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Information in Medical Sciences

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Balu Athreya1 (March 19, 2014)

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Part 1: Medical Sciences and Information

Contents1) Introduction; 2) What is information from the medical perspective?; 3) Health and Disease viewed as defects in information processing.

Summary and questions: Information and information-processing are the absolute basis of life, including  reproduction (DNA and genes), exchange of energy (breath and metabolism), exchange of information with external world (all the senses and the mind/brain functions), internal messages (chemicals, hormones etc) and maintenance of integrity of the physical self (immune functions). Thus, “information” is one of the fundamental aspects of nature relevant to biology and medicine.

What is information? To the information scientists whose focus is on sending a message from here to there, “bit” is a piece of information, a message, a code. The contents do not matter. Emotions involved in the message do not matter. Not even the purpose. Information in biology is a message, a code for a “purpose”, to shape new things.

Information (message) in life sciences is a code for a potential future event, physical or biological. It is inherent in Nature.  For information to unfold, for the potential to unfold, causes and conditions have to be right. The information(the code, the message) can be accessed only in the future. Information technology is about sending a bit of information through space - from one place to another with fidelity. In biology, the primacy is in sending information through time.

Information implies a message source (stimulus), a medium for transmission, the process of transmission, receptor unit, transduction, response and outcome. This is common for all biological functions, at every step, at the micro and at the macro level.

My essay in two parts, aimed primarily at physicians and medical researchers, is to emphasize the extremely important role information plays in biology in general and in medicine in particular. Although these concepts are very familiar to physicists and information scientists, they are not among physicians. Physicians take the role of information for granted and many of them say so.  

I suggest that it is possible to build a theory that places information as an inherent property of nature in biology and medicine. The Information Theory of Shannon, Wheeler and others should be applicable in biology also since basic biological functions take place at atomic and molecular levels. New theories may have to be developed to explain biological phenomena. This approach may give us new avenues of investigating emergent properties in the life process and a deeper understanding of human diseases.

I hope these essays will stimulate research to answer several questions including the following:

  1. Will medical research benefit by considering defects in information processing as the underlying mechanism of diseases?
  2. Will redefining information with a wider focus as is being done now enhance our understanding of diseases, including mental diseases?
  3. Will medical research benefit by utilizing the standard tools of General Theory of Information? If not, what new tools are needed?
  4. What new concepts and tools are needed to explain emergent properties in biology (and therefore, in medicine)?
  5. At what stage should one invoke quantum principles in the evolution of functions of specific cells and organs?

1. Introduction

"To do anything requires energy. To specify what is done requires information". Seth Lloyd

“Information” is one of the fundamental substrata of nature, just like matter and energy, space and time. This is particularly true in biology. This statement is supported by several common observations and numerous studies in biology and medicine. Physicists have been studying this aspect of Nature for several decades. Ancient philosophies, in both the east and the west, refer to this observation. Thus, this essay is not about a new observation, but a personal synthesis from a physician’s point of view.

Matter to become something in space and time needs not only energy, but also Information. It appears that “Both energy (and the matter which it is manifesting) and information are two different aspects of the same underlying primordial structure of the world” (Diaz Nafria, Zimmermann 2013).

Encouraged and enamored by the successes of the physical scientists in explaining the workings of the universe, biologists have also been using a mechanistic paradigm to study living organisms, as if they are machines. The dominant theme has been one of reductionism. However, physicists have been shifting their focus towards study of complex systems and emergent* systems properties for the past several decades. Biologists and medical scientists are slow in catching up.

Reductionism in science has given enormous understanding of the universe and has now reached a critical stage. Jim Henson, the creator of the Muppet once said: “When you keep peeling onions, you have whole lot of peels, but no onions”. It is now time to understand how these elements (peels) organize themselves into complex systems (onions). Study of Information and information processing are at the core of understanding complex systems and the phenomenon of emergence (2). It is time that biologists, particularly medical researchers, give greater importance to information as the fundamental science of living.

Biologists know intuitively that information drives all aspects of the life process. I suggest that information be recognized explicitly as an essential quantifiable part of biology, and therefore of medical sciences. Therefore, my primary focus in this essay is on information as the inherent, fundamental force of life process including its survival, proper functioning and reproduction. It stands to reason that human diseases are ultimately due to defects in the structure (syntax) of information or its transmission or in the response to information coming from internal or external sources.

There were several triggers for this personal realization.My encounter as a physician with children who have genetic syndromes led me to understand how genes act as carriers of “information” for a new life in the form of codes and how a defective code leads to defective information or information processing and consequently to a disease. It is no surprise that Claude Shannon, the father of Information Theory, started his career with a doctoral dissertation on “An algebra for theoretical genetics” (Gleick J 2011). Encounters with children who had metabolic syndromes and immune defects also taught me about signals, processing of signals and responses and how defects in any one step can lead to diseases. What “tells” the white cells to rush to a site with a foreign body? What “tells” T cells to annihilate themselves when their job is done? How does engagement of TLR (Toll-like receptor) by a PAMP (Pathogen associated molecular pattern) lead to organization of an inflammasome? (Franchi, Nunez 2012) Metabolic homeostasis is based on information processing. What is the clue for insulin to be pumped into the circulation, at the macro level and at the micro level? How does the body know to produce stress hormones early in the morning? Are these not adjustments to the homeostasis based on signal- response systems and feedback loops?

When treatment of rheumatic diseases with monoclonal antibodies targeting specific steps in immune response pathways arrived, I was elated. I thought that finally, we could help control, slow down and even stop joint destruction. I also realized how these pathways are full of feedback and feed forward loops and how naïve we are hitting one of them and hoping there will be no readjustments.

Yes, information is not a “one way transmission” down a telephone line in biology. It is a network communication system with coded messages, senders, receivers, modulators, stabilizers, starters, stoppers, feed backs, feed forwards, and bye-passes. They also have different time cycles. Things can go wrong anywhere with consequences all around. It is amazing that the network communication works so well, so reliably most of the time. When it does not, we have diseases.

Looking at biology in general, information and information-processing are the absolute basis of life, including reproduction (DNA and genes), exchange of energy (breath and metabolism), exchange of information with external world (all the senses and the mind/brain functions), internal messages (chemicals, hormones etc) and maintenance of integrity of the physical self (immune functions). By corollary, all diseases can be viewed as caused by corrupted information or defective information processing.

Daniel Koshland (2002), a distinguished scientist, who used to be the editor of Science, identified seven common thermodynamic and kinetic factors by which “life” and living systems operate. He described them in the acronym “PICERAS” and called them the “Seven Pillars of Life”. They are: 1. Program – organized plan describing both the ingredients and the kinetics of interaction between the ingredients. 2. Improvisation – allowing the programs to change if and when the environment changes. 3. Compartmentalization – providing special containers in which concentrations of essential chemical ingredients can be maintained in an ideal state and protected from the outside. 4. Energy – availability of continuous source of energy and ability to exchange energy in an open system. 5. Regeneration – includes regeneration of essential constituents and reproduction. 6. Adaptability – different from improvisation in that this is a behavioral response from within the existing repertoire and not a change in the fundamental program itself. 7.Seclusion – of pathways that “allows thousands of reactions to occur with high efficiency in the tiny volume of a cell, while simultaneously receiving selective signals that ensure an appropriate response to environmental changes.” Every one of these features is dependent on information (in the form of codes or signals or stimuli), information processing (in the form of transmission of signals with instructions for action) and responses. Compartmentalization, rapid reaction and energy coupling are the underpinnings. Oscillations, modulations, recalibrations, feedback loops and self-organization are “systems level” functions.

The other experience which led me to the concept of information at the core of biology is my practice of meditation and reflections on the nature of human consciousness. This was supplemented by my reading of several recent books on the neuroscience of consciousness. Ramana Maharishi, a mystic asks us to reflect on the “I” which is at the core of every thought. He calls it the “bare awareness”, “pure awareness” or the “transient I” (Cornelssen L 2003). Some neuroscientists call it the “core consciousness”. It is the background awareness on which all of our perceptions, memory formation, memory recall, and thinking take place. This is “information – processing” at the mental plane.

The other day I soaked green lentil in water to make sprouts. When I opened the lid the next day to assess progress, I was looking at “life” unfolding in the form of tiny sprouts and bubbles of gas. The once “lifeless” seeds are now “breathing”. In scientific terms, the seeds are responding to the presence of water. They are now exchanging energy with the environment. In the process, the form of the seed is changing in front of my eyes using the information contained in the seed.

Causes and conditions are right, once again, for the dormant codes of life in the seeds to express as life. The cause was there already. The “seed” became “aware” of the new environment and the “code” in the “seed” is unfolding. The effects are here. The cause is information specific for the green lentil coded in the molecules and atoms of the seed. The unfolding of that information is life.

But, what is life? Where did the “first seed” receive its code, its information for life? Those questions enter the realm of philosophy and metaphysics at our current level of understanding, although a few have ventured into this territory (Kuppers B-O 2010, von Weizsäcker C.F. 2006). 

In the following section, let us look at the definition of information as applicable to medical sciences and biology with some examples.

2. What is "information" from the medical perspective? 

In medical practice, the word is used in several different ways depending on what we are using the word “information” for. When we are taking a history of illness, or examining the patient, or looking at the laboratory tests and imaging studies, we are collecting “information about” the patient for the purpose of making a diagnosis. We use electronic records to “store information” about the patients. When we study genetic disorders, we are looking at “information transfer” at the molecular level. When we study infectious diseases or reaction to environmental agents, we are looking at the external agent as a piece of information to which the body “reacts”. Human behavior is, in a broad sense, response of individuals to information from inside or outside. Since the practice of medicine is entirely based on Information at all levels of its meaning, physicians seem to assume the fundamental nature of information in health and disease. 

For the purpose of biology (with specific emphasis for medical research), I consider information as an inherent quantitative property of matter with potential to influence emergence of order out of disorder in specific context using up energy in the process. At the most basic level, Information is carried in the form of electron transfers, chemical bonds and three dimensional structure of proteins. Time has to be taken into account in the definition of information in biology and medicine.

Shannon’s Mathematical Theory of Communication (Shannon C. E. and Weaver W 1949) is credited with the dawn of the Information age. His work and the work of others in the field of cybernetics made the term become influential in several fields of research. Molecular biology borrowed several of the terminologies from Information Sciences to explain biological functions, particularly in genetics and neurosciences.

Shannon’s theory is actually a mathematical theory about sending messages and not theory of information. In this theory, the effort is in quantifying information and the focus is on the process of selecting signals with meaning out of several possibilities. When related to thermodynamics, information is connected with the concept of entropy. Shannon’s model includes a source, an encoder, a message, a channel, a decoder and a receiver. [Reviewer 1: This statement is based on system biology. I my view, this is somehow disconnected in the extent the author does not deepen into the corresponding holistic view. Communication and information flow among system is seen altogether instead of seeing a parcel, from the level of paths to the environmental one]. The word information refers to a predetermined message to be passed on to a recipient under appropriate conditions and interpreted for action with consequent alteration in the system. Time plays a major part. In addition, we have to consider the semantic and pragmatic aspects of the message.

This applies to biological systems also. In biology, there is flow of information at multiple levels – within cells, between cells, between organs and between systems and between the organism and the environment. The need for selecting meaning out of “noise” is equally applicable at every level in biology. There is a source, a message, a channel and a receiver at every level.

In the technical field, a message has to be coded into a message. But message is different from information. We send and receive a message. But we “seek” information. The message becomes information for the receiver through interpretation. The input is a constant, whether it is a molecule such as glucose or an action potential. But it is interpreted by different molecules at different locations for different purposes and therefore with a unique message. [Reviewer 1: This is a rather philosophical discourse. That the messages is interpreted by the receiver is correct, but also that the message itself is incorruptible, though this can be discussed. It is the receptor that can change the message for different reasons but not the message itself. For example, now in the biological perspective, a sugar molecule can be the message itself, it is thus per se incorruptible. It keep on being the same molecule but if it interacts in glycolysis its receptor interprets it for some functions, whereas if it finds insulina the reaction dynamics will be different].

Code is a system of signs (which corresponds to signals or symbols) through which some idea is represented. Any character with meaning can be used as symbols for coding. In Information Technology, it is the binary code.  [Reviewer 1: In this point, it is right that the triplet is the code since it determines the amino acid, but the sequence of amino acids in the protein should be the code since it determines how the it is folded and finally the function of the protein.] In genetics, it is the triplet code at the level of the DNA. In the protein which the DNA codes for, the code is the sequence of amino acids, since it determines the three dimensional structure of the protein. All biological reactions at the cellular level are determined by the fit between the three dimensional structures of the molecules. In nerve cells and biological motors, it is change in voltage. 

Signals (and symbols) have to be encoded, stored and decoded. In biology, DNA and cellular proteins perform these functions. During decoding the receiver has to interpret the message properly, as understandable and useful information. The receiver uses its prior knowledge to make sense out of the message before an action is initiated (Diaz Nafria 2009). All of these apply to biology and therefore to medicine also.

In semiotics, sign was defined as “an object which stands for another to some mind”. This is the classic “triadic” system and describes the structure of a sign. The three parts are: 1.the subjective aspect related to the receiver or “interpretant”; 2. the objective aspect related to the object as is and 3. the sign itself. In this system, “sign is whatever is capable of being understood” (Capurro R and Hjorland B 2003).

Morris’s modification of the classic triadic system emphasizes the fact that the sign is what supports the triadic relationship between the three arms and emphasizes the functional relationship rather than the structural relationship (Capurro R and Hjorland B 2003). This leads to the idea of syntactic, semantic and pragmatic aspects of signs and messages. This is more applicable to biology and is the basis of biosemiotics.

Physical description of nature is information-based. Scientists studying quantum physics consider the universe itself as a quantum computer creating information (Floridi 2011 and Lloyd 2007). Lloyd considers information to be a quantity of matter that can be measured, just as energy is and relates information to the second law of thermodynamics.

“The bit is it” said John Wheeler (Wheeler, J A and Ford K 1998).

What is a bit? To Claude Shannon and the information scientists (Floridi 2011, Lloyd 2007, Wheeler and Ford 1998) with focus on the physics of communication, a bit is a piece of information that can be quantified. It is a code and can carry a message. For the information scientists, the focus is about sending a message from here to there. The contents and the physical medium are not of much concern. The purpose is only indirectly of concern. Emotions involved in the message do not matter.

In biology, the purpose is important. Emotion and personal values of the receiver take on added importance in medicine, mental health, behavior and human communication. Therefore, my focus in this essay is on the content of the information and its purpose. In the second part of this essay, I plan to relate biological phenomena with various concepts related to Information Theory.

The root verb for the word information is in forme which means to form, to shape. Information in biology is a message, a code for a “purpose”, to shape new things, more accurately for function. The word purpose suggests a source with a “mind” and its plans. Therefore, in biology it is better to use the word “function”.

Claude Shannon’s definition of the word Information is “whatever reduces uncertainty among alternative outcome probabilities”. Although this definition is loaded with mathematical and theoretical concepts, the word outcome is important both in information sciences and in biology. In information sciences, the outcome refers to what bits of information get transferred from here to there.

 In biology, Information processing at the level of the molecules and electrons defines outcome in the form of what happens to the cell and the organism – to life itself. In other words, information flows to and fro and across systems directing the organization and maintenance of complexity at all levels of life forms.

Information (message) in life sciences is a code for a potential future event, physical or biological. This is similar to the concepts of virtual or potential information and actual information suggested by Weizsäcker (2006) and by Diaz Nafria and Zimmermann (2013).

Information (message) is “carried” on physical agents, by physical agents. Therefore, it can be or is an attribute of a physical agent and inherent in it just as heat is inherent in fire. It is a quantifiable property of matter and requires energy to be manifested. I used the words, potential and future, because for information to unfold, for the potential to unfold, causes and conditions have to be right. Time is one such condition in biology.

[Reviewer 1: I believe this should be deepened since the relevance of time is highlighted, but the statement only points to the capacity to access information in the future]

Time is a necessary part of this definition since biology is based on evolution and a potential becomes actualized only with the passage of time, even if it is in femtoseconds. The other point is that once information is “formed” it cannot be erased as pointed out by Seth Lloyd (Lloyd S. 2007). It can only be transferred. And, the information can be accessed at any time in the future, any number of times. It will always give the same information as is seen with the DNA which can carry “its” information indefinitely unless its structure is corrupted.

Information technology is about sending a bit of information through space - from one place to another with fidelity. In biology, the primacy is in sending information through time. Fidelity is not assured, and may not be desirable. Flexibility and an ability to choose from one of many alternatives in response to the environment is an asset.

Information is accessed in space and in time. It can be accessed any number of times without depleting the source once it is structured. It can be accessed now or later. But it needs time to unfold, from potentiality to actualization. Thus, information is tied intimately with time and space. Unfolding of information gives the sense of time and the sense of uni-directionality.

What we now call “emergent properties” in biology is opening up of new avenues of information in a complex system as an integrative “systems property”. Integration of flow of information between the components of the system leads to the development of new properties. Information processing at the molecular and cellular level cannot adequately explain these properties of the system.

Past events can be inferred from the unfolded information. Milk can be inferred from the butter, the seed from the tree. But the source cannot be reconstituted from the effect. You cannot put the tree back into the seed from which it “emerged”. Unfolding of information in time makes the process unidirectional. Entropy makes it so, as we will discuss in Part 2. Time is unidirectional, at least in this universe.

But, information can be transferred from one system to another. It can be passed on. Indeed, once information is generated, it can only be transferred to a different place. It cannot be erased (Kuppers 2010; Lloyd 2007).

Information can point to the source. But it is not the source. It is an attribute of the source.

Matter, energy, time and space make the physical aspects of the universe. When you add “life” to the universe, awareness becomes an additional essential element. Awareness is an “emergent” property of the brain as a systems property. This awareness implies a source of information and a receiver. It also implies a medium for the transfer of information and a mechanism for the transfer. Finally, in biology, information is for a function (“purpose”). [Reviewer 1: I completely agree with this point, though the functions of thousand of proteins are unknown as well as what lots of genes codify. Over time we have seen how informations as ITS (inter-genetic spaces) have a function, being excellent markers to determine fungus for example.]

Information implies a source, a medium for transmission, the process of transmission, unit that receives the information and outcome. This is common at all levels of life forms, for exchange of energy, exchange of information with external world, internal messages, maintenance of integrity of the physical self and reproduction. The source determines the output, but with plenty of variations. This output depends upon external (environmental), internal messages (feedback circuits) and internal (mechanisms of transduction) conditions. Some message sources are simple and some complicated. The same is true of the receiver and responding systems.

In biology, every step is made up of such a flow of information, at the macro level and at the micro level. Let us take inflammation for example. Inflammation is the name given to a series of events that occurs in the tissues of a living organism – plant, animal, bird and human – as a reaction to the presence of a “foreign” body. The tissue detects a piece or a “bit” of “information” when a “foreign” inanimate or animate body enters the system.

The body senses something “different” and the outcome is inflammation. What is that something that is different? It is a signal or bit of information in the form of products of an invading organism or tissue damage. It is called PAMP and DAMP depending on whether it is related to a pathogen (Pathogen Associated Molecular Pattern or PAMP) or to tissue damage (Damage Associated Molecular Pattern or DAMP). Either way it is a piece of “information” to indicate that something that should not be there, is there. The response is modification of the three dimensional structures of certain proteins and arrangements of protein-protein complexes inside the cells (formation of a platform for action called Inflammasome). One such protein is NLRP3 which stays auto-repressed (Off position) until “activated” by one of the damage signals (DAMP or PAMP). The response is “activation” of this protein (On position). This activation then becomes the signal or information for the next series of steps leading to the production of a protein called IL-1beta.

Il-1beta acts and produces its effect on tissues that results in the bodily signs of inflammation such as fever, body pain and swelling of the inflamed site etc. In order for these to occur, Il-1beta attaches itself to a receptor on the surface of the cells. This receptor has connections to the inside of the cell as well. The receptor is in a particular three dimensional structure when not engaged by the Il-1 beta protein. Let me call it “potential information” (or a 0 position or an off position of a switch) in the receptor. When the Il-1beta protein attaches to the receptor it undergoes a change in structure which is a 1 or an “on” position for the “inflammation switch”. This in turn triggers a cascade inside the cell. The receptor is kept in check by Il-1 receptor antagonist. We will talk about this in a later section.

Instruction for a change in structure is the information. (Or is it the changed structure that becomes the information?) The information is now passed on down the line inside the cytoplasm of the cell till it reaches the inside of the nucleus. After several more precise attachments to specific proteins, the message reaches the specific genes which produce the proteins necessary to fight the foreign invader.

At every step it is a bit of information passed down to the next step in the ladder. At every step it is a “mechanical” or a chemical fit between the signal or code and a “receptor” which causes a change in the structure of the receptor. At every step it is the three dimensional configuration in space that allows the signal to move forward in time (downstream effects). Changes in the structure of any one of the codes (corrupted information in the form of mutation) in this pathway result in inadequate or excessive response to stimuli and thus to physical injury.

It appears that for purposes of biological functions, information defined as inherent property of matter is carried primarily in the three dimensional structures of proteins. However, folding of a linear array of amino acids into a functional protein depends on electron orbits, proton transfer and chemical bonds. [Reviewer 1: This comment is irrelevant here, and leads to break the continuity of the reading]

Let us look at two examples of how three dimensional structures influence biological functions through review of two articles. One is the three dimensional structure of glucocorticoid receptor (Kauppi B et al 2003). The other is on how the three dimensional structure of TLR4-MD-2 complex determines its ability to react with bacterial antigens (Park BS et al 2009).

In the first article (Kauppi et al 2003), the authors studied the three dimensional crystal structure of the Glucocorticoid Receptor (GR) in complex with one chemical (RU 486) which inhibits (antagonistic) the downstream effects and another chemical (dexamethasone) that activates the downstream effects (agonist). GR is a protein responsible for the effects of glucocorticoids in human physiology. One end of the GR connects with the hormone, glucocorticoid and this is called the ligand binding domain (LBD). The other end is called the DNA binding domain which is necessary for the production of proteins that cause the effects of the glucocorticoid.

There are 4 different crystal structures of GR – GR1, GR2, GR3 and GR4. The authors show that the orientation of helix 12 in GR 3 which binds RU 486 is exact opposite to that of the same part of the molecule in GR4 which binds dexamethasone. The steroid (both RU 486 and dexamethasone) is held in place by hydrophobic residues that outline the cavity in which it binds to the receptor. The steroid is kept in orientation by two hydrogen bonds from the A ring of the steroid to Gln 570 and Arg 611 and a water molecule in the receptor protein. On the other end of the steroid with the D ring, the 17 beta hydroxyl group bonds via a hydrogen to Gln 642 and a water molecule to Cys 736. It appears that the A ring sits in a portion of the GR with conserved side chains. The connection between the 17 beta hydroxyl group and Gln 642 gives the specificity for recognition of the ligand.

In the second study (Park BS et al 2009), a similar observation is made in the response of the body to bacterial antigens (in this study, it is bacterial lipopolysaccharide, LPS) through the innate immune system. The extracellular domain (the part that stays outside the cell) of TLR (a part of the innate immune system) dimerizes (joins with another one of the same receptor) when it binds with the LPS (called its ligand). This triggers the recruitment of specific adapter proteins inside the cell resulting in an inflammatory response.

Specifically, TLR 4 in association with MD 2 is responsible for the recognition of LPS. LPS interacts with a large hydrophobic pocket within the MD2 molecule and bridges it with TLR. This fit depends on the phosphate groups in the LPS. “The two phosphate groups of lipid A bind to the TLR – MD2 complex by interacting with positively charged residues in TLR 4, TLR 4* and MD 2 making a hydrogen bond to S118 of MD 2”.

Summarizing these two sample studies, three dimensional structures allowing for contacts between specific protein and the receptor through which the information is transferred are determined by hydrogen bonding and related forces. Proper three dimensional fit between proteins and other substances allows for interactions with consequent downstream effects. Therefore, the fundamental piece of information (code, signal) must be at the level of ions and chemical bonds where physical laws and laws of the quantum world operate. 


What are the implications when knowledge from the Information Sciences is applied to study of health and disease in humans?

3. Health and Disease viewed as defects in information processing

Health and disease can be considered ultimately as defects in genetic or metabolic homeostasis. In the words of Barton Childs (1999) “Neither gene nor experience are themselves harmful. Disease ensues when these two influences coincide to constrain the powers of one or more homeostatic systems, a state expressed in an array of genes that, in concert with a singular set of experiences, has promoted a particular pathway of development to make an individual unique”. Information transfer and feedback are at the core of homeostasis.

Defects in genetic information or its expression can lead to disease phenotype. Individual gene products are part of a complex working towards the homeostatic functioning of specific systems. Each system is composed of multiple pathways and therefore one can speak of “homeo-dynamic” pathways (Barton Childs 1999) which interact with each other adding to the multiple feedback loops. Finally, the organisms interact and respond to the environment in their normal development. Every step involves information transfer. Defects in information transfer at the level of the gene, defects in the selection of proper pathways at the genetic level and in the homeostatic systems, and between the individual and the environment can result in disease. 

At the cellular level, the message from the internal milieu (milieu intèrieur) or from outside has to be passed through the cell membrane into the cytoplasm and then into the nucleus for an appropriate response. This requires a receptor at the cell surface and a signal transduction system of communication for transferring information from the environment to the interior of the cell.The mechanism of signal transduction inside the cell is well-orchestrated and well-organized.

Reth and Weynand (1997) noted eight different steps involved in information transfer requiring protein-protein interaction and energy transfers. (Figure 1) They are: 1. Receptor, a transmembrane protein which undergoes aggregation or conformational change on binding with its ligand and becomes 2. a signal for the transducer elements which are usually enzymes associated with the intracellular parts of the receptor. The transducer is activated by the changes due to ligand-ligation. 3. A signal manager situated at the top of a branch point with alternate pathways of signal transduction is switched on. 4. Several signal processors activating a signal cascade. 5. Signal regulators which amplify or diminish the efficiency and duration of information transfer down the pathway. 6. Scaffold proteins which are protein complexes in which several signaling elements are functionally united as in an inflammasome. 7. signal termination proteins that stop the reaction. 8. The final product, the effector, which is usually an enzyme, transcription factor or cytoskeletal protein.


Figure 1: Signal transduction
(based on Reth & Wienands, 1997)

This description makes clear that: 1. the language used is the same as in IT and indicates transfer of information through signals and that 2. this is part of biological homeostatic systems. When signal transduction functions normally, we have a healthy phenotype. Defect at any level will interfere homeostasis and with the ability of the organism to develop into an independent unit capable of survival in that environment. The result of such a defect will be a disease phenotype (Barton Childs 1999). 

There are several examples. In an autoinflammatory condition called TRAPS (Tumor Necrosis factor Associated Periodic Syndrome), the primary defect is a mutation in the gene for TNFRSF1A, located in chromosome 12p13, which encodes for the 55 Kd TNF receptor protein. Although the exact mechanism is not fully established, it is clear that a single amino acid substitution in the extracellular domain of this receptor protein results in a syndrome characterized by repeated attacks of febrile episodes, rash, arthritis, serositis and fasciitis (Barron K, Athreya BH and Kastner D 2012). A similar autoinflammatory syndrome (DIRA) has been described in which the defect is in the receptor for IL1 receptor antagonist (Barron K, Athreya BH and Kastner D 2012).

Hanahan and Weinsberg (2011) discuss how signal molecules function through integrated circuits with nodes, branches and feedback loops to maintain cells in a “normal” homeostatic state – survival vs death, proliferation vs maintenance and differentiation vs stasis. All these channels of communication and information transfer are reprogrammed in cancer cells. (Figure 2). The authors also point out that one hallmark of cancer is the reprogramming of energy metabolism in favor of cell proliferation at the expense of survival. 


Figure 2: Intracellular signaling networks regulate the operation of the cancer cells. (Reprinted from Hanahan & Weinberg, 2011, with permission from Elsevier)

When health and disease are viewed from the point of view of information and response to information one cannot stop at the cellular level and at the level of the organism. The organism has to live with other organisms in a community and in a specific set of environmental circumstances. Humans have in addition their socio-economic circumstances. Even when genetic and/or metabolic abnormality in the homeostatic system is at fault, the phenotype will often depend on the circumstances of the individual such as age, sex, socioeconomic conditions and individual behavior (Barton Childs 1999, Link BG, Phelan J 1995).

For example, HIV infection is due to a virus that hijacks human immune system. It is sexually transmitted. The proximate causes are evident. But what is the fundamental cause? It may be lack of knowledge in one individual and in another a consequence of life style. In one, the life style of living with multiple partners may be the preferred one. In another it might have been forced by socio-economic circumstances. Thus, when a disease is considered as a defect in homeostasis, the defect may be at the cellular level, multi-organ level or at the socio-economic level. Such a view based on homeostasis and information processing will force us to look at all the steps in the causation of diseases as pointed out by Barton Childs (Barton Childs 1999, Link and Phelan 1995).

As pointed out earlier, proteins function only in their three dimensional structure. The cell has extensive machinery in operation to make sure that the newly synthesized polypeptides fold properly with the help of other proteins such as chaperones and folding enzymes. Slow-folding and mis-folded proteins are removed and recycled (Kleizen B, Braakman I 2013). Defects in protein folding and defects in removal of defective proteins are the basis of several diseases including Alzheimer, Parkinson, and Huntigton disease (Dill KA, MacCallum JL 2012 ) and some cardiomyopathies (Willis MS, Patterson C. 2013).

Metastable proteins are those that fold up to a point but not completely. They reach their mature three dimensional shape when in contact with their target protein – their ligand. Alpha 1 antitrypsin and other SERPINS are examples. Their functional information is in their meta-stable structure.

For example, Alpha 1 antitrypsin (A1AT) is functional as a proteinase inhibitor only when it is meta-stable (Bottomley S P 2010). A1A causes conformational change in the proteinase (its ligand, its target) by translocating the reactive loop of the proteinase and thus making it dysfunctional. In the process, it gets into a stable state. In the presence of mutations, A1AT cannot function as proteinase inhibitor and the mis-folded protein accumulates resulting in clinical syndromes. Similar defects in the structure of other serpins such as antithromibin III and C1 inhibitor also lead to disease states.

Channel capacity, noise reduction and entropy of probability distributions are concepts developed in information technology. More recently these concepts from the information theory have been applied in cell biology (Thomas PJ 2011). In a study on signal processing in the TNF pathway (signal transduction pathway) these concepts were used to quantitatively predict and measure the amount of information transduced at a single cell level. The investigators showed that “noise reduction” takes place at a single cell level when a cell receives signals of different strengths from several sources (Cheong R et al 2011).

It is reasonable to hypothesize that information is a basic property of matter at all levels in biology, all the way down to atoms and molecules. It appears that biological function are being studied from the point of view of quantum physics (quantum biology) (Brooks M 2011 ) also. For example, studies on the ability of drosophila to sense smell of two kinds of acetophenes, one with hydrogen and one with deuterium show that quantum mechanical properties are involved in the sense of smell at least in the fruit fly. This involves a quantum phenomenon called electron tunneling. This mechanism may also be operational in our sense of sight and the fit between the vibrational frequency of the light and the photoreceptor.

In summary, Information is inherent as a quantitative property of matter for energy to act on in space and time at the micro and macro levels. Information exchange is a fundamental requirement for life forms to exist. Every cell, every tissue, every virus, bacterium, plant, animal and human live by exchanging information within oneself and with the other living and non-living entities in our environment. Information exchange is the basis of metabolism, immunity, reproduction, genetics, memory, and communication.

Information theorists refer to bits of information as a code. This makes sense when you look at the genetic code, immunological memory and human consciousness. These functions are possible because of coded information passed along and interchanged. At a physical level, atoms and subatomic particles have the “potential” to become what we see in nature when causes and conditions are right, however improbable it may be. Particles at the quantum level are governed by statistical laws. Therefore, quantum principles will have to be invoked at this level. At a macro level, exchange of information is evident. At system level, information passes in different directions in a coordinated fashion to integrate and maintain function. Disruption at any one level may be compensated or result in a disordered state – disease and death.

Therefore, in addition to emphasizing the need for application of information theory to study biological phenomena, we need to acknowledge information as one of the fundamental aspects of nature – in addition to matter, energy, space and time.

Acknowledgements: Doctor Paul Plotz asked fundamental questions to help me clarify my own understanding of thermodynamic laws. He gave several hours of his time and gave me encouragement, in addition to giving useful comments and valuable suggestions. Dr. Dan Brennan and Dr.Peter Kim taught me  fundamentals of physics and physical chemistry and directed me to basic books on Information Theory and Physical Chemistry.  Dr.Karyl Barron gave needed encouragement. Prof.Mahabala suggested that information in biology is a different kind of “beast” and referred me to the idea of “cellular automaton”.

Prof.Diaz-Nafria  opened my eyes to critical sources of information in this field. He made several helpful remarks which led to substantial changes to my understanding of this subject and therefore to significant changes in the content of this essay.

      My sincere thanks to all of them.

References:

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NOTES:

(1) Balu H.Athreya M.D is Professor Emeritus of Pediatrics at University of Pennsylvania and Thomas Jefferson University, Philadelphia, PA. USA and Teaching Consultant, Alfred I. duPont Hospital for Children, Wilmington, DE. USA

(2) An interdisciplinary team on Emergence summarized its conclusions as follows: “ Emergence means complex organizational structures growing out of simple rules. Emergence means stable inevitability in the way certain things are. Emergence means unpredictability in the sense of small events causing great and qualitative changes in larger ones. Emergence means fundamental impossibility of control. Emergence is a law of nature to which humans are subservient.” Quoted by Robert Laughlin in his book on “A Different Universe”. (Basic Books, Cambridge,MA.2006)


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