The Time is Now

Picture1     I have looked forward with much anticipation to the time when we could travel a bit farther down the road of discovery together.  Finally, the time is now.  Let me quickly lay out some of the scenery for your view.  Our destination is not very far away, it is the vast and beautiful landscape of Redox Signaling; a technology that has the potential of providing us, when fully explored, with some of the greatest advances into the science of life that we can experience, accompanied by the power for good that comes from such knowledge.  Over the last several posts (made a few years ago) we have covered some of the terrain that leads to this redox signaling landscape.  Let me remind you of some of the scenery we passed along the way:

·        The Atomic Scenery:  to really appreciate what life is, we considered what is happening on the smallest scale, the details of the fine fabric that holds us together in the worlds much smaller than we can see.  The atoms that make molecules that make machines in cells that make cells that make tissues that make systems that make our body.  The same physical laws that make us also make up everything that surrounds us.

·        The Signaling Networks of Life:  The incredibly complex and beautiful orchestration of life that exists inside us requires that all of the billions of billions of billions of molecules inside us are connected together in a vast signaling network.  Molecules in our brain signal molecules in our muscles signal molecules in our heart signal molecules in our gut and so forth.  Signals from our exterior world, light, heat, sound, touch also interconnect with those inside us.  Redox Signaling is perhaps the most fundamental of all our internal signaling networks.

·        Control Semaphores:  Exploring the semaphores that control the signaling networks within us might be one of the more boring aspects, but without it the traffic signals inside us would become hopelessly jammed and life would not be so great.  Redox signals control these semaphores.  Recall that diabetes was seen as a problem that happens when the signaling networks get fouled up.

·        Homeostatic Balance:  We then took a close up view of the universal law of nature that governs how all of this works.  What brings us back into balance when things get out of balance?  We explored one or two of the consequences of this law and how life must compensate for a lack (or an excess) of needed supplies: nutritional supplies, oxygen, water, and energy.  We also looked at the vast extent of this law that like gravity governs all things from the smallest scale to the biggest scale everywhere.

·        Uncountable Consequences: Crude attempts and much vigorous waving was done to emphasize the power that is found in understanding these most fundamental principles of life.  When the bright light of truth illuminates our path, nothing is impossible, all obstacles are visible and tractable.  We must let the light so shine to reap the benefits.  A great diet, a great government, great management of resources, great relationships and great health is all possible as more truth is revealed to us, it is a worthy goal to pursue such truths and build the torch for those that follow.

At this point in the journey it might be a bit confusing why we had to go through all of this scenery to get us into redox signaling territory, but let me assure you that the view will be more appreciated after you have gone through the effort to get there.

First off, you passed through the atomic scenery because REDOX (REDuction/OXidation) happens on the atomic level.  You need to think at the scale of an atom to understand what it really means.  REDOX is a process that happens when atoms pass electrons back and forth between themselves.  Oxidation happens when an electron is “stolen” from an atom or molecule.  Reduction happens when an electron is received by an atom.  Obviously when an electron is stolen from one atom, it can be received by another and so the process of passing an electron between atoms is called a REDOX process.  The oxygen atom really likes to steal electrons that are hanging around and so the oxidation (electron stealing) process has been named after it.  When electrons are stolen, the properties of the atoms change.  Iron atoms make a hard and shiny metal surface, when electrons are stolen from them by oxygen they turn into orange crumbling rust (Iron oxide).  Wood releases lots of energy when it is oxidized (it burns), but transforms into a crumbling pile of carbon.

By the way, this does not make oxygen “bad”, we certainly have a need for oxygen inside our bodies.  As we will see a bit down the road, there are many types of oxidants inside us (along with oxygen) that are not “bad” and serve very important purposes.  The landscape of redox signaling molecules that we will be exploring are mostly oxidants, in one form or another.  We could not live a minute without them.  The real issue is where there are too many oxidants or even too many antioxidants concentrated somewhere in our body.  A local REDOX imbalance can make things very “bad” and can cause massive damage in cells and tissues.  Here is where this law of homeostatic balance becomes so very important and where the terrain of redox signaling begins.  The accumulation of oxidants and free radicals inside cells is like the accumulation of smoke inside a house.  It causes everything inside the cell, including the genes, to take notice.  This accumulation must stimulate processes that will bring things back into balance.  It turns out that most of the most intricate and beautiful signaling networks in our body, the incredible orchestration of signaling activity between the countless molecules inside our trillions of cells, are made in attempts to restore homeostatic balance to the cells after it has been disturbed.  This is the true test of a living organism.  Living organisms can regain balance after they have been pushed out of balance.  When an organism cannot do this, it is an indication that it is dead or will not be alive for very long.

We are just crossing into the redox signaling territory, but can you make out some of the beautiful landmarks already?  The mysteries of detecting damaged tissues, the keys to regaining chemical balance, the benefits of clearing up confusing signaling, the emergence of natural cell regeneration.  The mysteries of preserving healthy tissue.  See you all soon as we continue onward.

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Redox Signaling — Smoke Signals from Metabolic Fires

Fire

Firesmoke

As we sit inside our cozy homes, in front of the fireplace that brings us warmth and energy, we feel the benefits and all seems well. What happens if smoke from the fire started billowing out into the room? We are immediately alerted, smoke alarms go off, we are moved to immediate action. We realize that besides providing energy, fires can be dangerous. Fire produces smoke, free radicals, carbon monoxide, sparks and ash, fires can get out of control. In order to harness the ample benefits of fire, we have made special places in our homes where the fires can be controlled. We have devices that control the fire, harvest the energy, and alert us if the smoke builds up. This scenario provides us a great analogy of what is happening inside our trillions of cells. Inside every one of our cells, fuels are delivered, like oils and gasoline (fatty acids and sugars), that burn with the provided oxygen inside an average of 200 controlled furnaces (called mitochondria) in every cell, this fire produces smoke (ROS) that is eliminated by scrubbers (antioxidants) and detected by smoke detectors (thioredoxin semaphores, Nf-kappaB). All of these devices must be in place inside our cells to harness the energy of these metabolic fires.

At the junctions inside the cells where the oxygen pathways and fuel pathways merge, the fire of life provides energy. Even on a molecular level, nothing happens without energy. The major reason that we search for food and take in oxygen is to provide the fuel molecules and oxygen molecules maintain these vital fires of life inside our cells. Within this fire of life, the universal energy molecule, ATP, is forged. ATP powers all of the molecular machines, players, instruments, everything that requires energy in our cells. Every time you blink an eye, think a thought, twitch a muscle or feel a breeze, trillions of ATP molecules are spent to fuel the action. If the fire of life were to go out, in seconds the cell would run out of its supply of ATP energy molecules and the concert of life in the cell would quickly come to an end. There is nothing more important to a cell than to keep these fires burning.

The “smoke” that comes out of these cellular fires, reactive oxygen species (ROS), composed mostly of superoxide free radicals (O2*-) and hydrogen peroxide (H2O2), increases when the fires of life flare up inside the mitochondrial furnaces. These ROS (smoke) molecules affect the semaphore molecules (smoke detectors) that, in turn, change “color” and redirect molecules along the pathways. In other words, these smoke detectors are intelligent and are wired to make changes inside the cell. This is at the essence of redox signaling. The ROS superoxide free radicals (O2*-) and hydrogen peroxide molecules (H2O2), just like smoke, are highly energetic and reactive, and can also damage certain sensitive structures in the cell (like the DNA). Thus plant and animal cells have adapted to produce various types of antioxidant enzymes (smoke scrubbers), such as glutathione and SOD that can eliminate ROS “smoke” and keep it out of sensitive areas. As might be expected, these antioxidant enzymes are tightly regulated and controlled by redox signaling networks. For example, too much hydrogen peroxide in the cell will activate the redox signaling semaphores along pathways that turn down the metabolic fires and increase the production of antioxidants (smoke scrubbers) needed to eliminate the ROS (smoke).

Many of the redox regulatory processes are aimed at maintaining proper homeostatic balance of redox potentials in all the fluids in the various parts of the cells and tissues. Shifts in the redox potential (smoke signals) of vital fluids in and around the cells will generally activate redox signaling pathways that are designed to ultimately return the redox state to “normal” again. In the past decade, we have learned that it is dangerous to try to force the elimination of all superoxide free radicals or hydrogen peroxide in our body. In fact, the body will try to counterbalance any efforts to change the established natural balance by producing more of the lacking species to compensate. In order to maintain life processes, we require well-balanced control of these types ROS in our body. There are a variety of redox signaling pathways that naturally maintain normal redox balances and potentials throughout all the fluids in our body. Without both the oxidants and the antioxidants inside these vital fluids, this homeostatic balance would quickly be destroyed, and we would surely die. ROS is an essential signaling molecule.

If we were to completely eliminate the smoke from the fires inside our cells, the smoke detector semaphores would not be activated when the fires flare up and get out of control. ROS smoke is required to make the whole system work. Without ROS smoke, the damage detection mechanisms are shut down. In the vast majority of cancer cells, for example, the redox signaling system has been shut down, the mitochondrial furnaces have been shut down, the redox detection semaphores (smoke detectors) are not able to work. Without the aid of this redox signaling system, these damaged cells cannot be effectively detected, repaired or destroyed; they become immortal and remain broken. Smoldering fires are not extinguished, damage is propagated. Life is threatened.

As we contemplate these concepts, we realize that life is preserved by those devices inside our cells that maintain proper redox balance. It creates that cozy space inside our cells, where all is well; the fires are burning at their proper level, the smoke is being handled and the energy efficiently harnessed. When fires flare up, smoke billows out, alarms go off, smoke detectors are activated that will push the genes that will bring it all back into control. That is one description of redox signaling.

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Redox Pathways Interconnect the Body

Neural-pathways
These last few weeks, much has happened in the world of Redox Signaling. James Watson, who co-discovered the 3-D helical structure of DNA, has stepped forward with an article in the prestigious Lancet journal to champion this field of science, stating that he considers his work in this field to be his greatest accomplishment since DNA. You can type “Watson Redox ROS” into any search engine to explore this. The formal research on redox signaling has to do with how reactive oxygen species (ROS, examples: H2O2, O2*-,ClO-,etc.), reactive nitrogen species (RNS example: NO) and reactive sulfur species (RSS example: H2S) interact with the molecular semaphores in the vast ocean of fluids inside us. These molecular semaphores are proteins (like thioredoxin) that change conformation and state when they come into contact with these reactive molecules and redirect molecular traffic in our cells. Imagine the implications.
Amazing as these molecular processes of life inside our cells may seem to us, possibly even more amazing is that trillions of individual cells combine to form the complex tissues and organs that pump our blood, think our thoughts and move our muscles. The enormity and complexity of any one of these machines is mind-boggling. Take a moment and ponder the importance of the proper function the cells, with all of the molecular machinery inside them, to the vital functionality of the whole organism. These tiny molecular machines are all seemingly unaware of the crucial role they play in the big picture as they complete their tasks with incredible precision and speed. And yet they cannot be completely oblivious to everything that is happening even trillions of cells away. The tiny molecules that move our muscles, for example, must react to signals from our brain originating from relatively vast distances away, they are sensitive to these signals and know exactly what to do when they come. In fact, it would be wrong to say that all of these tiny molecular machines act independently of each other, even if they are separated from each other by truly astronomical distances on the atomic scale. In a very real sense, they all are connected by the signals that they send to each other.
Single-cell organisms do not have to be connected to anything beyond what is happening in their immediate environment. Signals from the outside mostly help the single-cell organism to find food or light and help it avoid dangers. In a sense, single-cell organisms are selfish, their biological mechanisms are tuned mostly to their own individual survival, their molecular machinery is focused on sustaining proper internal function and they do not need the complex, elaborate external messaging systems that exist in multi-cellular organisms. This gives single-cell organisms, like bacteria, a disadvantage when compared with multi-cellular organisms. We will see, later on, that our immune system is able to detect and kill bacteria with the help of a combination of reactive oxygen species (ROS) that rips apart bacteria and simultaneously activates redox signaling networks in and between our cells. Over hundreds of millions of years, bacteria and primitive single-cell organisms have not been able to adapt to dominate multi-cellular life. In principle, our immune system is universally effective.
It might be interesting to contemplate, for a moment, what the fundamental differences are between single-cell and multi-cellular organisms. Cooperation, almost by its definition, seems to be the key to success in multi-cellular organisms; cooperation that is mediated by the connections made between the cells. If we are working on the scale of the molecular machinery inside each of the individual cells, then being connected means that cells can send messages between each other that will alter the way these tiny molecular machines conduct business in each of the connected cells. It may even mean that individual cells can be asked to sacrifice themselves and shut down for the good of the whole organism. The individual cells are programmed to obey the directives that are sent through their connections. These connections become absolutely essential for the survival of the organism.
Suppose, for example, that a single cell in your body cuts off the connections it has to all the other cells. This rogue cell can no longer receive the messages and directives from the rest of your cells and starts to act in a way as to preserve its own survival, similar to a single-cell organism. It becomes a cancerous cell. If it is successful in its struggle to survive and duplicate itself, then the whole organism will eventually die. In a very real sense, it is the connections made between cells that allow them to cooperate and to fulfill their own appointed role. Through these connections, billions of your cells every day realize that they are damaged and are called upon to selflessly sacrifice themselves, to die and to be replaced by the division of neighboring healthy cells, in order to help preserve the health of the organism as a whole.
On the most fundamental level, the molecular machines in your cells react, shift and change based on the messages that come into them through the connections that exist between your cells. They all work to fulfill their appointed roles, precisely and faithfully. There are literally thousands of different types of messages that are sent between cells, both chemical and electrical, that influence the way these tiny molecular machines function. In a very real sense, all of the 50 to 100 trillion cells in your body are all intricately connected and unified to provide you with the precious gift of life that you now possess.

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