Information is a basic unit of nature - Part 2

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

In the first part I focused on information as fundamental to the life process. Personal experience as a physician, personal observations of nature and review of the literature gave direction to my thinking.  Then I realized that I have to know the basic theories of Information as a scientific discipline and started reading books on this topic and related fields ^1,2,3,4. The current essay is a review of the scientific study of Information and how the concepts developed as part of Information Theory (IT) can be applied to processing of information in living organisms.

The mathematical theory of Information is based on the concept of data.  John Wheeler who coined the term “it from bit” seems to suggest that the ultimate nature of physical reality (“it”) is derived from Information, the “bit”. 

There are different definitions of the word “information” within the field of the mathematical theory and its physical applications. When biological information is added to the discussions, other scientific disciplines with their own vocabularies need to be accommodated in this definition. Floridi² has provided a conceptual map and definitions of terms to study the various components of Information (Figure 1). I plan to use this map for the concepts it provides and to relate these concepts to examples of information processing in biological organisms.

Warren Weaver and Claude Shannon recognized three aspects of information for scientific analysis. They are the technical problems (dealing with quantification of information), semantic problems (dealing with meaning and “truth”) and “influential” problems (dealing with the effect of information on human behavior). They did not mention the effect of information in biology as part of “influential” problems. Their own focus was on the technical aspects.

According to the Information Theory (IT), General Definition of Information states that an instance of information is said to be present if, and only if, it consists of well-formed, meaningful data.  Information theory deals with information based on the concept of data.

This mathematical theory of information as data is applicable to biological information also. Figure 1 shows the various steps connecting data to meaningful information. From life sciences point of view, meaningful information may be physiological functions through its instructional pathway or knowledge through the semantic pathway, although this dichotomy is conceptual only.

What is a datum?   It is defined as “lack of uniformity” or “a distinction that makes a difference”. According to the Information Theory (IT), datum is when x and y are uninterpreted variables and their relationship is one of “being distinct”. Before a datum is interpreted by intelligent organisms, it is accessible through inference, since it has to be there for the information to be possible. As pointed out in part 1, before pure data gets interpreted or subjected to cognition, it “is empirically inferred from and is required by experience, since they are what has to be there in the world for our information to be possible at all²”.

This basic intuitive sense of lack of uniformity is called the dedomena in the IT. This is the basis of lack of uniformity between two physical states (called signals) or between symbols made by these signals as perceived by intelligent organism.     

This definition information as “well-formed, meaningful data” allows application of IT to biological information also since information depends on well formed data with a syntax and a meaning and data depend on the occurrence of differences in the physical state. In what format, medium and language, the data is encoded (electrical signals or genetic code) is not relevant. Genetic code, three dimensional structure of a protein, hydrogen bond are as good as Morse codes or digital codes (0 and 1). Principles of IT can be applied to information processing in biology as has already been pointed out in Part 1 (processing of TNF signaling in cells^5,6)

It is important to point out that this definition of information as data is too restrictive for use in biology, although the concepts are useful for future research.

Now that we have defined the relationship between Information and data, let us look at different types of data which give a piece of information. According to IT, there are five categories of data. They are, primary, secondary, meta, operational and derivative.

Primary data is seen in the form of 0’s and 1’s or a series of numbers. In biology, codons may be considered as primary data. Any biological switch such as receptors before attachment to its ligand can be considered primary data. The all- or-none aspects of action potential can also be considered as such. All of these are equivalent to the 0 or 1 positions in IT. My guess is that when we go deeper and deeper to the molecular level in biology, positive and negative charges carried on molecules may have to be considered as the primary data.

Secondary data is the converse of primary; or the absence of data. Absence of data is useful as a piece of information. Knockout mice are examples of this idea. Misfolded proteins and missence mutations represent secondary data. At the knowledge level, absence of anti-DNA antibody, in a proper setting, excludes the diagnosis of SLE; or the absence of anti-streptococcal antibody by any method rules out Acute Rheumatic Fever.

Metadata gives an indication of some other data, most often primary data. They may describe properties or location or availability of information, rather than describe the information itself. Environmental information such as pH at which reactions occur and medium (aqueous or lipid) in which reactions occur belong to this category. At a macro level, environmental triggers for a disease belong to this category also.

Operational data is about the dynamics of the operation and performance of the system itself. Efficiency of processing of information leading to the effect may be altered by “noise” as described in Part 1 (TNF signaling in the cell in the midst of noise) and competing metabolic pathway may belong to this category.

Finally, Derivative data are indirect sources of information. When data are used to search for clues and patterns of things other than those directly addressed by data themselves, they are considered to be derivative data. For example, a low potassium may be the data suggesting that the glucocorticoid – glucocorticoid receptor pathway is underperforming or overactive. Clinically, fatigue may be the indirect source of information about the status of glucocorticoid metabolism. 

Based on one or more of these types of data, information may become available if they are well-constructed and have a meaning. This information may be of one of two major categories – semantic or environmental. Semantic information refers to content. This may be either instructional or statement of a fact (factual, a truth). Factual, semantic content of information is of paramount importance in the field of neurosciences and essential to human communication, construction of knowledge, consciousness, thinking etc. Most of what I wish to focus on is about the instructional nature of information.

 Before we discuss ideas related to instructional information, a word about environmental information. As defined by IT theorists, environmental information points to data which might be meaningful independent of an intelligent “producer” or “informer” of the data. As an example, Floridi points to the rings in the trunk of a tree which offers information about the age of the tree. If we accept this definition in biology, nature is full of such information. I wonder whether we may not need a different definition, because of the way genes (epigenetics), immune system and metabolic systems work. There is primary data for the direct response. But it is modified by environmental clues. In philosophy, such information is grouped under “causes and conditions” for everything that happens in this world. This should be called environmental information in biology and neurosciences.

Well-formed, meaningful data give rise to semantic content of information. Semantic information can be representing reality as is (as in finger patterns), can be for a specific purpose of reality ( as in genetic code, commands) as instruction or about reality as in textbooks and maps. Instructional information is not a description about a situation. It is meant to bring about a new state of the system. According to the linguistic root of the word, Information, in forme is to bring about, to create. This is the mode of information in all of basic biology. Genes bring about new proteins. New proteins bring about new biochemical reactions. Biological stimuli of all kinds bring about responses. All biological pieces of information are instructional in nature.

Factual information about reality is the basis of knowledge and communication, whether it is true information, misinformation or disinformation. These are not the subjects of this essay.

Such compartmentalization is too restrictive for use in biology. However, it provides a framework to study concepts related to information and information processing in nature and in man-made environment.

Information and processing of information is at the core of all of biology. For example, a recent issue of Science⁷ has several essays on unsolved problems in cell biology. Almost every question deals with the ability of single cells to sense information and respond. How does the cell know where to position its proteins for efficient functioning? How does the cell know to avoid or go towards tiny gradients of chemicals in their environment? To behave appropriately in a multi-cellular organism, a single cell has to know in which tissue it is. How do they “know”?

In the same issue there was another essay on the Unfolded Protein Response⁸ and its role in homeostatic regulation. All signaling proteins needed to communicate with the cells environment are assembled and folded in the endoplasmic reticulum before they are secreted or sent to the surface of the cell to receive signals from the environment. These proteins are involved in receiving signals from the environment and direct the cells to respond with migration, division, differentiation or death. All of these functions (responses to stimuli) are information-based.

It is clear that information as data is inherent in every step of genetics. DNA molecule contains the genetic code for all life forms. DNA is made of nucleotides which consist of a sugar moiety, a phosphate molecule and a base. This base may be one of four kinds – A, G, C and T. Gene is a segment of the DNA molecule which carries information to make a functional protein. Proteins are composed of amino acids and there are 20 amino acids.

The gene is made of a code consisting of a unique combination of the three nucleotides mentioned earlier. This is called the codon. Since there are 4 nucloetides it is possible to get 64 different possible combinations of three-letter codons. One of the combinations acts as a start signal and three as stop signal and all others code for the 20 aminoacids. Redundancy is built in.

In the double-stranded DNA, A always combines with C and G always combines with T. Indeed these proportions between A and C, and G and T gave a clue to the structure of DNA.The genetic code has to be transcribed first in the form of RNA, in which a mirror image of a single strand of DNA forms with C wherever A was and vice versa. The sugar is of a different variety. RNA gets translated into the a chain of amino acids ( 2 dimensional) which are then assembled into proteins with a 3-dimensional structure.  This 3 dimensional structure and the locations of energy-bonds are important elements in receptor- substrate interactions and proper interpretation of the message.

Information carried by genes is more than semantic information. In essence, gene carries information for a purpose. It is instructional for the development and functions of the organism. “Biological information …… is procedural: it is information for something, not about something”.

Let us look at brain, mind and their functions. Neuroscience is about information processing. The nervous system consists of a network of cells and its extensions that manage information about the organism’s internal milieu to maintain homeostasis (such as temperature control) and about the environment to increase the chances for survival and reproduction. Even a unicellular organism has to receive signals from both internal and external environments and respond. Information-processing network is a complicated structure in multi-cellular organisms. It has a portion to deal with signals from outside, a system to deal with signals from inside and systems with ability to receive, store, recall these stimuli and respond. The entire system is based on neurotransmitter chemicals and electrochemical signals. When neurotransmitters bind to receptors, pores (called ion channels) open in the membrane, through which charged particles can flow.  This electrochemical phenomenon carries information for excitation or inhibition of the neuron receiving the signal. The electrochemical signals carried along axons are called action potentials. They are signals with Boolean function (all or none) and the frequency of these action potentials carries information.

We know now that thinking, feeling, remembering, recalling involve networks in the CNS. Anatomical correlates of various cognitive functions are known. Even forbidden territories such as self and consciousness are under scrutiny ^9,10. How simple electrochemical phenomena give rise to complex mental functions such as these is a mystery to be solved.

When I try to think of human consciousness and my own sense of “background awareness” as part of my daily meditations, I see several levels of information. The word awareness implies awareness about something. In deep sleep and in coma due to whatever reason, there is no general background awareness. Therefore, there can be no sense of “I”. Under the influence of some drugs and intoxicants, prolonged starvation and prolonged isolation, one is awake and aware but the awareness is different¹⁰. This awareness gives an altered sense of an “I”. The pure, basic awareness of someone waking up from normal sleep is not there. With injury to the brain from trauma or infection, there may be different levels of wakefulness, alertness and awareness. Some may be aware but not able to respond. It appears that at some basic level of awareness, the person will have a sense of “I”. For example, when someone is waking up from deep sleep or from anesthesia, and during deep meditation there is a moment when the person is aware of “life” and being alive without the details of his/her individuality. This is called the “transient I” or Pure Awareness by oriental mystics.

When you are fully aware, your mid is full of thoughts. Your “I” is fully active. Without that basic pure awareness you cannot be aware of your awareness. It is on that basic awareness, all perceptions are received, feelings are felt, concepts are formed, ownership is created, memory is formed, stored and recalled, will to act is generated and imaginations take flight from. Thus an “I” is created.

The main point is that all of these are about information being passed on, received and acted upon. Information is at the core of all philosophical discussions of the nature of human consciousness. What gives continuity to the individual from birth to death is information about oneself even when the structures undergo change and parts get replaced.

What is surprising is that even single particles of colloid suspended in a liquid seem to be “aware” of their presence and location! By immersing a nanometer size colloid particle and trapping it in the focal spot of a laser and monitoring the Brownian fluctuations, Franosch et al¹¹ have shown that the observed changes in the spectral density are due to the colloid’s self-interaction in response to the environment.

One other important point is that information processing requires energy. Therefore, information-processing is subject to thermodynamic laws both in the physical and in the biological world. Physicists have been discussing for several decades that information may be a third fundamental unit , after matter and energy. More recently, Stuart Umpleby, a Systems Scientist has attempted to bring these three concepts together although our knowledge about units of information is not as rich as on physical objects¹². More recently Bremermann has suggested a triangular relationship between matter, energy and information at an atomic level ¹³. By combining the relationship between matter and energy with the relationship between energy and information he has shown a new relationship between matter and information. Indeed Bremermman has calculated a constant (10⁴⁷ bits/gm/sec) a boundary beyond which the flow of data (information) cannot be improved physically. It is the limit at which symbols can be processed by matter.

Biology is all about chemistry. Chemistry is all about atoms, molecules and electrons. Electrons are “quantum mechanical beasts at heart”.  Chemistry in biology is also based on principles and laws of physical chemistry. Will it be a surprise to see quantum play a part in biology? As pointed out in part 1, some work is already being done in this area and there are several books relating life processes to  quantum biology^14,15.

 Now it is time to venture into borderline territory of metaphysics. Physics is theory of phenomena and metaphysics is about what might lie behind these phenomena. Information is about the physics and the chemistry of nature, about life and about consciousness, and therefore of life and the roots of phenomena. The field of information may be the bridge between biology, physics and metaphysics.

This is why I defined Information as potential for a future event, physical or biological, inherent in Nature.  Matter and energy are involved and the event takes place in space and time when causes and conditions are present.

Life as we know it and consciousness as we know it were inherently possible for them to appear, however low the probability was at an earlier time. (I did not use the words “in the beginning”) As chaotic as the Universe seems to be for this world to appear and life to evolve and as complicated and delicate as life is, they were inherently possible from the onset however improbable the chances were. Without bits of information inherent in primordial matter under “causes and conditions”, how could life have appeared?  This sounds like a tautological argument. Even so, this view is more likely to be acceptable to those who dislike the cold, logical, materialistic explanation of the Universe.

Information has to be recognized as a fundamental unit of Nature to explain the visible universe, including its living matter, all of which are made of matter and energy unfolding under appropriate conditions, in space and time.

1.       Gleick J. The Information. New York: Pantheon Books, 2011.

2.       Floridi F. Information – A Very Short Introduction Oxford University Press. 2011

3.       Wheeler, J A and Ford K. Geon, Black Holes and Quantum foam: A Life in Physics. New York: Norton, 1998.

4.       Pierce JR. An Introduction to Information Theory. 2^nd edDover Publications New York.1980

5.       Thomas PJ  Every bit counts. Science 334: 321-322, 2011

6.       Cheong R, Rhee A, Wang CJ, Nemenman I and Levchencko A.  Information transduction capacity of noisy biochemical signaling networks.  Science  334: 354 - 358, 2011

7.       Science November 25, 2011

8.       Walter P, Ron D. The unfolded protein response: From stress pathway to homeostasis regulation.  Science 334:1081-1086, 2011

9.       Meeks TW, Jeste DV. Neurobiology of Wisdom. Arch gen Psychiatry 66: 355-365, 2009

10.   Blakemore S. Consciousness – An Introduction. Oxford university Press. 2004

11.   Franosch T, Grimm M, Belushkin M, Mor FM, Foffi G, Forró L, Jeney S. Resonances arising from hydrodynamic memory in Brownian motion.Nature   478: 85-88, 2011

12.   Umpleby SA. Physical relationships among Matter, Energy and Information. Systems and Behavioral Science 24:369, 2007

13.   Bremermann H.J. Quantum noise and information. Fifth Berkeley Symposium on Mathematical Statistics and probability. Berkeley,CA. University of California Press 1965

14.    Allemann R, Scrutton N. Quantum tunneling in enzyme-catalyzed reactions. RSC Publishing, Cambridge, UK 2009

15.   Abbott D, Davies P C w, Pati AK. Quantum aspects of life. Imperial College Press, London. UK 2008

Information is a Fundamental unit in Biology

Friends, 

This essay, in 2 parts, has been in the making for over 3 years. I have been thinking about this idea even longer. I was not sure whether I am stating the obvious and therefore it is trivial. Or, am I out on a limb and therefore making a fool of myself? I have discussed these ideas with a few scientists. Some of them are currently reviewing this. However, a recent article in Scientific American confirmed for me that my ideas are worth sharing. Physicists are already looking at this question. Therefore, I decided to post it in order to get feedbacks, correct mistakes and improve  before a formal publication.

Hope you will have time to read this essay.  I request you to please send me your comments and critical questions.

Thank you.

Information” is A Fundamental unit in Biology

Part 1

 “Information” is one of the fundamental units of nature, just like matter and energy, space and time. This is particularly true in biology. This insight is supported by several common observations and numerous studies in biology and medicine. 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.

Information has to be recognized as a fundamental unit of Nature to explain the visible universe made of matter and energy unfolding in space and time.

There were several triggers for this personal realization.

My encounter as a physician with children who had genetic syndromes led me to think about genes as carriers of information and how a defective gene leads to defective information and a disease. It was no surprise when I read that Claude Shannon, the father of Information Theory, started his career with a doctoral dissertation on “ An algebra for theoretical genetics”.

Encounters with children who had metabolic syndromes and immune defects also led me to think of signals, information processing and their defects. What “tells” the white cells to come running to a site with a foreign body? What “tells” T cells to annihilate themselves when their job is done?

Metabolic homeostasis is based on information processing. What is the clue for insulin to be pumped into the circulation? Is not the “influx” of sugar into the blood stream a bit of information for the pancreas?

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).

Daniel Koshland,¹  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.

The other direction which led me to the concept of information at the core of biology is my practice of meditation for 40 years and investigations into the nature of human consciousness. This was supplemented by my reading of several recent books on the neuroscience of consciousness.  Ramana Maharishi, a mystic and a saint whom I had the privilege of seeing in the 1940’s 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” ².    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. In one recent book on human consciousness, Dr.Nunez  proposes a “crazy” idea that mind and brain are intertwined at a quantum level just as particle and energy are.

Finally, there were two experiences with nature which made me realize that a basic sense of awareness (without a sense of ownership) is essential for all human thoughts and perceptions. Awareness implies information.

The other day I soaked some green gram (a variety of pulse/ beans from India) 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 our eyes.

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 gram 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.

With life comes awareness. All forms of life are “aware” in the sense of being in touch with itself and with the environment. We know it by the way all life-forms react and respond to the environment. Individual cells of the body do. Micro-organisms do. Even a virus does. Animals do. Trees do.

Trees grow their limbs towards sunlight. They anticipate the arrival of winter and of spring. Trees tend to pollinate at the same time. Trees seem to “remember” past events! How is that possible? Obviously they sense the change in the inclination of the sun, duration of sunlight, humidity, temperature etc. Whatever it is, trees and plants are “aware” of some clue, some signal, some information in the environment and respond.

A few years back, I observed a pair of ospreys raise a family over a period of many months. They had built a nest in the Choptank river on a wooden pillar meant for mooring a boat. We had a vacation home in Maryland and this nest was literally in our backyard. I observed this osprey pair from the day they built their nest through an entire breeding season.  I observed how the mother laid her eggs, protected them through rain and shine, saw them hatch, fed the chicks and stayed with them until the youngest learnt to fly!

How did the female and the male know that they are a “pair”, leading to loyalty and caring? What told them that they have to build a nest? What made the male help the process? Once I saw the mother stay on top of the eggs through a harsh thunderstorm. What made her do that? How did she know that those were “her” eggs? When the mother was hatching, I have seen the “father” bring fish for her. How did he know? I have seen the adult birds take turns caring for the chicks. It was amazing to see the mother teaching the young ones to fly. And she stayed in the nest until the youngest and weakest learnt to fly and then one day all of them were gone!

Obviously the birds are conscious. They are aware. They know. They do not have our language. They do not know “love”, “loyalty”, “commitment” etc the way we do with our extra capacity for language. In principle, they “know”. They know their territory. They know where food is. They know their babies.

Neurobiologists and behavioral scientists have mapped out the circuitry in the brain to explain many of the behaviors in humans, animals and birds. The biology of growth and propagation of plants and tress is well known. But my primary focus is on information as the inherent, fundamental force of life process and its survival.

“Information” IS the basis of life. What is information?

“The bit is it” said John Wheeler ³. What is a bit? To Claude Shannon and the information scientists^3,4, for whom the physics of communication is the focus, bit is a piece of information. It is a message. It is a code. For the information scientists, the focus is about sending a message from here to there. The contents do not matter. Emotions involved in the message do not matter. Not even the purpose.

 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 these biological facts with Information Theory as proposed by Claude Shannon and others.

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. According to the information theory also, Instruction (for something) is one of the components of information.

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.

Information (message) in life sciences is a code for a potential future event, physical or biological, inherent in Nature; therefore inherent in matter and in energy.  I used the words, potential and future. 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.

A message (information) is carried on physical agents, by physical agents. Therefore, it can be or is an attribute of a physical agent and inherent in it. Physical description of nature is information based. Floridi ⁴ points out how “The universe is fundamentally composed of data…….with material objects as a complex secondary manifestation”.  Like butter in milk; like a plant in the seed.

Information is a fundamental unit of nature, like matter and energy. At least in biology, information in the form of codes is the basis of life and of consciousness.

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

What we now call “emergent properties” in biology is inherent information unfolding over time into complex phenomena. The potential for the emergent property has to be there in the original units and building blocks of cells and tissues. Whether this is true in the physical world also is not clear to me. My guess is that it has to be at the molecular and quantum levels.

When defining the word “datum”, Floridi ⁴points out that the presence of pure data, before they are interpreted or subject to cognition “is empirically inferred from and is required by experience, since they are what has to be there in the world for our information to be possible at all”.

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”. Time is unidirectional, at least in this universe. Unfolding of information in time makes the process unidirectional.

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

Matter, energy, time and space are the basic units of the physical universe. When you add “life” to the universe, awareness becomes an additional essential element. Awareness implies a source of information and a receiver.  It also implies a medium of transfer of information and a mechanism for the transfer. Finally, in biology, information is for a “purpose”.

Information implies a source, a medium for transmission, the process of transmission, receptor unit and outcome. This is common at all levels 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 depends upon external (environmental) and internal (mechanisms of transduction) conditions. Some message sources are simple and some complicated. The same is true of the receptor 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. What the tissue detects when a “foreign” body enters is a piece of “information”.

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 the foreign body. It is called PAMP and DAMP. (Pathogen associated molecular patterns and Damage associated molecular patterns”) which constitute the “information” to the tissue that something that should not be there is there. This is all or none type of message. The response is modification of the three dimensional structures of certain proteins inside the cells.  One such protein is NLRP3 which stays auto-repressed until “activated” by one of the damage signals (DAMP or PAMP).  The response is “unfolding” of this protein. This unfolding then becomes the signal or information for the next series of steps leading to the production of a protein called IL 1beta.

Il1beta 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, Il1beta 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 Il1 beta protein. Let me call it “potential information” (or a 0 position or an off position of a switch) in the receptor. When the Il1beta 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 change in structure is the information. (Or is it the changed structure that becomes the information?)

As we shall see in Part 2 of this essay, according to the Information Theory of Claude Shannon and others, the 0 and 1 positions of the receptor (the data) are the basis of lack of uniformity of this universe.

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 the “receptor” which causes a change in structure of the receptor.  This makes transmission of information possible. 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 (information) in this pathway result in inadequate or excessive response to stimuli (a bit of information) and thus to physical injury.

When we go one level deeper, what makes the three dimensional interactions possible? This enters the domain of chemical bonds, energy exchanges and Van der Waals forces. Since I am unfamiliar with these topics, I decided to learn how three dimensional structures influence biological functions. I read books and articles on the subject and discussed ideas with a protein chemist and a physicist.

I wish to focus on two articles to make my point. One was on the three dimensional structure of glucocorticoid receptor⁵.  The other paper was on how the structure of TLR4-MD-2 complex determines its ability to react to (with?) bacterial antigens⁶.

Glucocorticoid receptor (GR) is a protein responsible for the effects of glucocorticoids on the physiology of the body. 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. In the paper I read, the authors studied the three dimensional crystal structure of the GR in complex with one chemical (RU 486) which inhibits (antagonistic) the downstream effects and another chemical (dexamethasone) that activates the downstream effects (agonist).

There are 4 different crystal structures of GC – GC1, GC2,GC3 and GC4. The authors show how the orientation of helix 12 in GR3 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.

Three dimensional structures allowing for contacts between specific areas of the agent with an information and the receptor through which the information is translated are determined by hydrogen bonding and related forces.

A similar observation is made in the response of the body to bacterial antigens (in this study, it is 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, information at the molecular level is coded at the level of chemical bonds and van der waal forces. This information is needed for modification of three dimensional structure of proteins and other molecules. 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 .  

Seth Lloyd is quoted as saying: "To do anything requires energy. To specify what is done requires information".

 Is it, therefore, possible to build a theory that places information as an inherent property of nature in biology? If it is, should it be placed at the level of the ions and formation of chemical bonds? Or, should it be placed at the level of atoms and electrons? Is the information in the original three-dimensional structure of the protein or the molecule itself or is it in its potential for change under certain conditions? Is information an inherent property of the larger molecule or of the energy bonds? Will this approach give us new avenues of investigating emergent properties of matter into biological entities?

 When we take Claude Shannon’s definition of “information as whatever reduces uncertainty among alternate outcome probabilities….”,  it is reasonable to hypothesize that information is a basic unit at all levels in biology – even at the quantum level since particles at the quantum level are governed by statistical laws.

This is a speculation at present. However, there are some studies in quantum biology⁷. 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 smells at least in the fruitfly. 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.

More recently information theory has been applied in cell biology⁸. Channel capacity, noise reduction and entropy of probability distributions are the basis of application of IT in the communication systems. Now signal processing in the TNF pathway (signal transduction pathway) has been studied using these concepts to quantitatively predict and measure the amount of information transduced at a single cell level and also show that “noise reduction” takes place at a single cell level when a cell receives signals of different strengths from several sources⁹. 

Living forms (objects) are made of “matter”. Once these forms get “animated”, we get “life forms”. At a basic level, life is energy exchange. Life depends on energy exchange depending ultimately on the sun. Life cannot exist without energy exchange; but energy exchange can go on without life.

Living forms have a sense of awareness. All living creatures are “aware”. They all react to the environment. This is possible only if there is a “receiver” and a “responder”.  This is “awareness” at a fundamental level. Without awareness and ability to respond to internal and external signals, life cannot exist. Awareness is of information. Information exchange is dependent on energy exchange.

Enter higher life forms and human beings with their special brains and their capacities. Their awareness is different. Their brains are capable of meta-awareness, an awareness of awareness. When this is explained and understood through the use of symbols of language and of concepts, we reach the highest form of awareness (third-order) in the humans.

Earlier, I had referred to a book by Nunez.  His point is that mind and brain are two aspects of Nature just as matter and energy are, particle and wave are. He says that consciousness (awareness, information) is not generated in the brain; but it is a fundamental property of nature and of the brain. Information is not generated but is inherent in nature.

Brain is a sensing mechanism and at a higher level it is capable of sensing the process of sensing, which is awareness. We have a brain and therefore we are capable of being aware. We are aware of our brain and of thinking because we are aware. Without brain, “information” will be there, but “who” cares? Without life, there is no functioning brain and how is awareness possible? This is circular reasoning. But, as pointed out by Molitor ¹⁰, we use this logic with other aspects of nature. For example we say that “charges are acted on by electrical fields” and “electrical fields are generated by charged particles”. 

In summary, Information is inherent in the universe and 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. I wonder whether it is logical to think of information as inherent in matter for energy to act on in space and time at the micro and macro levels. Can any useful hypothesis be generated by placing information at the core of biological phenomena more precisely?

Information defined as “potential for a future event” is inherent in nature and by implication in matter and in energy. The actualization of that potential is a future event in space and time. Matter changes or has potential to change. Energy-levels change. Information is stable and the source can be tapped any number of times without loss of information.

The other point is that 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 are all possible because of coded information passed along and interchanged. Ultimately these have to be explained at the energy-exchange level which is again transmission and reception of a “code” or a “bit” of information.

“Bits” of information for a future event (the effect) have to be inherent in the cause. At a physical level, atoms and subatomic particles have “potential” to become what we see in nature, however improbable it may be, when causes and conditions are right. Particles at the quantum level are governed by statistical laws. Therefore, quantum principles will have to be invoked at this level.

My sincere thanks to Dr. Dan Brennan and Dr.Peter Kim for teaching me some fundamentals and directing me to basic books on Information Theory and Physical Chemistry.  I thank Dr.Karyl Barron for her suggestions and encouragement.  
 References:       

1. Koshland D. PICERAS – Seven Pillars of Life. Science 2002; 295: 2215-2216.
2. Cornelssen, Lucy. Hunting the I. Sri Ramanasramam, India. 2003.
3. Wheeler, J A and Ford K. Geon, Black Holes and Quantum foam: A Life in Physics. New York: Norton, 1998.
4. Floridi F. Information – A Very Short Introduction Oxford University Press. 2011
5. The three dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand – binding domain.    J Biol Chem 278: 22748-754, 2003
6. The structural basis of lipopolysaccharide recognition by the TLR-MD2 complex.  Nature 458: 1191-1196, 2009
7. Brooks, M The weirdness inside us. New Scientist October 2011. Pages 34 – 36
8. Thomas PJ  Every bit counts. Science 334: 321-322, 2011
9. Cheong R, Rhee A, Wang CJ, Nemenman I and Levchencko A.  Information transduction capacity of noisy biochemical signaling networks.  Science  334: 354 - 358, 2011
10. Molitor  SC Book review of  Brain, Mind and structure of reality by Nunez PL. JAMA    304: 218, 2010

Balu

Informed Consent

Is it truly an informed consent when a piece of paper is given to you to sign on your way to the operating room? The first insult is that the Consent Form is presented at an awkward time when you are so scared you do not even know what to ask. Next, the “informed consent form” is written in such a “legalese” you will need a lawyer to interpret what it says – preferably the same one who wrote it! Finally, the consent form goes into such great detail on everything that can go wrong, that if you really start thinking about each one of them, you may choose to suffer than sign that paper!!

It is sad that what should have been done to involve patients in a thoughtful decision making process has been made into a “risk management tool”. These consent forms do not even perform that function well. Evidence accumulated over the past several years has shown that the “informed consent” forms fail to truly inform the patients. They do not help avoid malpractice suits either.

A study that analyzed the consent forms collected from several US hospitals showed that some of them were “short and vague”, some of them “long and confusing”, many of them used legalistic language and only 25% of them went beyond just the description of the procedure to include information on risks, benefits and alternatives.

The status of informed consent was the topic of an essay on “Uninformed Consent” by Ms.Debra Franklin in the March 2011 issue of the Scientific American. She describes new tools of technology that are being developed to include and involve patients in the process of obtaining informed consent. These tools formalize and organize the components of Informed Consent and emphasize “education” of the patient so that when the patient signs a consent, it is truly an “informed” consent. Although these tools have not been tested, this is a good start.

These “software” tools of technology are interactive and are either aimed at doctors or at patients. I looked at two of them, mentioned in the article by Ms.Debra Franklin. They are Emmi Solutions and iMedConsent.
Emmi Solutions is patient centered, interactive, uses images, written at a level most people can understand, is in English and Spanish and is based on input from patients and doctors. The program I opened was on Angioplasty. The topic is presented under seven headings: Your Body, Your Condition, Pre-Procedure information, details of the procedure, Post-procedure recommendations, Risks and benefits and Alternatives.

iMedConsent is for physicians. Templates with details on several hundred procedures are available. They can be modified to suit the specific needs of individual patients. The program I looked at was on Cholecystectomy. This also followed the same format as the Emmi in explaining the body, the condition, preparation, procedure, post-operative instruction, risks and benefits and alternative.

Obviously these tools need testing. Also, what about patients who do not have computers or cannot interact with computers?

Ultimately, face-to-face “communication is essential no matter what the approach”. The computer will help to make sure the conversation did take place and all the elements of truly informed consent were covered. It will also assure us that the interaction is documented. Prudent, “compulsive” clinicians have been doing these all the time. Machine can only formalize the details and the process and inform everyone that it was done.

Like the gold

Looking at my old journals (daily dairy), I found several observations based on my personal experience as a pediatrician. I plan to re-write some of them for these blogs. Here is the first one.

She comes from a horrible social background. She is past the age of innocence. God knows what all she had been up to. But, now….

She is a pathetic looking girl - sick, seriously sick with lupus. Has lost all her mental faculties, so it seems. She cannot remember what happened yesterday. Her legs have become useless, cannot even hold her up to stand. She has no bladder and bowel control.

The mother is mixed up. She is so mixed up she cannot even come to see her daughter. But she is a mother with feelings, full of them. A helpless woman. Each time there is sad news (and she gets plenty of them everyday) she disappears. No one knows where she goes to. Is escaping her way of coping? Does she go wandering to forget her miseries?

Coming back to this young girl, she gets sudden and brief moments of clarity. At that moment, she knows what is happening to her and gets scared. Won’t you? You can see her face and read her fears. Amidst those sunken eyes, bald head, dried lips, is a mouth full of ulcers through which a pathetic cry comes out. She has tears in her eyes. Then comes a special spark in her face and with a gentle and pathetic smile she says: “Dr………. I am scared; will you pray for me?”

I hold my tears but hold her hands and say: “Of course, I will T…., I will pray for you”. For that one moment I see the Divine Spark in her eyes, the same Spark that lit me, and lit all of us. With that, the technician wheeled her to the operating room. Ms. T….. never saw her personal, miserable world again!

Yes, even in the midst of suffering, hopelessness, helplessness and sadness, the Spark of Life can be seen, even if for only a moment.

Socrates had objections to Written words

In Sanskrit there is a statement: “sahasram vada; ekam abhi ma likha” which means “Say 1000 words; but do not write even one”. Vedic tradition grew up on verbal recital and memorization. Greek tradition was also following the same course – until written words appeared at about the time of Socrates. It appears that Socrates was worried that students will obtain information from written words, but will not know how to think critically. We know he was wrong.

At present, we the “digital immigrants” worry the same way about our young “digital generation”. We worry that in the midst of these images and bits and “bytes” of information, the next generation may have problems with critical thinking skills. There are a few studies to substantiate such a concern.

The new generation of “technology-assisted” learners, are somewhat akin to the “book-assisted” learners that Socrates worried about. Our young ones learn from images and sound-bites and rapid summaries. There is no helping hand. Students multitask. They skim through information. They want instant answers. They forget that information is not knowledge and that they have to take an active part in making knowledge out of this information.

As pointed out by Maryanna Wolf in her book on Proust and the Squid (HarperCollins 2007) and in a recent issue of Science (August 19, 2011), writing and learning from written words was not natural for the human brain. It took at least 2 millenia for the human brain to evolve and adapt its structures and networks to this uniquely human activity. Will the neural networks developed over the past two millenia be useful in the new learning environment? Or, will the brain evolve new strategies to adapt to the new world of learning through images and streaming bits of information? How can we help the new young generation develop their reasoning and analytical skills and improve the so-called executive functions of the brain?

Socrates was of the opinion that spoken words are full of meaning and emotions, with added stress and nuances during the delivery. Written words are rigid. Written words “cannot talk back” if you ask a question. Nor can it offer clarification. Written words can be mistaken for reality if not examined critically with the help of a teacher, he thought. Decoding the words and their meanings is not the same as knowledge acquired by thinking about the thing words stand for with all their connections and implications. Socrates thought that reading from books might lead to superficial, false knowledge and “empty arrogance”.

The second objection was that written books will be harmful to memory formation. We all know that it is true to some extent. It does not destroy memory; but there is less need for it. It is not all bad. Computers can store memory better than we humans can. They can store lot more facts and more important, they can recall in fraction of a second and without ever forgetting. So why use the brain like a “filing cabinet”?

The benefit of the arrival of written words and books was that the brain needed less territory and energy to store memory. That allowed the brain to develop its correlative and analytical functions. The other advantage of written words was that accumulated knowledge could be transmitted to the next generation. Clearly, the arrival of written words is the basis of human civilization.

With information technology, we can store more information in less space than in books. We can look for correlations and patterns with simulations and complex calculations. However, information is not knowledge. By focusing on information, looking at moving images and disappearing screens and with the use of immediate feedback and quick rewards, are we losing our ability to stay focused and think through a problem?

The answer to this last question happens to be “yes’ and “no”. Yes, our youngsters are not focused, they multi-task and are quick with joy-sticks but not with executive functions. At the same time, children’s ability to think analytically and creatively and to stay focused can be improved with the use of the same technology. It is interesting to note that working memory is an important component of creative and analytical thinking and this can be enhanced by specially developed computer programs.

What are the executive functions of the brain? These are the qualities needed to control our impulses, focus on a problem, think creatively, assign priorities, make proper judgments and plan for a course of action. These functions depend on development of neural networks which connect the sensory, motor, emotional and rational parts of the brain. Many of the circuits are not fully connected till late adolescence.

All of (Most of us) develop these functions over the course of our young lives. Can we facilitate the developments of these functions in children? Sure, we can. Recent studies on helping young children to develop executive functions show that approaches that seem to work include “computerized training” with specially developed lessons, hybrid computer-noncomputer programs, special “Tools of the mind” and classroom curricula. (Science 333:959-964, 2011). Yes, information technology can be used to maintain those functions which we are afraid our younger generation may lose.

Finally Socrates thought that written words will result in loss of control over language. I do not know what he meant. Socrates probably thought that learning from written mode will lead to superficial understanding since there is no teacher to push the student to ask questions and ask for clarifications, make sure the student understands the meaning of words and the structure and the beauty of the language. The student is likely to move on with incomplete knowledge (not looking up the dictionary and ask for clarification) and thus lose control over knowledge. He said that “Once a thing is put in writing, the composition, whatever it may be, drifts all over the place, getting into the hands not only of those who understand it but equally of those who have no business with it…..”. In essence, we know how when a word is put on print, we lose control over it. We do not know who will use it and for what purpose. Is it not true even more when something is written into cyberspace?

As a physician-educator, I know that those concerns are still valid. Look at text messages, e mails and Twitter. There is no need for spelling or grammar. In medicine, when a clinical question arises, the students are able to get a reference or two about the subject in a second by signing into Pubmed or Google Scholar. They read the abstract but only a few go to the original and read it carefully and critically to assess the quality of research and the validity of the conclusion. Much less time is spent on deciding whether the “information” in that article is relevant to the specific situation.

This problem is even worse when patients search the internet and come up with everything that can go wrong with their condition. They do not realize that most of the material is unfiltered and untested and there may be even some dangerous ideas. The anxiety generated becomes worse than the disease itself.

We all know that Socrates was wrong in opposing written words and “books”. If he were alive he would admit his mistake. We also know that his concerns are of relevance once again. However, the age of information is here to stay. It has unleashed an explosion of available information. But information is not knowledge. The technology of acquiring information should not become an end in itself. Like all new technologies, information technology comes with its strengths and weakness. Like all new technologies, we will not know the full impact of this technology on individual learning and on the society for several decades to come. We do not know how this will alter the need for our brains to rearrange its circuitry for analytical thinking.

We have to adapt the information technology and adapt to it wisely and with prudence.

References:
Proust and the Squid. Maryanne Wolf. HarperCollins, New York 2007.
Science Issue of August 19, 2011

Technology affected Learners

The American Academy of Pediatrics conducts a survey of graduating residents each year. Results of a survey conducted between May and September of 2010 showed that a majority of them use IT tools for acquiring medical information, patient care and for personal communication. They use photos and video clips for both personal and professional purposes. Wisely enough, they use physicians-only social networking sites for professional purposes. (AAP News September 2011, page 17)

The current generation of learners is called the digital “natives”. They acquire information and use it effortlessly. Their learning style and skills are different. Teachers have to be aware of it.

In a lecture given by Prof.Krishnan at Hyderabad, India, young folks growing up with technology are called “Technology affected learners”. He makes SIX points about technology assisted learning. I list them here together with my comments (in italics) on what teachers can do to make the learners think.

1.Knowledge is free. (“Information is free”. You have to create knowledge out of it. We do not have to use the brain like a filing cabinet. Computers do a better job of “remembering” vast amount of data. Our brains are better used to think with the information)

2.Learners have less time to learn. (You have to make the time to learn)

3.We shape our own learning. ( Develop your own tools for thinking)

4.Peer network is the new expert. (Beware of the self-appointed “expert”)

5.Knowledge sources are always suspect (Check out the source for yourself. Make sure you know who is sponsoring it and why)

6.Newton’s Third law of Learning: For every point of view you find on the internet, there is an equal and opposite point of view. (You can find an article to support your point of view on any clinical problem! Beware and keep an open mind)

To this I will add what Margaret Mead said many years back. The days of vertical learning are over. These are the days of horizontal and parallel learning. You can learn from your students and the younger ones. You do not teach and/or learn. You share information and knowledge.

Wisdom – that is another story.

Ethics, Objectivity and Subjectivity

Recently I attended a conference on ethics. It was too didactic to my taste. Even the case discussion was centered on objective principles of biomedical ethics as given in text-books. Adequate emphasis was not given to problems related to personal values, emotions and communication.

Competency of patients to make medical decision was mentioned as part of autonomy; but there was no discussion on how to evaluate that competency, particularly that of an emotionally distraught mother of a pediatric patient. That made me think.

It appears to me that the excess emphasis on “objective” criteria in an area full of values and emotions is a reflection on the history of how the field of medical ethics evolved. Modern medical ethics has three major roots – humanism, science and law. First, the maltreatment of victims of war as subjects of cruel research during World War II. Then, there was the famous experiment in Tuskagee where several patients were infected with syphilis without their knowledge. Second, this is the age of science. Measurement is a fundamental part of science. Every subjective symptom and quality need to be quantified and measured. That obsession still goes on. Third, when patients sue their doctors, it is difficult for the court to decide whether the patient’s rights were violated and whether there was any breach of ethics. It is helpful to have objective criteria for proper application of law. They are all good reasons. It appears that ethical criteria are driven primarily by legality.

The weakness of the current ethical criteria is the excess emphasis on objectivity. Of course, we need objective criteria to “judge”. But that does not take into account the following realities. The future is, for the most part, unknowable. The physician has to make decisions under uncertain conditions. The situations are loaded with emotions of patients, the relatives, the doctors and other medical personnel. The situations are also loaded with personal values of the patients and physicians and everyone else involved with the patient.

Indeed many of the problems arise because of differences in expectations and values. This in turn is based on unequal information. Patients have a limited and often incomplete or distorted appreciation of the facts. They might have read up on an issue. That does not mean they know the risks and benefits as well as the physician. Non-physicians and support personnel with limited medical knowledge who are involved with patient care may have their own view of realities and values.

Ultimately it comes down to good communication between all parties concerned. If there is good, easy, honest communication, many of these situations can be avoided. Actually, in two of the patients presented that day, the problem was one of communication – not violation of objective principles of ethics.