscious and subconscious stress) it will continually convey “running constantly” to the cell and the cell will either die prematurely or become dysfunctional. If from the peace that flows from the heart it will convey “rest and run” but in a perfect balance. This is the basis of our Revolution New Medicine Protocol to release the running programs from the mind and let the heart or supreme conscious mind instruct the 50 trillion cell community perfectly.
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