

### A UNIFIED THEORY OF DISEASE

Is information failure the basis of all diseases?

Dr. Rajkumar Chetty MD FRCPath

Copyright © 2018 Dr. Rajkumar Chetty MD FRCPath

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CONTENTS

1. Systemic View Of Disease: Need For An Unified Thinking On Human Diseases

2. The Social Dependence On Medicine

3. Animals And The Way They 'Treat' Themselves

4. A Historical View On Diseases

5. Can We Define 'Disease'?

6. How Do We Diagnose Disease: The Detective Inside The Doctor

7. Information Failure As The Basis Of Human Disease

8. Shannon Model Of Information Theory As Applied To Understanding Of Human Disease

9. Cellular Information Failure As The Basis Of Human Diseases

10. Disorder In Biosystemic Information

11. Pharmaceutical Exploitation Of Cellular Information Vindicates The Information Failure Theory Of Disease

# 1. SYSTEMIC VIEW OF DISEASE: NEED FOR AN UNIFIED THINKING ON HUMAN DISEASES

All of us suffer from some ailment or other, every now and then. Sickness is a part of our life. Fortunately, we are able to get over our sickness, with or without medical help. But, some of us are not so lucky. The unlucky ones succumb to the illnesses.

Sickness is an unpleasant thing. It wears you down. Even a simple headache can put you off for a few hours. A simple fever can make you feel awful. There are some diseases that drag on for years, sometimes till the very end. Diabetes is one such example. It is a typical example of a disease that cannot be cured but only medically managed.

Even an injury is a type of diseases. Obviously, injuries can be orders of magnitude different. A simple fall and a bruise is not so much of a problem. But, serious trauma can be debilitating and can often lead to cessation of life.

Let us say your car develops a problem. You take your car to the mechanic. You have to describe to him the problem you noticed in your car. This is more like the symptoms you have when you are suffering from a disease. The mechanic generally has a good idea where he has to look simply based on the description you have given of the problem. The doctor does the same. Your description of the health complaints to the doctor allows him to exclude a number of possible suspects and narrow down to a few potential leads.

Some of us are good in 'Do it yourself (DIY)' approach. We can not only fix our cars but also some of our minor body ailments. But, quite often we do not mess with cars beyond our limited 'expertise' and the same applies for our DIY medical treatments also. These days there is so much information available on the Internet about human diseases and the patients are often very well informed about their diseases. Quite often, the patients become 'expert patients' because they know so much about their diseases, gleaned from the Internet.

A disease can be considered to be some sort of a disorderly state inside your body. There is some problem that affects the orderly function of the human body which may last for a short duration, or may last till you cease to exist. No human is an exception. All of us, at some point or other in our lives, will develop illnesses without any doubt. This may suggest that our body as a system is prone to disorder. To be honest, it is very true. I am sure there is no machine in the world that works without fault all its life. Bio-systems are no exception. They are susceptible to malfunction.

Diseases are malfunctions of your body. In principle they are no different from malfunctions in your gadgets. Repair of your gadgets by mechanics and engineers requires time. The error has to be identified and a solution found for fixing it. Professional mechanics have tools for 'diagnosing' the 'disease' of the machine and they have established guidelines for fixing the faults. Doctors are 'mechanics' for the body. They spend years studying and training to become doctors. They have to study in great detail about body physiology and pathology of diseases. The only difference between doctors and the gadget mechanics is life and death. A mistake by a doctor can mean the end for the patient. This is an irreplaceable mistake. But, the mechanics dealing with machines can afford to take their own time and need not worry too much about the fatal outcomes. Nobody is going to weep over a dead machine, are they? We also have to remember that we do not worry too much about very old machines 'dying'. Because we all know that machines have their life span. We do not expect machines to work longer than 8-10 years on average. But, on the contrary, humans are unable to accept the inevitability of death that occurs due to old age and the consequent wear and tear of the body. Nowadays, we consider death at ages in the region of 70 years as untimely and cannot come to terms with it.

One of the other unusual aspects of medical profession is that they face the wrath of the public when patients cannot be saved. The relatives of the dead patient, or harmed patient, can hold the doctor in court for damages. We hardly do that to our mechanics, do we? No wonder doctors pay huge premiums for malpractice insurances to defend them.

My idea of discussing this similarity between a mechanic and a doctor is only to show that diseases are fundamentally systemic faults.

Advances in medical sciences over the last 50 years have enriched our knowledge about human diseases. Human Genome sequencing projects are poised to throw open the gates for more knowledge about our diseases. This is all exciting, no doubt. But, truly, do we know about the true nature of disease? Of course we do but I have my own doubts about whether we really have grasped the deeper meanings of the concept of disease.

I am a medical doctor and I have also specialised in Biochemistry and Pharmaceutical medicine. My belief is that medical sciences have promoted a reductionist thinking for too long. There is no doubt that it is necessary to understand the precise, molecular and cellular basis of the disease phenomenon but unfortunately modern medicine has drowned itself in too much detail. Conceptualization has gone missing. There is no attempt to philosophize about the nature of diseases which is sad.

Systemic disorder is not unique to human body. Any system, that comprises of multiple and dissimilar components, is prone to disorder. Our society is like the human body in that there are billions of human beings working together just as billions of cells work together inside the human body. Sociologists and economists try to solve the maladies that affect the society like poverty, unemployment, civil unrest, terrorism, overpopulation, illiteracy, debt etc. In my view all these social maladies are conceptually very similar to the diseases that affect our body. Each type of these maladies has a variety of causes and a number of solutions. Identifying these social disorders is one thing but it is a different ball game when it comes to finding a remedy that works. Moreover, it is not difficult to see that many of these social problems like poverty, illiteracy, unemployment etc. have a relation to each other and may even have a common cause that needs to be addressed rather than each one at a time. Eradication of the root cause may alleviate many of the social ills in one shot. This is systemic thinking. That is the difference between macroeconomics and microeconomics.

What I mean is that a headache or body pain or fever can be treated simply with a pain killer. This certainly relieves the immediate problem. But it does not help prevent any recurrence of the same problem or growth of the problem in case the patient had an underlying illness. If the doctor does not bother about these considerations then he has failed in his duty just as the politicians and sociologists fail when they address a social problem superficially. When there is an unrest or protest in a particular place that warns the sociologists of some problem. Dealing with protesters with a police action and arrest may help solve the problem temporarily but will it help in the long-term?

What I feel, as a practising doctor, is that we need some serious insights into the broad principles of human disease. There is now a craving amongst many medical professionals for more of concepts and less of details. I have hardly seen any articles in medical literature in the last few decades that looks at some sort of a holistic view of human diseases cutting across organ systems. In fact, I do not recall any. What is the reason? What is happening? Is there something wrong here?

Let us go back to the example of social ills. I am sure there are so many articles and books being written about the social problems I listed above. There are, in addition, television debates as well. Economists, politicians, sociologists, and people from other disciplines keep writing and talking about these problems and there is a general sense of a broad-based thinking here. This is missing in medicine. This is my worry. Why cannot there be a broad synthesis of medical knowledge out of seemingly disparate and needlessly detailed minutiae?

The modern medical students are bewildered by the number of diseases and syndromes and there is a widely held belief that medical science has become very complicated and unwieldy and hence the need for increasing sub-specialisation. Nowadays it is the norm to see a specialist for your illnesses and there are specialists for heart, kidneys, lungs, brain and so on. Each organ speciality has got so much information pouring in as a result of medical research and this is leading to further sub-specialisation. No doctor can hope to know all about the minute details about all human diseases. In fact, doctors these days are so much reluctant to venture beyond the boundaries of their own medical specialty and do not hesitate to refer their patients to other specialists at the earliest suspicion of involvement of another organ system! Specialist doctors have a narrow view of their patients and are often unable to look at the whole simply because of the way medical sciences have evolved and the way medical practice itself has evolved. Sometimes it can be days or weeks before you see another specialist, having seen one before, and if someone has many complaints then he may be seeing many different specialists at varying points in time. It is not uncommon for some information to be missed by the doctors if there are multiple medical conditions for the same patient. Moreover, many medicines have side effects and some of them are not compatible with certain other medicines. The doctors cannot know all about these drug-drug interactions and incompatibilities and this may mean that patients could be put on medicines that should not be used together. Wrong prescriptions account for a substantial amount of iatrogenic harm.

Modern medicine is a descriptive science. Diseases are described to minute detail. Doctors are trained to look at the diseases as a detective trying to solve a mystery. The doctor collects more evidence by way of diagnostic tests and symptoms and signs. The aim of the doctor is to narrow down the 'suspects' and do more tests to confirm the diagnosis. In most cases this works. But, there are still a number of diseases where the diagnosis is not easy. It is like unsolved crimes. In many patients the diagnosis is never made even until death. In some countries undiagnosed death should be followed by a post-mortem examination to help make the missed diagnosis. This is obviously of help to the relatives to know the cause of the death but also has enormous educational value to the doctor and his team. This is different from the need for forensic evidence which also requires post-mortem examinations. Whether it is for forensic detective work, or for nailing the diagnosis for educational purpose, the point is that the cause of the disease can never be known until after death.

This book is an effort to probe a simpler understanding of disease from a biological perspective and probably show that there can be simplicity underneath the apparent complexity. This book is about the nature of human diseases and my quest to understand human diseases from a systemic perspective. As a medical doctor who is also a Biochemist I want to explore the phenomenon of human disease and understand it from a more fundamental point of view and develop an unifying theory of human diseases. I want to go beyond the traditional approach of signs and symptoms of disease and their treatments. This is what doctors conventionally do. This is what medical students get taught in the medical school. But, I want to look at human disease as a systemic disturbance to your body that endangers the continuation of the property of life.

I feel it should be possible to apply system theory principles to human disease. The human body is a dynamic, self-regulating, and adaptive complex system. A disturbance to the human body as a system is rectified by automated, regulatory mechanisms that will restore the system back to its optimal state in a manner typical of cybernetic systems. Physiologists call this the phenomenon of homeostasis. Any random deviation from the normalcy is met with a swift response to set this deviation right. This dissipation of internal disruptions is characteristic of life systems, especially multi-cellular life systems.

The systems theory that has come about in the last few decades prefers to look at systems from a holistic view with less emphasis of the parts. The human body is a complex system that comprises of too many interacting parts like organs, tissues, and cells. You need to go above the reductionist approaches to understand the human body in health and disease. Human body, like other multi-cellular life forms, are control systems amenable to descriptions according to the Cybernetic theory. There are a number of feedback loops, based on information input, that operate to control the multiple components of the human body.

Cybernetics is almost synonymous with the system theory though there is a connotation of engineering systems when we talk about Cybernetics. But, no one can deny that our body has a number of engineering design principles in the organisation of our endocrine and nervous system. Cybernetics is the study of feedback control in a system that is based on communication. Its focus is on how the system processes the information, reacts to the information and changes the system in response to the information. A whole lot of human function is precisely based on this type of information-based communication between body parts that act as control systems by their own right, often putting precision engineering to shame.

Many diseases make you suffer for a long time and doctors call them chronic diseases. On the other hand, there are diseases that are killers. Death ensues in a very short time. What determines this? Are the chronic diseases an outcome of re-setting the system (the body) to a different equilibrium set point? Can our body perform well at this altered set point well enough to allow continuation of the property of life? Can we assume that killer acute killer diseases disturb the system so much that it cannot function in a way compatible with life?

The other intriguing argument I want to put forward is that disease is a phenomenon that is unique to multi-cellular life forms. What is the reason behind my thinking? I have a feeling that this question has probably never been raised among biologists before. The question is: do unicellular life forms suffer from disease? Or, is disease a truly a multi-cellular life property? There is no doubt that this is a fundamentally important question that probably needs an answer.

As I said before I view diseases as a disorderly state. The disorder we are referring to is the disorder that prevails amongst groups of cells. A single cell does not face disorder, can it? For a disorder to arise there has to be many cells in the first place. I can almost bet my last penny that unicellular life forms, like bacteria and viruses, will not suffer from anything similar to the disease phenomenon we see in multi-cellular life forms. I claim that the phenomenon of disease is peculiar to multi-cellular life forms like us. Animals, even other than man, do suffer from diseases as the veterinary doctors would acknowledge. But, can we say the same for bacteria, fungi and viruses?

I think there has to be a convincing argument for this rather tall claim that only multi-cellular life forms will suffer from diseases. This is an intriguing biological characteristic that needs proper explanation. I just cannot claim something like this and get away with it. Where is the support for this claim?

My starting point for this argument is the assumption that a disease is a state of inter-cellular disorder. If this assumption is right then there is no problem. How can we prove that this? For this we need to delve into the nature of the diseases.

# 2. THE SOCIAL DEPENDENCE ON MEDICINE

Doctors are considered next only to God. They are expected to perform miracles curing all diseases. They are expected to prevent death. Patients and their relatives have a great sense of gratitude to their doctors when all goes well. Many doctors become almost like family to their patients because the cured patient and their relatives do not easily forget the favour the doctor did to them.

Hospitals have evolved over time. People almost by default visit the hospital when something is not alright with their body. I said before that this is no different from taking our car to the mechanic or taking the faulty machines and equipment to the service centres. We try to do a little bit of DIY with our cars and machines depending on our knowledge and practice. Minor problems with your machines can be fixed if you had some basic knowledge of their design and function. Even if you are not medically trained a little bit of self-cure is possible if you follow some tips which is freely available from books and magazines. Internet is such an easy source of information these days about medical topics.

Hundreds of years ago nobody really was really an expert because we did not know anything about human diseases. Shamans and village healers pretended to know about the ailments and adopted treatments based on unscientific principles. But, the poor people of the past had no way of knowing this and there was no other option anyway. Similarly, if you are a member of a native tribe, living a jungle or a mountain, you are also not going to be having the luxury of a doctor or a hospital. You would probably be having the services of a community member who pretends to be a healer. This is the case even in many rural parts of the world even today where villagers are still lacking proper healthcare.

Self-help is possible even today for some minor illnesses. You do not need a doctor for it. But, once things look a bit serious we run to the hospital. Quite often patients who are in their end stage of their lives, due to some sort of serious illnesses, such as advanced cancers or major traumatic injuries, are still taken to the hospitals in their dying moments almost as if it is the right thing to do and probably the only thing to do. It is the right thing to do if there is hope but in many cases there is none, but you do not want to accept it. Yet, people look at rushing to the hospital as the natural thing to do because that is where the doctors are and they are Gods.

Rushing to hospital in an emergency, sometimes even for non-emergency, is a widespread human behaviour. The majority of people end up in the hospital if they survive those precious few minutes needed for their transportation. There is big hope in their minds that some miracle will happen. There does not seem to be any other option really in their minds. That is why even a dying patient is rushed to the hospital almost as a ritual. When death comes it feels somehow right that it happened in a hospital. Even when death was inevitable people prefer to die in a hospital. This may be because of that slim hope some miracle can happen due to an ingenious nurse or doctor.

Cancer hospitals in many parts of the world seem to have taken the view that it is futile to keep some of the terminally ill cancer patients in their wards. Many a time dying patients, such as those with terminal cancer, are sent home to die in peace. Dying in such circumstances at their own homes, in the midst of their loved ones, may even be considered by many as dignified. But, this is a rarity. In many hospitals these days there is a 'Do not resuscitate' policy in effect. What this policy means is that dying patients, who have some chronic, incurable conditions, will not receive any attempts to be resuscitated if they suffered a cardio-respiratory arrest. This is because even if they are temporarily brought back to life their pre-existing conditions will prevent them from surviving much longer. Then what is the point of calling the Emergency teams? These teams usually consist of anaesthetists, emergency room doctors, cardiologists, nurses etc. and they have to rush literally in seconds to the site of the emergency call leaving behind what they have been doing at the time of the Code Blue call. It is a waste of time to be focussing on such hopeless patients and these valuable resources can be directed at patients who have a chance.

In a way people living primitive life in remote parts of the world are probably less afraid of death than people living in advanced societies. Even diseases are not feared simply because they do not know about them anyway. Primitive man living thousands of years ago had no clue about the diseases. They were not, therefore, worried about the consequence of the diseases. Today we worry about heart attacks, cancer, obesity, diabetes, arthritis and a whole range of diseases. Even lay press covers a lot of articles on such diseases and people worry about them. Many spend time worrying about the chances they might get those diseases. The ones who got them worry about the cost of the treatment and the disruption in their personal lives. Those with the advanced diseases know the eventual outcome and start worrying about the impending death.

Primitive people of the past at least had no such worries. Because they had no idea about the diseases and there was nothing they had to fear about. Disease and death are viewed as destiny by primitive people. They accept death as something unavoidable. There are no institutionalised preparations for the inevitable death. Death is accepted as normal. It may even be viewed as God's punishment. There is little need for elaborate pre-death dramas. The structure of their simple societies offers little scope for them anyway. If you do not have a hospital, or a doctor, where would you rush them to?

The fear of death is probably correlated to the complexity of the societies. In a highly complex modern society people have too many strings attached to their personal lives. If someone is about to die, or has serious disease that will affect his ability to work, there are more worries about the implications to the family from a financial point of view. Who will pay for the mortgage, the credit card companies, and educational expenses for the children, food for the surviving family etc.? These worries come to the forefront in our minds when we face death. Because our society is now structured in such a way that earning a salary is like breathing oxygen. When you are about to die, or get incapacitated due to crippling disease, the primary worry is this cessation of earning and the effect it has on the lives of the family members. This leads to frantic efforts to prevent the inevitable death, like rushing to the hospital in blind faith.

What does this discussion above in the last few paragraphs mean? Does it mean it is wrong to access healthcare in an institution if you suffer from a disease? Probably no, but what is wrong is the over expectation from the public about what the medical community can do for you. Not only we have come to expect the miracles from doctors and hospitals but we have gone one step further in the wrong direction. We now have learnt to blame the doctor and the hospital for perceived failures to reverse the course of the disease and death. This is a worrying development in our society over the last 40-50 years. People have realised that someone can be held responsible for their diseases and also death. The way this works is that a doctor is expected by default to know about your disease and the way to treat it. If the doctor fails to make the diagnosis, or there is a delay in the diagnosis, resulting in morbidity or mortality, then the doctor is at fault and not you who had the 'faulty' body. The hospital also is held accountable. Many patients, or their relatives, have earned fortunes from their illnesses. Only in the 20th century diseases became money-spinners. Diseases may lower survival fitness in Darwinian terms but the evolution of healthcare in the modern world has led to a curious situation whereby the patients can exploit the weakness to their own advantage.

Going back to the point I raised a little while ago as to why people almost always ritually take the diseased and dying to the treatment centres I guess this is because this concept is so much entrenched in their minds that they have started believing that access to healthcare is their birth right. The government is seen to be ultimately responsible for providing this care for the diseased. In many countries like the US there is no free health care. The insurance companies have taken on this role as sponsors of heath care delivery but the patient pays the premium. Because you have paid for it you expect good service in return.

Of course doctors do a great job in majority of the cases but, due to various factors, sometimes things go wrong. Mistakes happen. Wrong diagnosis could be made or they could be delays in making the diagnosis. This may be because of the limitations of the hospital as an organisation. For a person who walks in with headache the doctor cannot simply order a CT scan to rule out a brain tumour. They have to rationalise their thinking and go for the simple Paracetamol first. Then look at signs and symptoms and response to initial treatment. At some stage the doctor may think about more serious causes of the headache if the symptom persists for a long time, or recurs often. The doctor tries to prioritise more expensive investigations for patients who need them most. An insurance company will not approve a CT scan of the head for everybody with headache. This is only an example. This applies to a lot of other disease conditions where a doctor has to work like a detective trying to look at the obvious and more common conditions before thinking about rare possibilities. Apart from resource availability within the hospital to do CT scans and MRI scans for everybody there may be external pressures from insurance companies. So, availability of modern technology is one thing but using it indiscreetly is another.

# 3. ANIMALS AND THE WAY THEY 'TREAT' THEMSELVES

Is disease an exclusively human phenomenon? The answer is absolutely no. Even animals fall sick. That is why we have vets. For that matter even plants can become ill.

All multi-cellular life forms will be prone to disease. Even aliens, if they are multi-cellular, will not escape from disease.

Even the unicellular life forms like the bacteria can get infected by viruses called bacteriophages. These bacteriophages can infect a bacterial cell and hijack the host to utilize the bacterial cell machinery to make copies of the phages that will burst out at one stage by killing the bacteria or live inside the bacterial host in a symbiotic way making more copies as the bacteria divides.

Let us now focus on how wild animals treat themselves when they fall sick. In domesticated animals of course we have vets who do that. What about animals living in the wild?

The observation of animals eating foods not part of their usual diet, has led to the belief that animals self-medicate themselves with natural remedies found in leaves, roots, seeds and rock minerals. This has been referred to as Zoopharmacognosy.

African elephants, when they are pregnant and nearing their term, have been observed to seek out a shrub (a member of the borage family) that grew in areas even far away from their shelter. The leaves and bark of this tree are chewed by the elephants and a few days later they give birth. It appears that the elephants seek a natural remedy to induce themselves into labour. It is very interesting that Kenyan women are known to use the same plant to make a labour-inducing tea!!

Chimps have been observed to roll up the prickly Aspilla shrubs and then swallow them. They are also known to peel the stems and eat the pith of Vernonia plant. It is interesting that Tanzanian folk medicine includes both Vernonia and Aspilla for stomach upsets and fevers. These plants have been studied to have anti-microbial properties and anti-parasitic effects also.

Baboons in Ethiopia living near the Awash water falls have learnt to use some medicinal property of the tree Balanite aegyptica (Desert date). What is intriguing is that only baboons living below the water falls ate the tree's fruit and not those baboons who live above the water falls. The reason is the balanite fruit has the property of repelling a parasitic worm found inside the water snails in this area. When the baboons eat the water snails they get infected with the parasites. Those baboons living above the water falls do not come in contact with these water snails and therefore are not affected by these parasites. Therefore, these baboons do not touch these balanite fruits!

Colobus monkeys living on the island of Zanzibar steal and eat the charcoal from the bonfires made by the people living here. The reason is hard to believe. They act like toxicologists. By eating the charcoal they are doing exactly what hospitals do to treat poison victims. Charcoal has the property of adsorbing toxic chemicals!! The Colobus monkey is trying to counteract the toxic phenols contained in the mangos and almond that grow here!! Can you believe that?

Even some birds like the South American parrot and macaw are able to get rid of toxic compounds in the diet by adopting similar approaches. They eat solid with a high kaolin content to rid themselves of poisons like cyanide contained in the fruit seeds they eat. Kaolin has been used centuries in different cultures for treatment of stomach and intestinal upsets. Kaolin is also a standard content in some modern medicine formulations used for intestinal complaints.

In Northern California dusky-footed rats bring fresh bay leaves into their sleeping nests to control an abundance of fleas. Studies have shown that these bay leave extracts worked with as much as 80% comparable efficiency as a powerful chemical repellent called Diethyl Toluamide sold in the shops.

Avoiding parasites and pathogens is something animals do. They have a variety of ploys to achieve this objective. Avoidance of grazing on forage adjacent to recently dropped faeces has been documented in sheep, horses and cattle. Felids and canids even practice den sanitation. One aspect of the feeding behaviour of carnivores and omnivores is the risk of getting infected when they eat the dead carcass of some animal that has probably even died of an infectious disease or has been dead for a long time and therefore has grown microbes. Because pathogens are species-specific this cross-infection does not happen. It turns out that animals will never eat the dead carcass of a dead animal of a conspecific which has been referred to as cannibalism taboo. Perhaps this can be said to be true of even human who never eat other humans. We humans may have stumbled upon the idea of frying or baking their meats in order to get rid of the pathogens!! The taste that followed this fire-induced grilling was only an added perhaps an unexpected bonus.

Avoidance of pathogens by quarantine may be thought to be a practice adopted by humans especially in national borders. Even animals tend to do that. Repulsion of strange conspecifics has been seen practiced by primates. Rodents cannibalize sick infants to protect the littermates.

Animals are well known to lick their wounds to help in the healing process. It is well known that saliva contains a number of anti-microbial and wound-healing substances including lactoferrin, lysozyme, epidermal growth factors etc. Laboratory experiments have demonstrated that dog saliva can prevent the growth of E.coli and S. canis which are two most common organisms that cause wound contamination in animals. Male rats compulsively lick the penis after copulation. Rat saliva has been shown to effective in warding off bacteria that can cause genital infections.

Grooming as a ploy to remove ecto-parasites like ticks, fleas and lice is well known in the animal kingdom. A number of studies have shown this in ungulates, mice, cats. Animals also resort to fly-repelling behaviours like ear twitching, head-tossing, leg stamping, muscle-twitching etc.

It can be safely said that many types of behaviours are used by animals to control their diseases. Avoidance of pathogens, avoidance of parasites, intake of medicinal plants, quarantine, caring for the sick, sexual selection of partners endowed with disease-resistant genes, and even controlled exposure to pathogens to potentiate the immune system are some of those types of behaviours. The mothers of some early maturing species tend to pass on the infant around to group members to expose the infant to pathogens in a limited way. Species that have a long maturation stage do not show this behaviour. Weanling young of carnivores are sensitized to microbes as the mother brings the kill dragging it over dirt and filth.

Ultimately, these diverse animal behaviours clearly point to one thing. All life forms have one major goal - that is to preserve their lives. Pathogens and parasites are impediments to their continued existence and animals want to get rid of them no different from humans. Why do these pathogens pose a threat to the life of the animals infected? How do they make the animals sick and diseased? Infections and infestations in other animal species have the same ill-effects as seen in humans.

Basically microbes are life systems by their own right. They seek nutrients to survive. They seek a place to survive in nature. For both these reasons they forcefully and slyly gain unlawful entry into other life systems. This is medically termed an infection. Given the number of diverse microbes there are innumerable types of infections suffered by animals including humans. The microbes target different organs in their host animals. Their entry in to the host disturbs the dynamics of the host survival. There may be effects on certain key processes that help maintain the constancy of the internal environment of the host. When this happens there is by my definition a disease. Outright death of the host animal may not be good for the invading microbial life system. Evolutionarily microbes and animals have sought a balance here. Some microbes do not cause debilitating or life-threatening disturbance to the host internal environment whereas there are other microbes which cause far more destruction or death. They attack vital organs like the lungs, heart or brain and kill.

In simple words infections are a battle between life systems for nutrients and survival. That is why animals evolve mechanisms to ward off the microbes.

# 4. A HISTORICAL VIEW ON DISEASES

Man has been troubled by diseases since ancient times. Our understanding of diseases has grown incredibly in the lost century and we have come a long way from treating diseases by magic and prayer.

Ancient man was convinced that disease was divine punishment, and therefore a mark of sin. This conviction was quite widespread in the ancient world. This belief was passed on by the Mesopotamian cultures to the biblical Hebrews, which continued well into the Christian Medieval Europe. Greeks believed that Gods could bring an illness or widespread pestilence, which needed prayer, sacrifice or purification to appease the offended God. The Egyptians considered every symptom like cough, fever, swelling, skin rash as individual diseases and there was very little effort to group the symptoms into categories. The ancient Chinese regarded disease not so much a result of punishment for sin but the inevitable result of acting contrary to ' _Tao_ ', the universal principle. Illnesses could also be caused by forces beyond one's control, like wind and atmospheric conditions, which upset the harmonious inner balance of ' _Yang_ ' and ' _Yin_ '.

For a very long time in the human history diseases were thought to be due to entry of some evil spirits. This was believed to happen when something wrong was committed by the diseased man and therefore disease was viewed as a punishment. The remedy was in setting right the wrong he had done, or in appeasing God through the doctor or shamanistic rituals. That is why practitioners of medicine have always been held in high regard in our society. It is very common for modern doctors to be treated with respect in many parts of the world and are often considered next only to God. Primitive man was no different. For him the witch doctor was the agency through which he can establish contact with God and seek help. Primitive societies even to date continue to have such 'medicine men' that lack any formal training and often have no knowledge of diseases but are sought for treatment simply out of belief or tradition. These village healers are usually priests in the local temples and/or shamans.

Expelling the evil spirit was required as treatment and this required help. In the pre-historic past, and in fact until very recent history, the help was sought through prayer, magic. Expulsion of the so-called evil spirit by rituals is practiced even today in rural parts of the world. Shamanism refers to the primitive practice of healing through the agency of a healer, often a village priest. The process of curing of diseases was believed to be achieved by mending the soul. Shamans were thought to be intermediaries to the spirit world and solutions to human problems, including diseases, were sought from the spirits. The shaman tries to cure diseases by gifting, threatening, flattering or wrestling the disease-spirit. Shamanism is based on the belief that invisible forces or spirits affect the lives of people by unwanted entry in to the visible world.

Diseases were thought to be caused by factors in the spiritual realm and someone needed to enter the spirit world to set them right. Shamans were the ones expected to do it. They did that by 'entering' supernatural realms or dimensions. Guidance was sought from the other worlds for problems, including diseases. Shamans were able to make people believe that they are in a different world by modifying the consciousness, either auto-hypnotically or through the use of entheogens. Entheogenic substances used included those that were derived from plants and fungi like Psilocybin mushrooms, Cannabis, Tobacco, Fly agaric, Deadly nightshade, Datura, San Pedro cactus, Morning glory, Hawaiian Baby Woodrose, Salvia divinorum etc. Extracts of these plants had substances that make the user go into a trance or into some form of altered consciousness. Shamans across different cultures also used many other methods of inducing beliefs in susceptible people. Drum-beating is used by shamans by _inuit_ in Siberia and also in many other cultures. Drum-beating is a widely used practice across ancient cultures for achieving an altered state of consciousness. It was supposed that this altered state of consciousness will allow travel between the real world and the spiritual world. In many North and South American cultures and in Asia feathers are used in healing rituals. The reason was that birds were believed to be messengers of spirits because they could fly in space. Smoking various tobaccos and psychoactive herbs like cannabis is used in shamanistic practices. Sadhus in India use Cannabis and shamans in Americas are known to use Tobacco in a ritualistic setting. Swords are used in some cultures as a protection for the shaman from evil spirits when he wanders in the spirit world.

Shamans still exist even today. They are seen primarily in indigenous cultures, living in jungles, tundras, deserts, and even in rural villages in the modern civilisation. I have seen this practiced even today by village priests in South India by so-called priests who attempt to drive the evil spirit out of the mind of the psychotic patient. They beat the patients with Neem leaves repeatedly and harshly, uttering 'magic' words, and they threaten the spirit with bad consequences if it failed to leave. One could say that shamans are prevalent even today in the parts of the world where there are many illiterate people and/or places where there is no access to modern medical care.

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The difficulty in treating mental illnesses even in modern times, even with all the advances in medicine, is evident. For many of the mental illnesses the aetiology is unclear and the treatment is too non-specific that it affects non-target parts of the brain a lot. Imagine what would have been the case in the distant past. Without the knowledge about the body organs, immune systems, microbes, our physiology what do you expect the primitive man to do? Modern medicine only started developing from about 18th and 19th century and has made rapid progress in the 20th century but diseases were prevalent since the origin of man hundreds of thousands of years ago. A lot of diseases man is suffering now are now known to be due to the life-style changes, like inactivity, excess fat or sugar intake, stress etc. but they are only a minority of illnesses afflicting man. There are many diseases that occur in man due to genetic mutations and susceptibility, infectious agents, nutritional lack, cancer, mental illnesses which may have bothered man since time immemorial.

Egyptians were great healers. Ancient papyri texts that have survived tell us that Egyptians had a good knowledge of medicinal herbs as well as repair of physical injuries. I suppose the healing and repair of physical wounds is more relevant in the ancient Egyptian society because of their long tradition of building massive monuments and the more than likely event of frequent physical harm to the workers. They had a system of sick leave and early retirement in case of injury to workers. Egyptian labourers were fed a diet rich in radish, onion and garlic which are now known to be rich in natural antibiotics like allicin, allistatin and raphanin. This must have helped to contain and outbreaks of diseases in crowded labour camps. Powdered liver, rich in Vitamin A, was given by Egyptians to cure night blindness! Honey was used an antiseptic by Egyptians to treat wounds. This ancient cure has been adopted by even the British military to treat soldiers who suffered burns. A study comparing the efficacy of honey and sulfadiazine in dressing the burn victims showed the honey was far more effective. This is attributed to the antioxidant and anti-microbial properties of honey. A concoction made from the Willow tree was used to treat toothache. It is now known the Willow bark is the basis of modern aspirin. Parasitic diseases have been afflicting Egyptians of the past and present. The ancient Egyptians used pomegranate (known to contain high levels of Tannin capable of paralyzing parasitic worms) to expel the parasites! It can be surmised that much of the medical knowledge possessed by the ancient Egyptians about human body and illnesses were derived from their practice of embalming the dead which required them to anatomically dissect the dead body. This gave them a good idea of organ functions at least which organ was responsible for what.

Greeks believed that most human ailments could be cured by praying to the God of Medicine, Asclepius. They built temples called Aesclepions where Greeks went to heal. Hippocrates changed the way Greeks saw the diseases. In fact, Hippocrates laid the foundation for Modern Medicine by separating medicine from divine. He initiated the practice of looking for symptoms and physical examination and obtaining a history from the patients. Modern day doctors are still doing them which speak of the enormous contribution made by Hippocrates to the medical sciences. The Hippocratic Oath is still undertaken by doctors when they embark on a career of medical healing!! Some of the medical appliances like scissors, forceps, catheters used by the Greeks in the olden days are still recognizable in a modern day surgical theatre. Greeks thought of human diseases as an imbalance in one of the four humours - Sanguine, Choleric, Melancholic and Phlegmatic. Diet, age, climate etc. affected these humours and led to the diseases. Till well into the Middle-ages, the Greeks were treating their diseases by trying to balance these humours. Greeks believed in a Goddess of hygiene called Hygeia, Hygeia was supposed to the daughter of Asclepius, the God of Medicine and healing. Along with these Gods they also worshipped Panacea (God of universal remedy) and Apollo (God of Music) who are all mentioned in the Hippocratic Oath recited even today. So, it can be safely assumed that even Hippocrates did not totally abandon a role for the healing Gods in the treatment of human diseases.

Romans placed more emphasis on cleanliness in preventing diseases. They knew that dirt and poor hygiene was somehow linked to human diseases, not very far from the modern truth. They built aqueducts to supply clean water to the citizens. Roman engineers built massive public baths to help their people clean themselves and prevent diseases. Roman baths can be seen in many places even today. In England there is a massive Roman bath that can be seen in the city of Bath. I have visited it a couple of times. It was apparently built almost 2500 years ago and it is unbelievably impressive!

Though medicine has been evolving over the millennia there are still some ancient medical practices that have survived till date suggesting that the ancient people did manage to understand the nature of some human diseases better. Acupuncture, developed by the Chinese almost 4000 years ago, is still widely in use across the world. Though it is removed from the modern theories of physiology and anatomy the wide uptake of this art of medicine indicates the possibility that the Chines probably deciphered the nature of many diseases in their own way. How placing needles on designated pressure points helps not only in treatment of pain but even other diseases is not known.

Craniotomy means opening up the skull. This practice has been used since pre-historic times even during the stone-age. Archaeologists have unearthed skulls with circular holes which shows that people have done this as part of some treatment. It is believed that pre-historic people attempted to open up the skull to drive away evil spirits which they thought were responsible for epilepsy or mental illnesses. But, the striking truth is that craniotomies are even today used as a standard neurosurgery procedure for management of brain tumours, hematomas and skull fractures.

Hippocrates had described the procedure of cauterization (burning) of a part of the body using heat for treatment of some conditions. Cauterization is still used today to cut tissue or to stop bleeding. Even procedures like caesarean sections and tracheostomy have been practiced by Romans and Greeks which is amazing.

History tells us that humanity has suffered from time to time disease outbreaks that had major impact on the society and the course of the human history. Often, the population dwindled following major epidemics. Death of tens and hundreds of thousands of people left the society in shatters.

Greek history has an account of a disease epidemic that happened around 430-424 BC. This is now believed to be a devastating plague, which some believe to have been typhoid fever. This disease is thought to have killed one third of the population of Athens, including their leader Pericles. This is one instance where you can demonstrate a big change in the course of history due to a microbial culprit. Pericles had dominated this part of the world around this time and it was said to be a golden period. All this came to a halt due to the fact he dies as a result of some disease that killed him and tens of thousands of his citizens!

The balance of power shifted from Athens to Sparta. A historian called Thucydides, who lived during this disease, also contracted the disease, but he survived to write about the plague. Based on his writings modern academics and medical scientists consider epidemic typhus the most likely cause of this outbreak.

Another historical epidemic was seen in the English colony of Jamestown, Virginia, where almost entire population was wiped out from this small town due to typhoid. Typhoid fever killed more than 6000 settlers between 1607 and 1624.

81,360 Union soldiers died of typhoid or dysentery during the American Civil War. As recently as the late 19th century, typhoid fever mortality averaged 65 per 100,000 people a year. This became even worse when the typhoid death rate was 174 per 100,000 people in 1891. Public sanitation conditions were poor during these times with rising populations. The industrial revolution that began early in the 19th century was beginning to cause an explosion in population but the consequence of crowding led to challenges in sanitation. A carrier of a disease in the society was easily able to transmit the disease to many others. The most notorious carrier of typhoid fever, known in medical history, was Mary Mallon, also known as Typhoid Mary. She became the first American carrier to be identified and traced back in 1907. Her profession was cooking which, unfortunately, was ideal for spreading Typhoid. She kept spreading the disease until the authorities tracked the source of the infection to her. She was made to quit cooking but she cheated the authorities and returned to her profession under a false name. Finally, she was kept under quarantine for over 26 years.

Modern medicine has given rise to unrealistic hope in the past couple of decades. We have started believing every medical condition should be treatable and manageable. There are a whole lot of diseases we can hardly do anything about. In spite of the incredible advances in medical sciences over the last century the concept of disease is still poorly understood. Surprisingly, as I told you before, there is a lack of agreement about what constitutes a disease and there has been very little effort to find an unified understanding of human disease. Medical knowledge has exploded in the last few decades to the extent that medical practice is increasingly becoming super-specialised. Doctors have to drown themselves in endless detail about various diseases of diverse organ systems and there is hardly any attempt to synthesise a unifying view of the phenomenon of disease.

# 5. CAN WE DEFINE 'DISEASE'?

Just what do we mean by the term 'disease'? Can we define 'disease'? I am sure most of us would define it as a pain, suffering, discomfort, disability, and a potential forerunner to death. These kinds of definitions are descriptive. Apart from describing what the diseases are, do they really tell anything about the nature of disease?

Though we have come a long way towards understanding the molecular basis of most diseases, it is difficult to believe that there is still no satisfactory definition of the term 'disease'. This does not apply to the lay public only. Even doctors have the same difficulty. This lack of clear definition of disease, and the hazy line of demarcation between 'disease' and 'non-disease', was highlighted in the survey conducted by the British Medical Journal (BMJ) in 2002. A huge list of conditions were thought of, by health care professionals, as indicative of diseases but were classified by BMJ as non-diseases.

The BMJ carried an article earlier in 1979, nearly 20 years prior to this 2002 survey, entitled ' _The Concept of Disease_ ' emphasising the ambiguity in the meaning of the term 'disease'3. The authors suggested that the name of 'disease' should refer to 'the sum of the abnormal phenomena displayed by a group of living organisms in association with a specified common characteristic, or a set of characteristics, by which they differ from the norm of their species in such as a way as to place them at a biological disadvantage'. Unfortunately, this definition only describes the clinical features of the disease and in no way throws light on the underlying pathogenic mechanisms. This definition is not adequate to understand disease because there is no mention of the reasons behind the abnormal phenomena that predispose the person to a biological disadvantage.

The World Health Organisation too has no definition of 'disease'! Can you believe that? This is the organisation, headquartered in Geneva, which has a global role in conquest of human disease! WHO has only a definition for the term 'health'. It defines health as 'a state of complete physical, mental and social well-being, and not merely the absence of disease and infirmity'. It is to be noted that there is no attempt to define disease here. Why is this? Is defining 'disease' that difficult that even WHO does not attempt it?

I looked up six leading textbooks of medicine, commonly used by medical students but was dismayed to find that none of them defined disease! They describe about all kinds of diseases, page after page, in several volumes big enough to be your pillow. But, believe it or not, none of them defined the term 'disease'. I thought this was odd. It really set me to think there is a need here. I am a medical doctor myself. I was getting on fine through all my years of medical education and practice until this point when I began to wonder about the nature of human diseases. Suddenly, it dawned on me that there is a need for a fresh thinking to develop a systemic understanding of human diseases.

Describing all signs and symptoms of diseases, their causes, and their treatments is enough for the practice of medicine. But, isn't there any scope for looking at diseases from a dynamic, systemic viewpoint? If a physicist looked at the human body as a complex adaptive system how would they understand the phenomenon of disease? If an engineer looked at the human body as an intricately designed, multi-component system with numerous control devices, would he be able to understand disease from a cybernetic point of view? If a biologist looked at the human body as an ecosystem would he find a different answer for the concept of disease? If an Information technologist viewed the human body as a society of cells, dependent on information, then what would be his take on disorder amongst the cells? Would he call this disease?

A textbook of Pathology and a textbook of Biochemistry, both world leaders in the field of medical education, do have a definition for the term 'disease'. The textbook of Pathology describes a disease process in terms of aetiology, pathogenesis, and morphological changes in cells and organs and the functional consequences, which result in clinical symptoms. This is a useful approach but each disease will have its own description though it is possible to group the diseases based on the aetiology (such as nutritional diseases, genetic diseases, autoimmune diseases, inflammatory diseases etc.). It is also possible to classify the diseases by their cellular origin, irrespective of their aetiology, into diseases of liver, kidneys, heart or nervous system etc. It is evident that the above approach to understand disease lacks an effort to find a common underlying basis of diseases, irrespective of the diverse aetiologies or the tissue of origin.

Harper's Textbook of Biochemistry defines disease as the result of 'a perturbation of either the structures like DNA, or the amount of certain bio-molecules, or important biochemical reactions and processes that operate to maintain the constancy of the internal cellular environment (with regard to pH, osmolality, concentration of electrolytes). These perturbations are induced by many agents and often lead to severe alterations in the internal environment for which compensatory mechanisms can only operate for a finite period of time beyond which disease results'. This is the closest and the best definition I found yet for the term 'disease'! It views the human body as a system that can undergo disturbances that impairs the maintenance of stability of the system.

Harper's definition is an attractive definition because it identifies a common underlying principle viz. perturbation of the internal environment. But, the deficiency of this approach is it fails to indicate a common proximate cause for the perturbation of the internal environment, and how this perturbation causes the disease or death. In addition, there is no explanation for the variations in the duration of the disease processes (acute or chronic) nor does it indicate the critical factor(s) that determine why certain diseases lead to death while others do not, though they can drag on for years causing considerable morbidity.

In this book I have explored the concept of disease from a biological perspective, viewing it as a failure to maintain the constancy of the internal environment of the body due to defects in intercellular communication. I have also shown that diverse disease-causing mechanisms produce convergent effects on key biochemical processes to bring about global disruption in the communication capabilities of the cells. I have attempted to show that multi-cellular life systems like humans, consisting of trillions of cells, are vulnerable to cellular disorder as a result of this breakdown of information transfer resulting in an inability to function as a cohesive unit. In summary, I claim that the information failure is the basis of cellular disorder associated with all human diseases.

# 6. HOW DO WE DIAGNOSE DISEASE: THE DETECTIVE INSIDE THE DOCTOR

Doctors will be frowned upon by peers if they follow a shotgun approach trying to use all possible modalities of modern diagnostic tests without regard to the sign and symptom the patient has. Doctor is like a detective. With the available evidence (sign and symptom seen in a patient and the history of the illness) the doctor tries to pinpoint the offending culprit (the cause of the disease). The cause of the disease could be a microbe, a poison or a cancer or anything. The doctor needs to rule out one by one based on the available evidence. The evidence includes mainly the symptom the patient has told him. He supplements this evidence by doing a physical examination where he looks for physical manifestations of the disease. Doctors call this the 'sign'. A 'sign' differs from a 'symptom' in medical parlance. A 'sign' is some external manifestation of the disease which the doctor found by a specific observational act during examination of the patient. Whereas a 'symptom' is one which the patient feels for himself - like a pain, vomiting, fever etc. Usually a 'symptom' is what the patient tells the doctor about what was the reason why he visited the doctor. This is called the presenting complaint in medical parlance again. Symptoms told by the patient and the signs elicited by the doctor tell a lot usually. In many cases it is like an open and shut case. There is a clear idea in the mind of the doctor what the problem is that is bothering the patient. In such cases he can already think about a treatment plan. At least, he can start thinking of treating the 'symptom'. Symptomatic treatment refers to the attempt made by the doctor to relieve the 'symptom' by simple remedies to buy some time. A patient coming with pain anywhere in the body will thank the doctor if he or she can relieve the pain first. The underlying, root cause of the pain needs to be worked out later. The doctor will rely on some diagnostic tests to do that. Once the cause is found then the doctor will work on a more definitive, long-lasting treatment aiming for a cure. It may take time and more diagnostic investigations.

Results of diagnostic tests add more weight towards or against presence or absence of disease. The purpose of a diagnostic test can be broadly two-fold. Either the doctor is interested in knowing the presence or absence of a diagnostic condition. Or, he is interested in finding the offending culprit that caused the disease. In the case of the latter scenario the doctor knows the presence of the disease but is interested in finding the cause. In both scenarios a positive or negative result in a diagnostic test tells a doctor something. He eliminates the offending culprit one by one.

In an emergency there is a justifiable need to do many diagnostic tests at the same time to save time. For non-emergency conditions this luxury is not there. The patient unfortunately thinks different. The patient thinks that, in the 21st century, with all the exciting medical advances, it should be easy to make the diagnosis. The modern patient is spoiled. He has high expectations. Many family practitioners in their clinics see patients who have minor symptoms. The patients with major symptoms, or emergency conditions, go to the hospital directly. For the family practitioner who sees only the non-emergency patients he has to consider common causes first while trying to make a diagnosis on a patient who is otherwise well. The patient may be somebody who is visiting the doctor straight from work or home, having done their usual chores. The doctor cannot afford to think of investigating rare medical conditions for everyone who has just walked in to his clinic while being able to carry about out his usual life. Moreover, for low-incidence rare conditions results of diagnostic tests can give misleading answers. In some diseases making a false-positive diagnosis is as harmful as having a false-negative diagnosis. All tests have a certain degree of false-positive and false negative rate. If the disease condition was a rare one this will have an impact on the false positive and false negative rate of the diagnostic test. The likelihood of a person having a disease due to an offending agent increases with increasing evidence. The increasing evidence can be in the form of a test result from a second or third diagnostic test. The combined evidence adds weight to the possibility that the patient really has the disease or that it is due to a particular causative agent. This is Bayesian probability.

It is almost no different from our perception about people. If someone has done something wrong our perception about that guy will depend on whether he has done the same thing before. If yes, then we say 'Oh, yeah, that guy is a troublemaker'. Inwardly, we have done a Bayesian probability assessment in our minds. We assess the pre-event probability whether the guy is a trouble-maker based on his behaviour before. The likelihood that he is a troublemaker increases with the past history. In the court a convict gets sentenced based on the weight of all evidence combined. Finger prints, witnesses, blood stains, CCTV footage etc. all adds up to the probability that a person accused really committed the crime. With less of the evidence available there is little possibility to pin the murder on the accused and he gets the benefit of doubt and the jury let him go. Similarly, it is true that some types of evidences from the crime scene may be misleading or inaccurate or even wrong. The wrong guy gets punished. There is a saying that the justice system works on the principle that all are innocent until proven guilty. Our justice system also works to uphold another laudable principle - the innocent should never get punished though an occasional guilty can escape. Many diagnostic tests are like this. They produce results that may have inherent uncertainties due to the analytical procedure or variations in the patient. The evidence produced by lab diagnostic results can be inconclusive or, even worse, point in the wrong direction. It can be false-positive or false-negative. That means the innocent gets punished and the guilty are escaping! Therefore, doctors combine the weight of clinical signs and symptoms to the diagnostic test result in order to make an interpretation before making that final judgement - the diagnosis.

The other implication is that once a diagnosis is made, rightly or wrongly, it remains in the medical records of the patient probably for a long time before it is disproved and removed. Even otherwise the patient carries the stigma of 'being diseased', especially a disease that has undesirable features like mental illnesses. This stigma may even last the life time of the person concerned. In the case of some high profile diseases like HIV, which is relatively a new comer because it was first discovered only in the 1980s, the diagnostic tests available at majority of hospitals in the beginning was the ELISA which was considered to be prone to inaccuracies. Western Blot method or the PCR assays were considered to be the confirmatory test for HIV but was not readily available except in some centres. It was therefore no uncommon to see many patients misdiagnosed as afflicted with AIDS virus while in reality they were not. These days the effect of media reach is so quick and deep that AIDS became well known even amongst people living in villages far away from cities. So, people knew about AIDS and that it is sexually transmitted and that there was no cure. When someone was 'misdiagnosed' with AIDS it had devastating consequences on the helpless person because they were outcast from the community much like lepers were outcast in ancient times.

Diagnostic tests produce results. Sometimes they are numbers and sometimes they are images. Doctors are taught to interpret them correctly. Normal persons are expected to have values within a range to be considered normal. But, setting a normal range itself is fraught with danger because these normal ranges are by definition fulfilled only in 95% of the population. 95% of people will have their values within plus or minus 2 standard deviations of the mean value for the population. This is how the normal ranges are set. The remaining 5% will be outside the normal range quoted. In other words, 5% of the people who have diagnostic tests will be considered 'abnormal' if you go purely by the lab test numbers.

The trouble with normal ranges is that there is a lot of variation between ethnic populations, geographical locations, age, gender etc. so setting a 'single size fits all' approach fails. You have to define normal ranges for each of these sub-groups of the population which takes a lot of time to do. Often, this sort of data accumulates over time and for newly introduced tests they will be found to be lacking and make interpretation more difficult. Diagnostic labs are usually very busy and find such tasks as setting a local population-specific normal range practically impossible except for some of the most pressing parameters.

Normal range data and the problem of 'mislabelling' as 'normal' and abnormal' is more vexing in the case of some diagnostic tests like tumour markers for example. Tumour markers are some biochemical molecules that are present in the blood of patients with cancer. There are many of them available for use in cancer diagnosis but the problem is that almost all of them are increased in conditions other than cancer also. That means the elevation in the tumour marker levels in the blood is not specific to cancer only. Even non-cancerous conditions also can cause these elevations and it can mislead the doctor if he does not take this into consideration.

About a decade ago there was this story of a guy who had a test done for diagnosing liver cancer. It was a simple blood test for one of the tumour markers for liver cancer. It was not a biopsy test which would have been far more confirmatory. The test done was a simple biochemical test which is known to be associated with other non-specific causes for an elevation in the blood levels other than liver cancer. This guy did have an elevated level of this biochemical tumour marker and the doctors in the British National Health Service gave him a diagnostic verdict of cancer combining the weight of evidence of his clinical symptoms and the biochemical test. The patient was devastated. He came to terms with the reality and decided to prepare for the end. He sold his assets and perhaps started writing his will or whatever. He is presumed to have left his job as well. Then the story took a turn. Though he was doomed to be dying this seemed to be not happening. He decided to call his doctor to enquire he is still not dying. The doctor repeated the biochemical tumour marker test. The results came back completely unexpected. The level of the liver tumour marker had dramatically dropped in his blood!! It later transpired that he perhaps had an elevation in this tumour marker due to a non-specific, non-tumour cause. This patient had every reason to feel ultra-joyous that he is not going to be dead yet. But, strangely, he decided to sue the hospital. Is it for not being dead? The basis of his law suit was that he had suffered damages due to the 'wrong' diagnosis not bodily but financially! Poor doctors!!

That is why cancer markers are never to be used for primary diagnosis for presence or absence of cancers in the general population. They are to be used only for high-risk populations who have some symptoms that suggest presence of cancer. In the case of the above patient he did in fact have some signs and symptoms suggestive of liver cancer. Even better is the application of these tumour markers for monitoring the response to treatment of cancer patients. It is expected that, with treatment, the levels of the tumour markers in blood will fall and hence may provide a good indication of the response to treatment. In some cases the tumour markers may fall to normal levels with successful treatment and continued monitoring will help to pick up a rising level suggestive of recurrence of tumour.

The take home message is that diagnostic tests can be non-specific in that there will always be conditions other than the disease of interest where some sort of alterations can be seen even in absence of the disease in question. This non-specificity is the root cause of the false positive rate of a diagnostic test.

The problem with diagnostic tests is that there is also the variability in results with time of assessments (morning or evening), feeding status, physical activity, method of blood collection, method used for analysis (which varies with analytical machines) etc. This again introduces some uncertainties in the reliability and reproducibility of diagnostic test results. A lay patient can often be seen to be entering into arguments with a lab about how variable the results are from his previous result and also what another lab elsewhere gave him. They are quick to blame that your lab is making mistakes because the results are not reproducible. As a lab professional I deal with such patients too often for my comfort. It is so difficult to make them understand. The worst thing is that they automatically assume that the results produced by the private laboratories are likely to be wrong as opposed to the results from reputed academic hospitals.

The over-reliance of diagnostic tests for diagnosis is said to have taken the charm away from medicine. Medicine was considered an art. The practitioners of medicine used their skills, judgement and experience to get clues about the patient's condition. As medical students we were told that some medical conditions can be diagnosed by good doctors even as the patients walk into the clinic! Observation is the key here. You have to act like a detective who can get a lot of valuable information at the scene of the crime simply by careful observation. Some doctors can make a diagnosis of some medical conditions simply by observing the patient walking into the clinic. A simple physical examination of the body by the doctor can give a lot of diagnostic clue. Whether the patient is jaundiced, oedematous or anaemic, has any rashes or bleeding etc. are vital diagnostic evidences that can nail the culprit. Doctors used to rely on the exact description of the presenting complaint to derive the vital clues. Now the doctors have become so busy or over-reliant on the diagnostic tools that they have stopped being listeners. This is one of the major grievances for the modern patient.

# 7. INFORMATION FAILURE AS THE BASIS OF HUMAN DISEASE

Information is now believed to be a fundamental property of matter in the universe. It plays a primal role in the way systems work. Invariably, all our social transactions are based on some form of information transfer or other. It is presumable that any multi-unit system will depend on information exchange between the individual components that constitute it. Claude Shannon, in his seminal paper in 1948, defined information as 'a reduction in the uncertainty' and formulated a mathematical theory for communication. The reduction in the uncertainty refers to the gain in the information about an entity, brought about by reproducing at one point either exactly or approximately a message selected at another point.

Basically, a typical communication system, as described by Shannon, consists of a message source, a coder to encrypt the information, a channel for communication, and finally a decoder to receive the information. His information theory was developed to understand the transmission of electronic signals. But this theory now has had an impact on biology as well, particularly with reference to DNA, because of the obvious relationship between DNA and biological information.

There is a paucity of research looking at information transfer between and within cells through processes distal to the DNA. There has been virtually no effort to view the body, made up of tens of trillions of cells, as a 'cellular society' reliant on information exchange between cells to function as a whole. Presumably, unlike DNA and protein sequences lending themselves to study of the principles of encoding and information content, the 'communication channels' in intercellular exchange of information and the mechanisms of decoding are not amenable to mathematical studies. The 'communication channels' in organisms include obviously the nerves but abundant amount of information transfer occurs in biological systems through non-neural routes through the agency of information-rich molecules which are secreted by endocrine, paracrine and autocrine systems. Information can be 'packed' in biochemical molecules by a series of well-regulated steps. Messages coming from a source are encoded by certain types of cells and the encoded message is transmitted via the blood stream or the nerves. The decoders are usually receptor molecules stationed at the outer surface of the cell. The receiver cell responds to these molecular messages with an appropriate biological response.

I believe that huge multi cellular organisms are vulnerable to cellular disorder and humans are no exception. The human body is estimated to contain tens of trillions of cells, which perform tasks according to their structural and functional specialisation. They function as one whole because they are inter-linked by a communication network the complexity of which is mind-boggling and still not completely understood. Information transfer is central to the process of metabolic control and cells constantly exchange information with regards to fuel levels, blood pressure, nutrient concentrations, oxygen, minerals like sodium, potassium, calcium, phosphate, magnesium etc. and any deviation in the internal environment is attended by compensatory mechanisms that will restore the constancy. Invariably, these adaptive mechanisms require a chain of communication between effectors and target cells, often involving several cell types. Physical, biological or chemical insults can lead to difficulties in cellular communication which can be localised to a particular organ or to a limited number of cell types, or can be widespread affecting multiple or, where death is imminent, all cell types. The resultant phenomenon is disease. Death is the final state in the evolution of the disease where the coherent functioning of all cells is no longer feasible due to global information failure. When the adaptive mechanisms of homeostasis fail, due to failure of one or more cell types to either generate or respond to informational molecules, the outcome is a disorderly state that is not responsive to the internal nor the external environment of the body. I call this state as disease and the body as a system will manifest biochemical and clinical features that are diagnostic.

That is why I feel that the phenomenon of disease should be unique to only multi-cellular life forms, and not unicellular life. For that matter, even (natural) death should be a unique multi-cellular life property. Unicellular microbes endlessly divide into daughter cells in the presence of adequate nutrient supply and so do cancer cells, which behave autonomously much like unicellular life.

Every homeostatic process in the human body, as said above, is achieved by hormonal and/or neuro-endocrine mechanisms through release of specific informational molecules. The sources of this information are the regulatory cells like endocrine glands and neural control centres like hypothalamus. These information generating cells themselves depend on information coming in the form of internal feedback from target cells or external information from the sensory organs. It is a two-way communication.

An incredible amount of information capture (from the external world) and transmission (to neural processing centres and onto effecter cells) occurs in our body relating to acquisition of nutrients, identification of the enemy or predator (for self-protection), and a reproductive mate (for propagating the genes). Practically all our energy and cellular capabilities are directed towards physical work to fulfil these functions. To carry out these biological roles the cells need to communicate between them, in terms of exchange of information about the current body situation, and whether the internal environment has the optimum chemical composition to prepare the body for work towards fulfilment of these functions. Any disturbance in the communication networks of body cells would lead to a breakdown of the adaptive mechanisms resulting in biochemical/systemic manifestations as said above. These biochemical disturbances, such as low oxygen availability, or low sodium, potassium, calcium or phosphate concentrations, which arise due to defective cell communication between selected cell types, could have a further cascading effect leading to global effects on information transfer, which is the forerunner of death.

# 8. SHANNON MODEL OF INFORMATION THEORY AS APPLIED TO UNDERSTANDING OF HUMAN DISEASE

This chapter is deliberately written without holding back any medical terminology. I thought this is the only way I can make a focussed attempt to list all types of diseases as I want to classify them. I have shied away from the conventional classification of diseases and used my own scheme. Non-medical readers may find this tough going but for your benefit I have devoted the next chapter where I am trying to explain the concept in a toned down way.

Based on the concept of Shannon's model, it can be deduced that errors in information transmission within the human body can occur due to:

i. **Defects in information source -** Defects in generation of intrinsic electrical signals (as in cardiac arrhythmias) or faults in rhythmic signal generation as pulsatile release of hormones like ACTH, gonadotrophins (menstrual disorders) etc. and/or circadian rhythm disturbances would represent cellular dysfunction due to changes at the level of the source of information. Alteration in the information content of the DNA due to damage by physical, biological and chemical agents or due to errors in DNA replication or genetic inheritance is an obvious cause of disease.

ii. **Coding, transmission and channel errors** \- Errors in transmitting the information which in the biological context would mean a) errors in neuron-to-neuron transmissions, b) errors in neuro-muscular transmissions, c) inappropriate signalling due to generation of informational molecules by cancers (ectopic hormones, growth factors etc.), activation/deactivation of regulatory genes affecting the information flow (inactivation of tumour suppressor genes, inappropriate activation of growth factor/mitogenic factors by oncogenes etc. d) effects of various poisons (produced by snake, fish, insects etc.) that lead to blockade/inappropriate activation of a number of human physiological processes like axonal conduction affecting neural transmissions, mast cell activation leading to anaphylactoid reactions, cardiac rhythm disturbances, neuromuscular conduction resulting in paralysis etc. e) problems in generation of informational molecules like in endocrine deficiency states (inability to make hormones like cortisol and aldosterone due to adrenal disease, inability to make growth hormone due to pituitary disease, inability to make thyroxine in thyroid disease, inability to make sex hormones due to gonadal disease etc.), f) errors in encoding the information through gene transcription into messenger RNA g) translation of messenger RNA into protein sequences, h) post-translational modifications such as glycosylation, methylation, acetylation that generally add informational value to the molecules such as site-directed export of newly synthesised molecules (e.g. Mannose-6-phosphate tag on lysosome-targeted enzymes the deficiency of which results in I-cell disease), and helps in recognition of receptors and enzymes etc. Oligosaccharide chains of glycoproteins play a role in signal recognition in molecular interactions also therefore qualify as mechanisms of conducting the information and i) lack of cofactors such as vitamins, minerals that are needed for enzymes that block the intermediary metabolic pathways and therefore interfere with flow of metabolic information.

iii. **Decoding (receiver) errors** Defects in information capture and processing of information can result due to a) 'Cross-talk' due to very similar informational molecules interacting with signal transduction machinery of each other resulting in unwanted, unintended activation of events often leading to cellular dysfunction (e.g. autoimmune disease due to antibodies directed against microbial antigens targeting host cell antigens due to antigenic similarity, and infectious diseases due to microbial entry into host cells through receptor uptake/internalisation pathways meant for host molecules because of structural similarities b) disruptive strategies of microbes which interfere with signal de-coding by immune cells resulting in immune evasion c) defects in hormone receptors and/or associated signal transduction systems leading to improper signal capture when the respective hormone binds (e.g. insulin resistance, thyroid hormone resistance, testicular feminisation syndrome due to androgen receptor defect, nephrogenic diabetes insipidus due to antidiuretic hormone (ADH) receptor resistance etc.), d) neuronal information processing defects due to organic damage to parts of central nervous system or due to toxins or lack of energy or oxygen supply or lack of sodium or potassium affecting the electrical activity of the neurons.

Classification of Human disease-causing processes according to the model of a typical Shannon information system

In the few paragraphs below I have tried to classify all types of human diseases into three broad headings:

I. Diseases due to defects in information source

II. Diseases due to coding, transmission errors

III. Diseases due to decoding errors.

It is as simple as that. What I am saying is that all types of diverse diseases afflicting man are explainable within one single framework of information transmission and its problems. This type of reasoning and analysis has never been done before. What looks like an endless rant in the next few pages actually look simple when you view them in light of the above three classes of diseases which again can be confined into one single them - information failure.

Readers have to pardon me and bear with the next few pages of hard medical terminology. I have done little to even try and reduce the tone of the language so that expert readers will grasp my point. I have simplified the concepts for the lay reader and used mild language explaining the same thing in the next chapter.

I. Diseases due to alterations at the information source

A. Errors in rhythmic signal generation by excitatory cells

1. Heart

Specialised cardiac cells have the capacity for self-excitation because of their lesser intracellular negativity due to their leakiness to sodium (-55 mV compared to -90 mV for most other cell types in the heart and the rest of the body). The electrical signal intrinsically originates in the sino-atrial node and travels down the inter-nodal pathways to the atrio-ventricular node, which then proceeds down the purkinje fibres to excite the ventricular muscle cells to bring about the ventricular contraction. Errors can occur in transmission, such as slow or accelerated conduction of impulses or abnormal impulse generation by non-pacemaker cells, particularly when impulse generation in sino-atrial node is absent or delayed. Ischaemic injury to cardiac tissues can cause depolarisation of cells in affected regions leading to variations in conduction velocities and areas of conduction block resulting in what is referred to as cardiac arrhythmias. Atrial and ventricular muscle diseases due to cardiomyopathy, myocarditis, rheumatic heart disease, hypertrophy of heart due to hypertensive heart disease can also lead to cardiac arrhythmias due to non-pacemaker cells taking on the role of signal generation (another example of diverse aetiologies producing common clinical outcomes). Even electrical shock to the body can upset the intrinsic electrical activity of the heart.

2. Respiratory centre in the brain

Acute brain oedema due to concussion and brain damage can affect the electrical activity of the respiratory centre in the brain, represented by groups of neurons situated in the medulla oblongata and pons at the base of the brain. These neuronal groups repetitively excite each other and no nerve section or brainstem lesion can abolish this rhythmic excitation. This respiratory centre is modulated by afferent information sensed by chemoreceptor cells in carotid and aortic bodies (oxygen concentration) and carried by Vagus and glossopharyngeal nerves, as well as information sensed by the stretch receptors in bronchi and bronchioles carried by the Vagus nerve. Drugs such as opiates, sodium valproate and anaesthetics can cause respiratory depression by affecting the neuronal activity in the respiratory centre leading to depression of the central nervous system (coma) due to lack of oxygen.

B. Errors in DNA and failure of information flow

1. Due to chromosomal disorders

Sex chromosomes: Turner's (45X) and Klinefelter's syndromes (47 XXY)

Autosomal chromosomes: Edward's (Trisomy 18), Down's (Trisomy 21) and Patau's (Trisomy 13) syndromes

2. Due to monogenic defects

Storage diseases: Glycogen storage diseases, Sphingolipidoses (Neimann-Pick, Gauchers, Krabbe's and metachromatic leukodystrophy), Gangliosidoses (Tay-Sachs), Mucopolysaccharidoses (Hunter's, Hurler's, Maroteaux-Lamy, Morquio)

Connective tissue disorders: diseases due to collagen biosynthetic defects (Ehlers-Danlos syndrome, Osteogenesis imperfecta, Marfan's syndrome, Cutis laxa, Pseudoxanthoma elasticum)

Cellular transport disorders: X-linked, Hypophosphataemic rickets, Hartnup disease, Cystinuria, Nephrogenic diabetes insipidus, Familial hypercholesterolemia, and Intestinal disaccharidase deficiency.

Aminoacidopathies: Phenylketonuria, Homocystinuria, Cystinosis, Alkaptonuria, Alpha-1-antitrypsin deficiency, Cystic fibrosis, Neurofibromatosis.

3. Due to specific gene mutations

Haemoglobinopathies: Alpha-thalassemia, Sickle cell anaemia, various variant haemoglobins (e.g Hb Cranston).

Disorders due to triple nucleotide repeat mutations13,14(expansion of CAG sequence within a gene leading to a sequence of polyglutamine within the coded protein): seen in Huntington's chorea, Spinocerebellar ataxia, Friedreich's ataxia, Myotonic dystrophy, Spinobulbar muscular atrophy, Fragile X mental retardation, Macchado-Joseph disease, Dentato-rabro-pallidoluysian atrophy).

Other disorders due to specific gene mutations include:

**Increased risk of diseases due to specific gene mutations** a) osteoporosis due to mutations in the regulatory site of type 1 collagen gene, b) Fragile X syndrome due to mutations in the flanking region of FMR1 gene, c) type 1 diabetes mellitus due to mutations in the flanking region of insulin gene, d) type 2 diabetes mellitus due to mutations in the intronic-regulatory site of Calpain 10 gene, e) breast and ovarian cancer due to mutations in BRCA 1& 2 genes, f) hereditary non-polyposis colorectal cancer due to mutations in HNPCC gene, g) Maturity onset diabetes in the young due to mutations in MODY 1,2, and 3 genes, h) Parkinsons disease due to mutations in alpha-synuclein gene, i) thrombosis risk due to Factor V Leiden mutation, j) Colorectal cancer due to APC gene mutations, k) early-onset Alzheimer's disease due to mutations in presenilin 1,2 gene or beta-amyloid precursor protein gene, and l) late-onset Alzheimer's disease due to apolipoprotein E4 allelle, m) inactivation of tumour suppressor genes by methylation of Cytidine residues in promoter sequences resulting in human cancers, n) loss of G1 checkpoint control in cell cycle due to p53 gene mutation seen in nearly half of all human cancers, o) ras oncogene mutation seen in nearly 25% of all human cancers reducing dependence on external mitogenic signals, p) increased genetic instability (increased mutability) in human cancers due to faulty detection, repair of DNA damage due to inactivation of proteins such as p53 and faulty mechanisms to eliminate DNA damaged cells, q) Xeroderma pigmentosum due to an X-linked defect in DNA repair in response to UV damage (endonuclease) increasing the susceptibility to cancer, and r) origin of cancers due to DNA damage due to chemical carcinogens (like polycyclic hydrocarbons, aromatic amines, azo dyes, nitrosamines, alkylating agents etc), radiation damage, oncogenic viruses (RNA viruses like papova, Adenovirus, Herpes, Hepadna viruses and DNA viruses like Retroviruses).

4. Defects in nucleotide biosynthesis due to nutritional deficiencies

Folate and vitamin B12 deficiencies can affect nucleotide biosynthesis (these are critical cofactors in the nucleotide biosynthetic enzymes) and therefore affect cell multiplication due to reduced supply of raw materials for DNA synthesis and replication.

II. Diseases due to coding, transmission and channel errors

A. Diseases due to neural, neuromuscular channel defects

i. Neural transmission disorders: Nerve palsies, neuritis, disorders of myelination like multiple sclerosis affecting transmission of neural impulse, degenerative damage to spinal cord, poliomyelitis etc.

ii. Neuromuscular disorders: a) Poisoning with Strychnine (producing muscular spasms), nerve agents such as organophosphate poisoning (muscle fasciculations due to inhibition of acetylcholinesterase activity causing an prolonged increase in acetyl choline action at the neuromuscular junction), b) Botulism (neurotoxin released by Clostridium botulinum blocks release of acetyl choline by proteolytically cleaving synaptobrevin on the synaptic junction causing muscle paralysis), c) Clostridium tetani, causative agent of tetanus, produces a toxin called tetanospasmin which acts at the synaptic level blocking release of inhibitory neurotransmitter resulting in continuous effects of excitatory neurotransmitter, d) Myasthenia Gravis (auto-antibody to acetyl choline receptor blocks muscle contraction).

B. Diseases due to inappropriate signalling

i. **Stimulation/blockade of hormone action by auto-antibodies** a) Grave's disease due to thyroid stimulating hormone (TSH) receptor stimulatory antibodies mimicking the action of TSH normally secreted by pituitary gland, b) Hashimoto's disease due to thyroglobulin antibodies which cause problems in its utilization to make thyroid hormones and therefore resulting in thyroid under activity, c) Pernicious anaemia (auto-antibody to Intrinsic factor blocks its action in assisting vitamin B12 absorption).

ii. **Diseases due to excessive release of informational molecules like hormones** a) Acromegaly due to secretion of inappropriately high amounts of growth hormone by pituitary, b) Cushing's syndrome due to excessive secretion of adrenocorticotrophic hormone (ACTH) by pituitary, c) Primary hyperparathyroidism due to secretion of excessive parathormone by the parathyroid glands, d) phaeochromocytoma due to overproduction of catecholamines by adrenal medulla, e) multiple endocrine neoplasia Type 1 & 2 and f) other hormonal over-activity states.

iii. **Diseases due to reduced secretion of informational molecules like hormones** a) Panhypopituitarism due to reduced production of pituitary hormones, b) hypothyroidism due to thyroid destruction or biosynthetic defects, c) diabetes insipidus due to inadequate secretion of anti-diuretic hormone by hypothalamus, d) defective cortisol and aldosterone production by adrenal gland due to enzymatic defects as in congenital adrenal hyperplasia, e) diabetes mellitus (Type 1) due to insulin deficiency.

iv. **Diseases due to ectopic production of informational molecules by tumours inconsistent with the needs of the body** a) Hypercalcaemia of malignancy due to production of parathormone-related peptide by tumours, b) Syndrome of inappropriate ADH due to production of ADH by small cell lung cancer, lymphoma, pancreatic cancer etc. & c) Cushing's syndrome due to ectopic production of adrenocorticotrophic hormone (ACTH) by tumours.

v. **Inappropriate activation of second messengers** a) Cholera (Cholera toxin increases cyclic AMP and constitutively stimulates adenylate cyclase by ADP-ribosylating Gs protein of the adenylate cyclase complex resulting in defective fluid reabsorption in gut, b) human bladder cancer due to a single base change in v-ras oncogene coding for p21 protein which is related to a G protein with reduced GTPase activity resulting in chronic stimulation of adenylate cyclase and overproduction of cyclic AMP affecting a variety of cyclic AMP-dependent protein kinases, c) ras oncogene of murine sarcoma virus is a GTP-binding protein with GTPase activity affecting activity of adenylate cyclase, and d) gas gangrene, caused by Clostridium perfringens, is due to a toxin that has lecithinase activity which can hydrolyse phosphorylcholine on cell membrane resulting in lysis of cells.

vi. **Inappropriate secretion of growth factors** Angiogenic factors (vascular endothelial growth factor and basic fibroblast growth factor) secreted by diverse tumours which attract and stimulate endothelial cells to form new blood vessels, and other mechanisms like down regulation of anti-angiogenic proteins such as thrombospondin 1 resulting in overgrowth of blood vessels. Other known growth-inducing agents include fms oncogene of feline sarcoma virus which is a macrophage colony stimulating factor, sis oncogene of simian sarcoma virus which is a truncated B-chain of Platelet-derived growth factor and erb-B gene of avian erythroblastosis virus which is a truncated form of the receptor for epidermal growth factor.

vii. **Altered tyrosine kinase-mediated cell signalling** Approximately half of the 20 known oncogenes of retroviruses are protein kinases, mostly of the tyrosine kinase type which can affect glycolytic enzymes, phophatidylinositol pathway in transmembrane signalling, intracellular adhesion molecule called vinculin which will determine the metastatic properties of the cancers and amplification of receptor-associated tyrosine kinase HER2/neu is seen in a considerable proportion of breast cancers and a disturbance in signalling pathways is seen in the majority of human cancers.

viii. **Disordered mitogenic control by inappropriate cell signalling** Constitutive mitogenic activity due to oncogenes (ras oncogene encodes a mutant protein that releases a continuous stream of mitogenic signals into the cell), and simian virus 40 produces a viral oncoprotein such as large T antigen which allows pre-senescent cells to circumvent senescence by sequestering and inactivating pRB and p53 tumour suppressor genes.

ix. **Tumorigenesis by inactivation of tumour suppressor genes** Inactivation of tumour suppressor genes, frequently by methylation of cytidine residues, leads to loss of certain mechanisms of growth control (e.g RB1, a tumor suppressor gene associated with retinoblastoma determines entry of cells into G1 cell cycle stage).

x. **Diseases due to abnormal activation of genes due to chromosomal translocations** Burkitt's lymphoma, a tumour of B lymphocytes, results when there is a chromosomal translocation involving chromosomes 8 & 14 bringing the myc oncogene in chromosome 14 under the control of enhancer sequences for immunoglobulin genes, and chronic granulocytic leukaemia results when chromosomal translocation occurs between 9 & 22 chromosomes (Philadelphia chromosome).

C. Interference in transcription/translation of genetic information

i. Poisons: α-sarcin, a fugal toxin, cleaves large RNA subunit and Ricins from castor beans are N-glycosidases that can inactivate ribosomes by cleaving a single adenine from the large subunit RNA affecting translation.

ii. Microbial toxins: a) Diphtheria toxin inactivates elongation factor-2 by ADP-ribosylating it, preventing protein synthesis in several tissues such as throat, heart, and nerve and b) Dysentery, caused by Shigella dysenteriae, is due to the shiga toxin STX which is a N-glycosidase that can depurinate 28S and 60S ribosomal subunits halting protein synthesis44.

D. Defects in flow of information in metabolic pathways

i. **Inborn errors of metabolism due to enzyme defects (due to mutations) represent a block in flow of information down the metabolic pathways** Examples include: a) Phenylketonuria due to deficiency of the enzyme phenylalanine hydroxylase, b) congenital adrenal hyperplasia due to 21 or 17-hydroxylase enzyme deficiency, c) glycogen storage diseases due to glucose 6-phosphatase or glycogen debranching enzyme deficiency, d) galactosemia due to galactokinase or galactose-1-phosphate uridyl transferase deficiency etc. These diseases are the outcomes of a failure of cell type(s) to carry out tasks such as synthesis of molecules or generation of energy in response to signals coming from other cells thereby breaking the information chain that is key to homeostatic control.

ii. **Metabolic diseases due to enzyme defects as a result of nutritional lack of essential co-factors like vitamins and minerals** e.g. a) Pyridoxine (a cofactor for transaminases) and folic acid (vital in transfer of one-carbon moieties like methyl and methylene groups in cellular metabolism) deficiencies interfering with homocysteine metabolism causing homocystinuria, b) vitamin B12 deficiency causing methylmalonic aciduria because it is a co-factor for the methylmalonic CoA mutase enzyme, c) vitamin K deficiency affecting the coagulation cascade because it is vital for a carboxylase enzyme that carboxylates glutamate residues on prothrombin molecule which is necessary for its ability to chelate calcium, and d) vitamin A is important in post-translational glycosylation of proteins which have functional and structural roles in maintenance of mucosal cell integrity the absence of which causes nightblindness, xeropthalmia and squamous dysplasia of epithelial cell lining in respiratory and urogenital tracts. The roles of minerals like calcium, phosphate, magnesium have already been discussed. Other elements like iodine (important in thyroid hormone structure) and iron (indispensable co-factor in heme moiety of the heme-containing enzymes like haemoglobin, myoglobin, catalase, tryptophan pyrrolase etc.) also need to be mentioned.

III. Decoding (receiver errors)

i. **'Cross-talk' in signal transduction machinery leading to autoimmune diseases** a) antigenic cross reactivity between M protein of group A streptococci and antigens in specific human tissues such as muscle (myosin), and kidney resulting in rheumatic heart disease, and acute post-streptococcal glomerulonephritis respectively, b) spondyloarthropathies due to anti-Klebsiella pneumoinae and anti-Shigella flexneri antibodies binding to HLA-B27 on the surface of synovial lining cells because these organisms share an arthritogenic epitope with HLA-B27 and c) other autoimmune diseases like atrophic gastritis (parietal cell antibodies), juvenile diabetes (islet cell autoantibodies), chronic active hepatitis (autoantibodies to liver-specific proteins), ulcerative colitis (autoantibodies to colon antigens), idiopathic thrombocytopaenic purpura (platelet antigens), autoimmune hemolytic anaemia (red cell autoantibodies), and Goodpasture's syndrome (basement membrane autoantibodies) where the initiating culprit is less well understood.

a. **Infectious diseases due to microbial entry into host cells through receptor uptake/internalisation pathways meant for host molecules because of structural similarities:** Various organisms have virulence factors/attachment factors that potentiate host cell entry due to sharing of structural similarities which enable use of host cell signal recognition machinery to gain entry. E.g. a) Staphylococcus aureus, which is known to cause pyogenic skin infections, have receptors for binding host tissue fibronectin, laminin, collagen, fibrinogen, b) Mycobacterium leprae, the causative agent for leprosy, binds host cell fibronectin potentiating entry into Schwann cells and epithelial cells, c) Bordotella pertussis binds fibronectin through its surface protein called the filamentous agglutinin, d) Borrelia burgdorferi, which causes lyme disease, binds integrin α11bβ3 on human platelets, e) Leishmania mexicana, causative agent of leismaniasis, binds complement receptor CR3, a member of β2 integrin family in macrophages, e) Adenovirus 2 encodes 2 proteins, the _fiber_ protein and the _penton_ base protein, which attach to integrin receptors promoting internalisation, f) Entamoeba histolytica, which causes amoebiasis, has a galactose or N-acetyl-D-galactosamine-inhibitable lectin mediating attachment of trophozoites to colonic mucins, g) Mycobacteria, Leishmania, Candida, Pneumocystitis Carinni and specific strains of enterobacteriae contain mannose-rich components within the cell wall that bind to mannose receptors on macrophages, and h) Chlamydia bind to glycosaminoglycans on host cell surface to gain entry.

ii. **Evasion of host immune mechanisms by microbes by interfering with the host immune recognition and effector mechanisms** a) Lipopolysaccharide (LPS), a type of endotoxin produced by Gram positive bacteria like Salmonella, Shigella, E.Coli and Neisseria meningitides forms a confluent layer on the bacterial surface preventing the complement-mediated cell lysis, b) Neisseria gonorrhoea produces a shorter LPS with an extra sialic acid added by its own transialidase which can block complement activation, c) Strains of Streptococci group A bears a protein called M protein which binds the complement cascade control protein H of the host preventing its activation, d) Proteins A & G of Streptococci and S. aureus both bind IgG directly preventing IgG-mediated phagocytosis, e) Tryptomastigotes of Trypanosoma cruzei, which causes sleeping sickness, produces a factor which accelerates the decay of complement C3 convertases limiting complement activation, f) Schistosomula of Schistosoma mansoni, the causative agent of Schistosomiasis, shed the complement-activating surface glycocalyx coat during transformation from the cercarial stage and also acquire the complement regulatory molecule called the decay-accelerating factor from the vertebral host, g) E.histolytica has a multi-functional galactose-specific lectin that blocks complement-mediated killing of the organism because of its homology with the mammalian complement inhibitor CD59, h) Hemophilus influenzae, causative agent for pneumonia, secretes IgA protease-like protein, I) S.pneumoniae, Candida albicans, E.histolytica produce proteases that can degrade complement C3, j) group A Streptococci secrete a protease that cleaves complement chemotactic factor C5a, k) Sialic acid-galactose-glucosamine terminal trisaccharide of the group B Streptococcal polysaccharides is structurally similar to a number of oligosaccharides found on mammalian glycoproteins which make them non-immunogenic, and l) Plasmodium falciparum trophozoites bind thrombospondin and also members of Immunoglobulin superfamily (Intercellular adhesion molecule-1, Vascular cell adhesion molecule) and the Selectin family and to the differentiation antigen CD36 mediating attachment of the infected cell to vascular endothelium sequestering them from splenic clearance.

iii. **Hormone resistance syndromes due to receptor defects** a) Isolated Growth hormone deficiency due to Growth hormone mutation, b) nephrogenic diabetes insipidus due to antidiuretic hormone resistance at the renal tubular level, c) thyroid hormone resistance due to receptor defects, d) testicular feminization syndrome due to androgen receptor defect, e) leprechaunism due to insulin receptor defect, f) familial hypercholesterolemia due to low density lipoprotein receptor defect, g) type III hyperlipidemia due to defect in intermediate density lipoprotein particle clearance, h) Laron-type dwarfism due to absence of mutation of the growth hormone receptor and I) Reaven's syndrome or Syndrome X (metabolic syndrome) due to insulin resistance.

iv. **Neurological diseases due to disruption in neuronal information processing** a) Organic psychoses due to a) intra-cerebral pathology due to tumours, abscesses, haemorrhage, encephalitis, meningitis and infarction which has resulted in neuronal cell death, b) due to metabolic disturbances like hypoxia, hyponatremia, hypernatremia, renal failure, hepatic enchephalopathy, hypothyroidism (Myxoedema coma), mucopolysaccharidoses (Hunter's, Hurler's, Tay-sachs, Sandhoff's diseases) and mucolipidoses (Mannosidosis, Fucosidosis, Sialidosis), vitamin deficiency (thiamine deficiency causing Wernicke-Korsakoff psychosis), hypoglycemia, c) drug intoxication with hypnotics, anti-depressants, LSD, amphetamines, anti-convulsants, and fungicides like organic mercurials, d) poisoning with hallucinogenic agents like psilocybes mushrooms containing psilocin and psilocybin, cannabis and amanita muscaria poisoning (containing active principles ibotinic acid and muscimol), poisoning with volatile gases and liquids, and ethanol excess, and e) systemic infections like malaria, HIV and pneumonia. The common principles of neuronal cell dysfunction are lack of energy (due to inadequate oxygen, fuel levels) and/or alterations in electrolytes like sodium and potassium, which affect the electrical properties of the neurons. Drugs and poisons can interfere with neuronal interactions as well by altering the balance of excitatory and inhibitory neurotransmitters and metabolic diseases like mucolipidoses cause defects in neuronal information transfer because the mucolipids like sphingomyelin, and gangliosides are crucial in binding neurons together as well as insulating the neuronal axons and dendrites preventing straying of electrical signals.

At the risk of appearing to be belligerent I still want to challenge any medic who can spot any flaws or objections in my unified theory of human disease. I want to hear from them.

# 9. CELLULAR INFORMATION FAILURE AS THE BASIS OF HUMAN DISEASES

As I said this chapter is for the non-medics. I have avoided as much medical terminology as possible and tried to convey the ideas in a simplified manner. Some would find it still hard to digest but I hope that those readers may have to try a bit harder.

I believe that huge multi cellular organisms are vulnerable to cellular disorder and humans are no exception. The human body is estimated to contain tens of trillions of cells, which perform tasks according to their structural and functional specialisation. They function as one whole because they are inter-linked by a communication network the complexity of which is mind-boggling and still not completely understood. As said a while ago, information transfer is central to the process of metabolic control and cells constantly exchange information with regards to fuel levels, blood pressure, nutrient concentrations, oxygen, minerals like sodium, potassium, calcium, phosphate, magnesium etc. and any deviation in the internal environment is attended by compensatory mechanisms that will restore the constancy.

• • •

I have explored the concept of disease from a biological perspective viewing it as a failure to maintain the constancy of the internal environment of the body due to defects in intercellular communication. I have shown that diverse disease-causing mechanisms produce convergent effects on key biochemical processes to bring about global disruption in the communication capabilities of the cells. I have attempted to show that multi-cellular life systems like humans, consisting of trillions of cells, are vulnerable to cellular disorder as a result of this breakdown of information transfer resulting in an inability to function as a cohesive unit. In summary, I claim that the information failure is the basis of cellular disorder associated with all human diseases.

When the adaptive mechanisms of homeostasis fail, due to failure of one or more cell types to either generate or respond to informational molecules, the outcome is a disorderly state that is not responsive to the internal or the external environment of the body. I call this state as disease and the body as a system will manifest biochemical and clinical features that are diagnostic.

Invariably, these adaptive mechanisms require a chain of communication between effectors and target cells, often involving several cell types. Every homeostatic process in the human body, as said above, is achieved by hormonal and/or neuro-endocrine mechanisms through release of specific informational molecules by regulatory cells like endocrine glands and neural control centres like hypothalamus in response to feedback from target cells. It is a two-way communication.

An incredible amount of information capture (from the external world) and transmission (to neural processing centres and onto effector cells) occurs in our body relating to acquisition of nutrients, identification of the enemy or predator (for self-protection), and a reproductive mate (for propagating the genes). Practically all our energy and cellular capabilities are directed towards physical work to fulfil these functions. Physical, biological or chemical insults can lead to difficulties in cellular communication which can be localised to a particular organ or to a limited number of cell types, or can be widespread affecting multiple or, where death is imminent, all cell types. The resultant phenomenon is disease. Death is the final state in the evolution of the disease where the coherent functioning of all cells is no longer feasible due to global information failure.

The primary reason why maintenance of the constancy of the internal environment is so crucial to the property of life in multicellular life forms is the absolute necessity of a localised and unique internal milieu that is distinguishable from the vast and changing external environment to fulfil the definition of a life system. In a philosophical sense, it is necessary for differentiating between 'self' and 'non-self' and in a biological sense this is needed to create an ideal composition of the fluids with the right amounts of life-supporting elements creating a conducive environment for life processes.

The internal body fluids of a human being, as well as any other multi cellular life form, have optimum concentrations of sodium, potassium, calcium, magnesium, phosphate, hydrogen ions, oxygen, carbon di oxide, water, fuels, other nutrients like vitamins, trace elements etc. These compounds and minerals are available in the external environment but they are not present in a circumscribed space and, in addition, their concentrations fluctuate quite widely and, most of all, may not be readily available in useable form, which are unfavourable features for sustenance of life. Any deviation in the body's internal environment is attended by compensatory mechanisms that will restore the constancy.

A stage is reached where there is equilibration of contents of the internal and external environment of your body. We colloquially call this state as death. In other words, life is possible only as long as the distinction between the external and internal environment can be maintained at the expense of considerable energy. Failing this, the distinction disappears and the principles of chemical equilibrium set in, dissolving the barrier between you as a life system and the vast expanses of the rest of the world!

I feel that the phenomenon of disease should be unique to only multi-cellular life forms, and not unicellular life. For that matter, even (natural) death should be an unique multi-cellular life property. Unicellular microbes endlessly divide into daughter cells in the presence of adequate nutrient supply and so do cancer cells, which behave autonomously much like unicellular life.

Earlier I alluded to the point that the biological information exchange can come under the principle of Claude Shannon's Information theory. Based on the concept of Shannon's model, it can be deduced that errors in information transmission within the human body can occur due to _Defects in information source, Coding, transmission and channel errors and Decoding (Receiver) errors._ I have elaborated this with a brief explanation for each category and some examples to illustrate the point.

Defects in information source:

There are at least 3 fundamental sources of information in the human body, and perhaps all animals. They are namely DNA, the heart and the brain.

In the case of DNA it is pretty obvious and we have discussed this a few times in this book already. We will come back to the relation between defects in DNA information and the origin of human disease a bit later after we have discussed the heart and brain first.

The heart is an electrically operated motor. This motor continues to work non-stop from the time you were in your mother's womb to the time you settle down finally in your grave. If it stops you stop living. The primary driver is the intrinsic electrical stimulus generated within the heart itself. The sino-atrial node, a patch of specialised heart tissue, located within the atrium, is the supreme site where the heart impulses are repetitively generated about 72 times a minute. Without any external input the cells here automatically fire, spreading this electrical impulse down a pre-determined conduction pathway to reach every nook and corner of the heart.

Amazingly, if you isolate a single heart muscle cell (not the whole heart) it can be shown to beat repetitively. That is, it contracts repetitively which you can see under the microscope. For this the isolated cell should be in a salt solution. If you put a number of these isolated heart muscle cells together in solution then amazingly, all of them will start beating in unison! This is because the cells start communicating with each other through the 'gaps' in their cell membranes, exchanging cytoplasmic contents, primarily sodium, potassium and chloride. Why does it happen? Because these electrically charged ions move in and out of the cell altering the electrical charge of the cell's interior. As I said a while ago, this change in voltage gradient across cell membrane is a signal for ion channels to open or shut and therefore has the potential to conduct a signal. That is why the isolated cells also need the salt in the medium, which allows cells to use this salt to maintain or alter the electrical environment. It is almost like the isolated cells are running on a battery. Do you know that your batteries have such salt solutions with positive and negative charges!! It is the same principle. Incredible, isn't it?

In fact, even the whole heart beats non-stop when separated from the body if kept in the right solution. I have seen a frog's heart beat in saline even when it is isolated from the frog's body! Even the human heart can beat alone, separated from the body, if kept in the right medium. That is why heart transplant is possible.

Basically, what happens in the intact heart is the electrical impulse from the primordial signal generator, the sino-atrial node, depolarises the cell membrane. This means that the negative charge of the inside of the cells is decreased due to movement of the ions across the cell membrane, through voltage-gated ion channels we talked about a while ago. This triggers an action potential in the heart muscle cells resulting in a contraction. The sequence of events is so similar to ordinary muscle contractions in the rest of the body (i.e. skeletal muscle). In the case of contraction of skeletal muscles like hand or legs, the stimulus comes from the brain in the form of an electrical stimulus or a neurotransmitter like acetylcholine (which operate the ligand-gated ion channels). In the heart this stimulus comes from intrinsically generated electrical impulses within the heart. Defects in generation of intrinsic electrical signals in the heart can result in abnormal heart rhythms. This can happen in conditions where there is damage to heart muscle such as lack of blood supply (heart attack), inflammation, enlargement etc.

Let us look at the brain now. We all know that the brain stores your information in the form of memories. We still do not have a full understanding of how this is achieved by the brain. The brain processes all your day-to-day social information and I have referred to this and its relationship to possible diseases in the decoder category as well.

A specialised part of the brain called the respiratory centre in the brain, represented by groups of neurons situated in the medulla oblongata and pons at the base of the brain, repetitively fire due to their intrinsic nature. This is so similar to the ability of the heart to generate impulses intrinsically. They excite each other and no nerve section or brainstem lesion can abolish this rhythmic excitation. This respiratory centre is modulated by afferent information sensed by chemoreceptor cells in carotid and aortic bodies (which sense the oxygen concentration) and carried by Vagus and Glossopharyngeal nerves, as well as information sensed by the stretch receptors in bronchi and bronchioles carried by the Vagus nerve. Drugs such as opiates, sodium valproate and anaesthetics can cause respiratory depression by affecting the neuronal activity in the respiratory centre leading to depression of the central nervous system (coma) due to lack of oxygen. Acute brain oedema due to concussion and brain damage can also affect the electrical activity-generating capacity of the respiratory centre.

Then we move on to the more obvious DNA as the basis for derangement of cellular information. Alteration in the information content of the DNA due to damage by physical, biological and chemical agents, or due to errors in DNA replication or genetic inheritance, is an obvious cause of disease. It could be a chromosomal defect (e.g. Down's syndrome) a monogenic defect (e.g. Cystic Fibrosis) or due to specific mutations (e.g. Sickle cell anaemia). Or gene mutations can result in diseases like Phenylketonuria, Albinism etc.

Many types of cancers are now known to be a result of mutations in important control genes. The cells go out of control because these mutations destroy the information present in those genes. Often, it takes only a tiny change in the gene sequences to completely affect the information they encode.

It is now suspected that even susceptibility to chronic infectious diseases could be genetically determined. In other words, people get infected because they lack the capacity to fight these infections. This ability to stand against the microbes is determined by the genes, which code for antibodies and associated 'molecular weapons' such as interferons and complement. This immune capacity is determined even at the population level in the form of herd immunity.

In short, diseases due to defects in information source would be comparable to central server problems or database corruption.

Coding, transmission and channel errors:

This category refers to problems that can arise in the generation of encrypted information. What I mean here is the error (s) that can occur in the transmission of the information between communicating cells. As Shannon stressed in his theory, the capacity of a communication system to handle the information can be measured. He showed that a communication system has a certain 'bandwidth', signal power, and will have to deal with noise. As long as the rate of information transfer is within these limits of the ability of the communication system then information transfer can be done with little error. Though, as said earlier, Shannon applied this mathematical relationship to electrical signal transfer people have seen the relevance of the same principles to all modes of information transfer, including biology.

I can see that a defect in the nerve compromises its capacity to transmit the impulse, which is basically a channel error. A defect in a hormone production for example is a coding error in Shannon's terms. A defect in the hormone receptor is going to compromise the decoding of the biological message and if Shannon is right will impact on the ability of the body to respond to the biochemical signals. In terms of the effect of this reduced or defective information transmission it depends on the hormone system affected. As a doctor I can see it as a disease.

Even though DNA is indeed the source of all cellular information the actual cellular communication is not through the DNA form. Instead, the DNA information is converted into informational molecules like the hormones, growth factors and neurotransmitters etc. Equally important is the conduction of electrical signals from specialised cell types in your body like brain and heart to individual organs down the information cables like nerves and spinal cord. Nerve palsies and disease such as Poliomyelitis are clear examples where the nerves are malfunctioning. In the case of Polio the cause is the poliovirus, which damages the nerve ganglions in the spinal cord. In the case of nerve palsies there are a number of causes including viruses, metabolic conditions like diabetes, physical damage etc.

The other major problem arises due to errors in generation of coded messages like hormones. Due to various types of physical, biological or chemical insults hormone-secreting organs like pituitary, thyroid gland, adrenal glands, pancreas, parathyroid gland etc. can become affected. The result is failure to produce these hormones. As mentioned before the hormones are very important informational molecules controlling vital biological programs ranging from growth, reproduction, metabolism etc. For example, lack of thyroid hormone can lead to hypothyroidism which basically means under active thyroid, commonly referred to as Goitre. The opposite is also true. Overproduction of thyroid hormones is also not good. Problems in generation of informational molecules, like in endocrine deficiency states, such as inability to make hormones like cortisol and aldosterone due to adrenal disease, inability to make growth hormone due to pituitary disease, inability to make thyroxine in thyroid disease, inability to make sex hormones due to gonadal disease etc. can be huge medical problems sometimes needing life-long treatments.

Sometimes, such hormonal molecules can be produced at the wrong times by the wrong organs. The most common situation when this is likely to occur is cancer. Cancer cells, by virtue of their ability to de-differentiate and re-differentiate, acquire the unwanted capacity to make hormones and growth factors, which they are not supposed to produce. Because the source of these molecules is from an abnormal location it is often referred to as ectopic production. But, the problem is that wherever these molecules are produced from the effects are the same. Inappropriate signalling due to generation of informational molecules by cancers (ectopic hormones, growth factors etc.), activation/deactivation of regulatory genes affecting the information flow (inactivation of tumour suppressor genes, inappropriate activation of growth factor/mitogenic factors by oncogenes etc.) can lead to a variety of disease conditions.

Poisoning is a common medical problem which doctors face in their routine practice. Effects of various poisons and venoms produced by snake, fish, insects etc. can lead to blockade/inappropriate activation of a number of human physiological processes like axonal conduction affecting neural transmissions, mast cell activation leading to anaphylactoid reactions, cardiac rhythm disturbances, neuromuscular conduction resulting in paralysis etc.

Viruses in general have an ability to interfere with our protein synthesis function. This is because they hijack the ribosomal apparatus and the rest of the protein synthesis machinery and prevent our own messenger RNAs from getting translated into encrypted proteins. Even though the DNA itself is intact and even the transcription of genes are normal it is the next step in the information process that is affected. Depending on the organ infected by the viruses a variety of diseases can result.

_Decoding (receiver) errors_ :

Defects in information capture and processing of cellular information can result due to a number of reasons. The primary problem is that the receiver cell is not able to make sense of the message either because it was not received correctly or because it was not processed correctly. It is easy to see the effects of brain malfunction causing psychiatric or neurological problems. Neuronal information processing defects can be due to organic damage to parts of central nervous system or due to tumours, toxins, infections like meningitis, encephalitis etc. or lack of energy or oxygen supply or lack of sodium or potassium affecting the electrical activity of the neurons. I wonder whether death is the effect of inability to capture vital information or is the cause of it, if you know what I mean **.** Try to give it a thought. I always find it fascinating to think about it. Coma is the state in which an individual loses the ability to respond to information from the external world but not his internal world. They can still keep their blood pressure under control, have blood at a stable pH, keep breathing to keep their oxygen concentration etc. It is true that they may need help with medical assistance in the form of life support machines to do so. It is yet incredible that his or her 'cellular society' is largely intact as far as information exchange is concerned, within the internal world of his.

I said earlier that cells do a lot of decoding function. They receive a variety of cellular messages and these messages have to be properly deciphered. For example, a hormone message will need a specific receptor to decipher the message. If this receptor is defective, due to a gene mutation etc. then the cell will be unable to properly read the hormone signal. This is a typical example of what is called a hormone resistance state. The hormone gene is fine and so is the ability of the concerned cell to make the hormone but the receptor molecule is the culprit. A number of diseases result due to such errors. The defect is in the hormone receptor which fails to act as a decoder. The outcome is an improper signal capture when the respective hormone signal binds the receptor. Many diseases are known to result due to such hormonal decoding defects such as insulin resistance, thyroid hormone resistance, testicular feminisation syndrome due to androgen receptor defect, Nephrogenic Diabetes Insipidus due to anti-diuretic hormone (ADH) receptor resistance etc.

In the case of insulin resistance the hormone insulin is available in plenty but they are ineffective. So, the cells act as if there is no insulin signal is around. The problem is the decoding inability of insulin receptor. Because insulin is not acting effectively, though available in plenty, the outcome is similar to insulin deficiency we see in diabetes mellitus. In the case of testicular feminisation syndrome the male sex hormone receptor is not able to decode the signal associated with the androgen, the male sex hormone. So, the biological effect of masculinity goes missing. The patients tend to become 'feminized' due to unopposed action of the female sex hormones.

Defects in cellular decoding can also arise if there is a 'Cross-talk' due to very similar informational molecules interacting with signal transduction machinery of each other resulting in unwanted, unintended activation of events often leading to cellular dysfunction. This is like the cross talk between two telephone lines when you can hear the conversation between two people you have no business with. An example is the autoimmune disease that arises due to antibodies directed against microbial antigens go off target. The misguided, 'cross-talking' antibodies hit the host cell antigens due to antigenic similarity. Classic example of this cross-talk is the Rheumatic heart disease, which results due to similarity between one of the molecules on the surface of the bacterium Streptococcus and a protein on the heart muscle. The antibody made by the patient, targeting the staphylococcus bacteria, veer off course and hit the patient's own heart muscle cells. Due to this 'cross-fire' heart muscle cells die. The patient develops heart disease.

Other types of examples for cross-talk would be the origin of infectious diseases due to microbial entry into host cells through receptor uptake/internalisation pathways meant for host molecules. This again happens due to the confusion of structural similarities. An example is again Staphylococcus aureus, which is known to cause pyogenic skin infections. They have receptors for binding human tissue connective tissue proteins like fibronectin, laminin, collagen, fibrinogen. Why would bacteria have these receptors that can bind human connective tissue proteins? That is a philosophical question to ask. Regardless of the philosophy the outcome of this bizarre phenomenon is that these bacteria can bind the human connective tissue proteins. As a result entry of these harmful bacteria in to the connective tissue is allowed where they stay happily. Once inside these bacteria flourish and cause the infections. Because of the location of the infection these bacteria cause predominantly skin infections.

Another example would be the case of the bacteria that causes Leprosy, called Mycobacterium leprae, which binds host cell fibronectin potentiating entry into nerve cells and skin cells. As we know leprosy bacteria have the affinity for nerves and skin and that is why the manifestations of this disease are unsightly.

Disruptive strategies of microbes which interfere with signal de-coding by immune cells can lead to immune evasion by the microbes and the consequent infectious disease. What this means is that microbes can prevent proper information exchange between our cells which are actively involved with fighting the microbes. What would happen in such a case? The immune cells would not know where to hit the microbe. In a typical immune attack our body cells (lymphocytes and neutrophils) should be able to know about the nature of the enemy microbes so that they can initiate an attack that is powerful and suitable for the microbe in question. The attack could consist of development of antibodies or other 'molecular weapons' like interferons and interleukins. In order to make precise, custom-fit antibodies the immune cells should talk to each other and exchange the information about the identity of the microbe. One type of immune attack is called the complement-mediated cell death. A cascade of reactions is initiated by a variety of proteins called complement proteins by the immune process. The final outcome of this complement activation is formation of a hollow-core, tube-like molecular structure that gets inserted on the cell wall of the microbial culprit. As a consequence, the microbial cell wall gets leaky and all cellular contents leak out killing the microbe. This is amazing. I think this is no different from the way we kill by shooting bullets that put holes on your body! Complement system is an effective and powerful weapon in our immune armoury!

An example of microbial interference in immune cell information transfer is the case where Lipopolysaccharide (LPS), a type of endotoxin produced by Gram positive bacteria like Salmonella (causative agent for Typhoid), Shigella (which causes dysentery), E.Coli (causes diarrhoea) and Neisseria meningitides (causes Meningitis) forms a confluent layer on the bacterial surface preventing the complement-mediated cell lysis. The effect is that your immune attack on these bacteria is nullified. Neisseria gonorrhoea produces a shorter LPS with an extra sialic acid added by its own transialidase, which can block complement activation. The effect is the same as above. The final outcome is that these microbes go unchecked freely colonising human organs.

Death, due to disease or injury, invariably involves a breakdown of the information network in the brain eventually. It is the direct or indirect cause of the death itself. Was it the information failure that caused the death or the other way round is difficult to answer in many cases? I feel looking at disease as a failure of information gives a totally different dimension to medical sciences. Going by this medical analogy, I guess the end of humanity, if it ever comes, will be orchestrated by failure in our information networks. Doomsday soothsayers often talk fondly of the end of the world. There is never a dearth of books discussing such possibilities. I do not want to join this band of pseudo-scientists but my impression is some form of information failure will accompany the end of humanity without doubt.

# 10. DISORDER IN BIOSYSTEMIC INFORMATION

Information has the fundamental property of leading to a state of negative entropy i.e., reduction of disorder. When two systems communicate the reduction in uncertainty leads to more coherent function as a whole. With stupendous numbers of communicating entities within a system, be it a human society or a human body, the chances of disorderly function is much greater. I stressed the ways and means complex systems encode and transfer information in previous chapters and how Shannon's information theory can provide a framework for understanding biological information transfer too.

A cancer is a perfect example of disordered communication. Cancer involves uncontrolled multiplication of any type of cell. A cancer cell does not behave like a well-regulated, normal cell. For a start, normal cells are not expected to multiply uncontrollably. Cell numbers in all organs and tissues are tightly controlled by exquisite mechanisms. For example, when you have an injury, there is a localised cellular multiplication to replace the cells that were lost due to the injury. If the injury had caused a discontinuity in your skin, new cells are made just in enough numbers to reseal the skin. All this happens without you wishing it consciously. There are an incredible amount of fully automated mechanisms involved here with the help of immune cells and fibroblasts. Right from sensing the skin injury, recruitment of cells to the damaged site, turning on gene programs for controlled synthesis of cell repair proteins and growth factors, activation of cell multiplication programs strictly in the region of interest, there is so much happening just less than a millimetre under your skin! Fibroblasts, a type of cells present in a variety of tissues, play a central role in organising these cellular events associated with tissue repair. Fibroblast is, in every sense of the word, a master builder and engineer. It controls so much of tissue building and repair activities at the site of injury for you.

Coming back to the topic of controlled cell division, I said the cancer cells lose this ability to shut down the cell division process. Therefore, there is cell multiplication without regard to resources and need. There is an unfair utilisation of nutrients for unnecessary cell division at the cost of normal cells. It is really a case of cellular population expansion with a potential to cause famine for the rest of the cells. That is why cancer patients lose weight, one of the characteristic features that make us clinicians suspect cancer in somebody with no other obvious causes for the patient's complaints. I am not saying I will suspect cancer in every one of my patients if they had a history of loss of weight recently. But, certainly, cancer will be in the back of my mind if some elderly patient presents with a complaint that cannot be correlated to any common diseases.

One of the interesting features of a normal cell is its ability to stop multiplying if they reach the boundary of the neighbour cell. This is called the contact inhibition. Tissues or organs can be viewed as a sheet of cells, arranged in a continuous layer. They touch each other on the sides, like our houses are constructed in a row adjoining each other. We cannot squeeze in some new construction between our house and that of your neighbour. You cannot go on building all around the street as you like. If you did that you are behaving exactly as a cancer cell would do. Town planning by the city council is all about orderly construction of buildings in the community.

Cancer cells proliferate uncontrollably because they lose the ability to sense the signals from its external environment, i.e., other fellow cells in your body. Under normal circumstances, a normal cell would respond to molecular signals coming from other cells and behave 'responsibly'.

A cell is surrounded by a cell membrane, which can be viewed as a territorial boundary for it. Its only way of contact with the outside world is through points of contact on this cell membrane. There are specialised molecules called receptors located on the cell membrane whose only job is to sense the external signals coming from cells near and far. In many cells, there are tiny 'gates' on the side of the cell membrane called the gap junctions. Through these gates also they are able to 'talk' to neighbour cells. I cannot help using this word talk though it sounds very anthropoid. But exchange of signals between cells happens this way without doubt. This information helps the cell to respond to the circumstances prevailing in the body. The _Notch_ signalling pathway is uniquely operating in the cell-to-cell physical contact. The peculiarity of the physical cell-to-cell contact as a communication mechanism is that both the message molecules and their receiver molecules are situated on the respective cell surfaces. Unlike the many other different types of molecular messages the _Notch_ systems uses bound messages, which can be decoded by bound receiver molecules on the neighbouring cells. It is believed that the Notch communication system plays a vital role in organ development and differentiation. What differentiation pathway the cells are supposed to take is mediated perhaps by such a direct cell-to-cell communication.

The cancer cells have defective cell-surface receptors. This is usually because of defective signal molecules brought about by mutations in the genes coding for these signal receptor proteins. Information transfer is no longer possible because the system is faulty. Does your radio or T.V work when they develop a malfunction in their aerials?

The outcome of this signal capture failure is disorder in cellular metabolism because the cancer cells do not know when to do what. They do not know when to stop multiplying because their only source of external information is lost. That is why I said in the beginning that cancer represents disordered communication. Just sit back and think for a moment what you would do if you are cut off from your outside world. You are left with no TV, no Radio, etc.

What do you think will happen in our society if people stopped responding to regulatory social laws? What would happen if people behaved as they liked, looting others, invading the lives of other people, keep constructing buildings as they liked and such like? Perhaps it would turn into a primitive, barbaric society.

We should not forget the fact that human beings have lived that way before they reached this point of civilisation. We have learnt to lead orderly lives may be for the past few thousand years only. Still we do find acts of aggression and unfairness in a number of situations. But, by and large, they have become more and more uncommon. The world today expects order. If you look at the history of Second World War, it is surprising that Hitler had his way of absolute barbarism for quite a few years before the world could do anything about it. I wonder if the lack of proper communication tools delayed the public outcry against him or that there was corrupt information floating around.

In today's environment it is unlikely any government or political leader in the world can do anything against social order. When ethnic cleansing happened in some countries recently, there was swift mobilisation of public support and other nations intervened immediately. When Pakistan's government was overthrown by the military, there were sanctions against it from US and other countries. When Saddam Hussein invaded Kuwait, he met with instant resistance. I guess intelligence operations as well as common media coverage help us to access information more quickly now than ever before, enabling mass public and governmental pressures.

Cancer is a state of cellular disorder, similar to the kinds of social disorder I mentioned above. It starts locally but spreads quite quickly. Our body has surveillance mechanisms to detect cancer cells as they originate, just as our immune systems fight the microbes. These immune surveillance mechanisms detect cancer cells as 'non-self' and attack them. When the number of cancer cells is low, and especially when some one's immune system is strong, the chances of successfully killing off the cancer cells are much greater. In fact, this may be happening in a lot of people and they never develop cancer. But, even if a few cancer cells escape detection they can quickly outgrow your capacity to kill them. Some cancer cells do give the slip and beyond a point, anti-cancer strategies are powerless in our body. Then the cancer cells are turned loose as 'cellular barbarians'.

Pathologists are medical specialists who microscopically examine cancer tissues to confirm their cancerous nature. They know how a cancer would look like. A sample of tissue taken from the suspect site is spread out thin on a slide to allow microscopic examination. All human tissues have characteristic appearances under the microscope. A liver cell can be unmistakably identified because pathologists are trained to look for the features associated with a normal liver cell. A bone cell will look different from a liver cell. A muscle cell has its own features and so do all others. When a suspected cancer specimen is examined, the pathologists quickly note that a liver tumour cell does not look like a normal liver cell. It has tell-tale marks of cancer. They stand out from the normal architecture of normal liver cells. The same applies for all types of tissue cancers. I said a while ago that all types of cells in our body could give rise to cancers. Usually, it is just one type of cell that turns cancerous. It is rare to find more than one type of cancer in a single patient. Perhaps it shows how deadly cancers are.

Our body cells are quite sophisticated biochemical machines. They have a number of functions such as the ability to make vital molecules, driven by the information contained in the nucleus. They can make hormones, growth factors, transport proteins, antibody proteins and a host of others. As I said earlier, this capacity to do specialized tasks is acquired during the process of tissue differentiation. The cells are able to make information-rich molecules and also are able to respond to molecular signals from elsewhere, by synthesising and secreting the appropriate receptor molecules. These products, in turn, have biological roles to play. It is a web, really, of inter-connected functions and it can be broken if some cell failed to do its job. The cancer cells can break this web by failing to do the jobs expected of them.

Before the cells differentiate into specialised types, the cells are unsophisticated. In other words, they are yet to acquire the capacity to make specialised molecules. There is a reason to why cells are unsophisticated in the embryonic stages. All biological information resides in the nucleus. Access to this information is highly regulated. Sometimes, it is not physically possible to access it for certain periods. One such instance is early embryonic development, before organs are formed. During embryonic development, the main priority is in churning out more and more cells so that the foetus can grow in size and gain more cell numbers quickly. Until the foetus grows to a sufficient size, there is very limited tissue differentiation, if at all. There is a mechanistic reason for it.

Information in the DNA is present in a sequence of nucleotide bases. It is a chain of nucleotide bases, arranged in a unique sequence. DNA has two strands of nucleotides coupled to each other in a complementary manner. They stay this way during most of the times except when the cell is dividing (Replication) or when the genes are decoded into products (Transcription). When the cell is dividing, the DNA strands separate from each other to allow access to the enzyme that makes a copy of the DNA by allowing it to physically move over the strand, reading the sequence as it goes along. It is something like a bar code reader reading the coded information. The most important requirement for DNA replicating enzyme is physical access to the sequences, which is of course one of the most highly regulated processes in the known universe. Literally, hundreds of different molecules control this event.

Gene transcription is the decoding process by which the information contained in the DNA is used for making products. Replication of DNA is not like this. The purpose of replication is to make identical copies of DNA so that they can be distributed to the daughter cells without bothering about decoding the information. The trouble is the same kind of DNA strand separation is necessary for gene decoding as well as gene copying. That is where the issue of preferential access arises. Which one should get the priority? Is it the gene-copying or gene-decoding function?

For accessing gene sequences for the purpose of gene decoding, it is enough if there is a localised separation of the DNA strands, precisely at the point of location of genes. The entire stretch of DNA need not separate. However, the genes are so widely distributed and normally there are so many genes needed for most of the biological functions, it is often necessary to decode quite a few genes simultaneously. This means the DNA strand separation has to happen at multiple points.

The enzyme responsible for gene decoding has to physically scan the genes just as the replicating enzyme does. An actively multiplying cell could have DNA replicating enzymes occupying most, if not all, regions of the entire stretch of DNA. Cancer cells are so rapidly dividing that most of the times their replicating enzymes will be occupying the DNA strands. The gene decoding enzymes will be unable to log in simply because the sites are fully occupied by the copying enzymes. The copying enzyme and decoding enzyme may clash if they happen to be scanning the same DNA sequence. As expected, they will be interfering with each other's function. It is like two trains running on the same track.

Normal cells do not allow the process of replication of DNA to clash with the process of decoding. Most cells in our body have a very slow rate of multiplication. That means their replicating enzymes will not be obstructing the gene decoding enzymes. This is not the case with the growing embryo. The main priority of growing embryos is to expand the cellular population before they can be allowed to specialise. Don't you need at least a considerable number of people before we can think of dividing the labour? Can we do that when we have only a few persons? The growing foetus concentrates on dedicating DNA information mainly to copying. This means the process of tissue differentiation will have to wait. Because if the cells differentiated into specialised cells, they will need to make specialised products by decoding the DNA. In that case, there will be competition between decoding and copying enzymes for access to the DNA. I told you both these functions couldn't go hand in hand when the cells are rapidly dividing. Therefore, the cells in the growing embryo remain purposely undifferentiated and unsophisticated. They are, for all practical purposes, primitive. They lack specialised capacities. They cannot make the kinds of wonderful molecules they would 'learn' to make after tissue differentiation. This is unavoidable because of the physical problems in working on DNA for two different purposes at the same time.

The cancer cells revert to this unsophisticated state precisely for this reason. Their DNA is occupied by copying enzymes all the time allowing very little access for the decoding enzymes. They cannot make many of the special molecules they could make before they turned cancerous. This means they revert back to embryonic form of existence. This has been confirmed by the finding of some growth factors in cancer cells that normally you would find only in foetuses. They are called the proto-oncogenes. A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression.

As said earlier, our cells normally have these proto-oncogenes but their products actually have roles in normal cell growth, differentiation and proliferation. Importantly, they are operational at certain crucial time points in our life span and are cell-specific as well. If you start expressing these proto-oncogene products at unnecessary time points, and in unnecessary cells, the result is going to be unnecessary cell divisions in the wrong cells at the wrong time. It is like going back in time. It is as if somebody shrank you back to the embryo! Fortunately, this happens only inside the cells that turned cancerous!

When these proto-oncogenes get activated due to mutations or chromosomal translocations etc. the result is cancer. The reason is that the products of these proto-oncogenes typically are growth factors or mitogens (agents that cause increased mitosis), or protein Tyrosine kinases (that will constitutively turn on important cell cycle control proteins or could be proteins that have the ability to act as DNA transcription agents activating unnecessary genes). As one might expect cell division is exquisitely controlled by a number of checkpoints and agents. Progression of the cell through these checkpoints is regulated by an extensive array of molecular signals. The products of these proto-oncogenes help override these checkpoints by providing the stimulatory signals. That is why they are dangerous.

Sometimes, the proto-oncogenes in our cells can be unnecessarily activated due to some viruses, which integrate their DNA/RNA into our genome. As I said earlier, Retroviruses for example have the ability to join their RNA into our DNA. The site at which this integration happens is random. If the site of joining is nearer to the proto-oncogenes we have been talking about then the result it abnormal activation of these proto-oncogenes at locations and time points they are not expected.

Even more interestingly, some viruses have these proto-oncogenes present in their own DNA. Why would they have the proto-oncogenes? Aren't they human genes? Yes, they are human genes but the viruses may have acquired them during a previous integration event where they were able to copy the human proto-oncogene.

That is very interesting but dangerous for us humans because the next time these viruses infect human cells they can cause cancer. So, the DNA-integrating viruses can cause cancer by way of activating unnecessary genes or by providing actually a copy of the proto-oncogene! Because the viral proto-oncogene is going to be attached to the human DNA at random locations we are going to be in a situation where these proto-oncogenes are not going to be under the same level of regulatory control. This is the reason why I said in my other book 'The Myth of Information Technology' that executable code transfer is dangerous in multi cellular systems.

Cancer cells can also do DNA scavenging similar to the bacteria. Bacteria have the ability bacteria to 'scavenge' DNA released from dead bacteria. I said that, in principle, it is no different from DNA transfer that occurs during bacterial conjugation. How come the cancer cells are also able to achieve this? Is it because they almost behave as if they were single-celled organisms like the bacteria, resorting to executable DNA code transfer?

The circumstance in which this type of cancer cell DNA transfer occurs is interesting. Treatment for cancer can be said to fall under three types: surgery (to de-bulk the tumour), radiotherapy (to kill cancer cells by harmful radiation energy and finally chemotherapy (use of highly toxic drugs).

When you remove a tumour surgically the doctor is actually removing the tumour cells from the body environment. But, when the patient is getting chemotherapy what happens is that cancer cells die but the dead cells are left inside the body. The dead cancer cells would undergo some sort of degradation that any dead cell or tissue in our body will be subjected to. Naturally, the dead cancer cell's cell wall dissolves liberating the DNA into the body. As I said the cancer cells have active proto-oncogenes that are capable of turning a normal cell into a cancer cell. The proto-oncogenes released from dead cancer cells are thought to be picked up by living cells and the outcome is that the recipient cell turns cancerous too. It is argued that such a mechanism could actually be the reason why the survival rate after surgery for any tumour is better than achieved by drug treatment. Surgical removal throws the bulk of the tumour out of the body whereas the chemotherapy and radiation kill from within.

One of the properties of embryonic cells is their ability to differentiate into any of the numerous cell types by the process called tissue differentiation. They have this unique ability to use information in the DNA for a brief period in the course of foetal development. They are called the stem cells. They are called the stem cells probably because they are like the stem of the tree, ready to branch out into many types of tree products like leaves, fruits and flowers. A cancer cell, by reverting back to the embryonic form, regains the property of stem cells. They are now able to branch out into different cell types in a disorderly manner. This results in production of molecules not relevant to the cellular environment. There is disorder and confusion amongst the cells.

The other problem with reversal to the embryonic form is their tendency to move away from their location. Embryonic cells have this property normally. It helps them to move spatially and aggregate with other cells to form the organs. This process, called organogenesis, relies on the motile character of embryonic cells. These cells are able to move because they are not solidly anchored to their base. Anchoring to the base requires the presence of structural molecules on the cell surface to hold the cells pegged to a molecular attachment structure. The embryonic cells lack them with a purpose. Unfortunately, by reverting to the embryonic form, the cancer cells lack them too. The result is liberation of tumour cells in to the blood stream. They hitch hike a ride to faraway cellular and organ locations and get settled there. This is the basis of spread of cancer, medically called metastasis. This is the most dangerous part of cancer development. A patient whose cancer has metastasised has little time to live. There is a progressive disorder in organ function to the point of death.

I find this spreading property of cancer a bit like spread of terrorism and misguided principles into the society for their ability to infiltrate the orderly mechanisms of a community. Their disorderly influences are too well known in our society. That is why I said cancer cells are barbarians. They lack sophistication, do not behave in an orderly fashion and fail to communicate properly. When humans behave this way, we call them a primitive society. But, thousands of years of social rules and advances in communication methods have made us learn to bring coherence in our ways of life, which we call as civilisation. If somebody behaved as they like in the modern world we do not hesitate to call them barbarians. Inside our body, if our cells wanted to call some cell as a barbarian, the choice is simple. It is the cancer cell.

The concept of stem cells is also interesting from the point of view of recurrence of cancer even after treatment. Cancer treatment is expensive and often associated with marked side effects. There are only a few types of cancer that can be treated to satisfactory levels in the sense that patients live longer and are potentially 'cured'. Cancer specialists refer to this as remission of disease because they very well know that the cancer may resurface any day. Even surgical removal of a tumour does not guarantee complete cure, as it is likely that cancer cells may be left in tiny quantities at the site of surgery, which grows back. Or, the cancer may have spread to other tissues and organs and removal of the tumour at the primary site does not affect the already spread tumour cells. The reason why cancer recurs is the fact there are a certain number of stem cells that remain within the tumour population that are different from the common progenitor cells that are rapidly dividing away. These cancer stem cells are known to be resistant to conventional chemotherapy and radiotherapy!

We know that even normal body tissues have a supply of stem cells, particularly when the tissue is capable of regeneration. This is prominently seen in the case of blood cells. Blood cells are formed in the bone marrow and one could readily see stem cells there, along with mature differentiated cells. The cancer also is similar in the sense the cancerous growth is comprised of mature progenitor cells as well as the stem cells. The stem cells are dormant and can spring back to life when the number of mature cells is decreased as after surgical de-bulking or after chemical or radiation treatment. It is almost as if the cancer population is under some sort of dynamic equilibrium.

Another interesting aspect of the cancer cell population is that there is a lot of heterogeneity amongst the cells. The cells are by no means uniform. The billions of cells inside a tumour are diverse. Where does this diversity arise? The answer lies in the fact that cancer cells mutate quite rapidly. There could be as many of hundreds of new mutations inside a cancer cell, even up to 800 or so. These mutations happen in a number of genes covering a range of cell function from cell signalling, cell adhesion, cytoskeleton etc. These mutations offer small, possibly additive survival advantage to the cancer cell.

A scientific paper published in _Science_ journal reported on the genomic landscape of the cancer cells. The team of researchers had looked at 1000s of genes in breast and colon cancer cells with a view to identifying the mutations in them. The team found that, on average, had upwards 80 mutations in a typical cancer cell. These mutations seem to occur more frequently in some genes and less frequently in others. Many of the gene mutations were harmless but some of them promoted cancer initiation and progression. Very interestingly, the cancer cells are able to overcome the effects of cancer treatment by way of mutations in the genes targeted by the drugs.

These days cancer drugs are becoming highly targeted to specific receptors or second messenger signalling molecules. These drugs work as long as the targeted drugs bind to these targets. For example, there are cancer drugs that target the epidermal growth factor receptor because inhibition of this growth factor will prevent cancer cell growth. Many pharmaceutical companies have spent considerable resources developing drugs that attack the growth factor receptors as a means of cancer treatment. There is accumulating evidence that a selection of patients become unresponsive to this anti-receptor therapy because they develop mutations in their growth factor receptors and/or subsequent signalling pathways that enable the cancer cell to bypass the block in signalling brought about by the cancer drug!

# 11. PHARMACEUTICAL EXPLOITATION OF CELLULAR INFORMATION VINDICATES THE INFORMATION FAILURE THEORY OF DISEASE

We do not realise how much of our currently available medical therapy is information-based. The funny thing is that even doctors do not realise this. In fact, none of the medical textbooks implicitly mention this fact. When you start looking at medical therapy from the perspective of information it is really illuminating and really reinforces my conviction that diseases are the result of failures of cellular information. As a doctor I know that many of the existing therapies can be explained in terms of information. In addition to my own experience as a practicing doctor I have also seen more evidence for this argument coming from my current job, which is actually in pharmaceutical research and development. I work on a daily basis with scientists who are involved in the process of discovering new drugs for various diseases. It is incredible that the most predominant focus of their research seems to be cell signalling. It is the hope of the pharmaceutical industry that modulation and or interference of cell signalling are the key to finding better drugs for curing diseases of a diverse nature.

Though I will be using a number of other examples later in this chapter I feel that a simple example will help to substantiate the concept. Let us look at a diabetic patient. He is being treated with Insulin injection, on a daily basis, because his pancreas has failed to produce insulin. By doing this what the doctor is actually delivering is a piece of biological information that was missing in the patient. The piece of information that is delivered is the Insulin biochemical code, which is fundamentally important for our body to run critical metabolic programs.

Insulin receptors transmit the insulin signal once they become occupied with the insulin molecule. I referred to insulin-medicated intracellular signalling pathways and it is easily one of the most complex in cell biology.

Binding of insulin to its receptor activates a cascade of release of second messengers. There are at least 6-9 of them known.

These second messengers carry the information further down into the cell's interior. They alter the functional activity status of at least 50 types of cellular proteins in diverse tissues! Insulin, through its second messenger systems, is capable of affecting the activity status of at least 6 different enzymes, 9 genes, and at least 3 carrier proteins. The biological programs driven by Insulin are not running properly in the insulin-deficient diabetic patient and the doctor does what an information technologist would do. He has rectified the situation by providing the missing Insulin, which is a kind of molecular software. This artificially administered insulin triggers the insulin receptor and activates the cellular programs. Whether it was synthesised insulin or it was derived from animal sources does not matter. All work fine.

Medical therapies are aimed at restoring constancy of the internal environment when the intrinsic compensatory mechanisms have failed. Diseases are treated by doctors in a variety of ways depending on the nature of the disease. Though there are hundreds of diseases, the treatment principles are only a few and they are designed to artificially maintaining the homeostasis as much as possible when natural regulatory mechanisms have failed. In order to achieve this objective doctors try various means such as i. replacement of fluids/blood (in diseases that reduce fluid volume) and control of blood pressure (in hypertensive disease), ii. Provision of nutrients in diseases of the gastrointestinal tract and (glucose, amino acid, fatty acid, vitamins, minerals) which helps replenish precursor materials for generating the informational molecules, iii. Provision of oxygen to combust the energy fuels (in diseases of cardiovascular and respiratory systems), iv. surgical restoration of the anatomical relationships of individual organs to enable function, v. administration of informational molecules like hormone treatments such as insulin for diabetes, Thyroxine for hypothyroidism, cortisol for adrenal deficiency etc. and neurotransmitter administration (e.g. L-Dihydroxyphenylalanine, the precursor of dopamine, for Parkinson's disease) vi. Eliminating sources of infection with antibiotics that are targeted at critical microbial metabolic pathways, vii. use of agents like immunosuppressives in a range of diseases that result due to overactive immune system with the objective of reducing or preventing the exchange of information between immune cells, viii. use of therapeutic agents to precisely target overactive biochemical pathways (e.g. statins to inhibit key cholesterol biosynthetic step in patients with hypercholesterolemia, propylthiouracil to inhibit thyroxine biosynthesis in subjects with hyperythyroidism, use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients with hypertension etc.) ix. Cancer treatments aimed at killing the cancer cells to prevent information-garbling, x. correction of faulty genetic information through gene therapy, and xi. Restoration of rhythmic information generation in the heart as in treatment of cardiac arrhythmias.

Pharmaceutical industries collectively spend in excess of $50 billion a year towards R&D. Individual pharmaceutical companies spend on average 15% of their annual revenues on R&D. A company that earns $30 billion a year will easily spend $3-4 billions on R&D. There is a sustained effort to finding better drugs for treatment of various diseases. Pharmaceutical companies own patents on some drugs but the life span of patent rights run out in 20 years. From the time of obtaining the patent the companies spend about 8-12 years, and approximately $800 million, to collect scientific evidence needed for proving the safety and efficacy of their drug. This evidence is needed for obtaining a license to sell the drug. That leaves hardly 8 years or so for the company to recoup the money spent and make a profit. When the patent runs out then the drug can be made cheaply by anyone interested as it is not the intellectual property of the discovering company any more. This means that the profits take a steep drop for the company concerned. In order to prevent the fall in total revenues for the company there is a push to finding newer drugs (with of course new patents) that will bring in fresh revenues. This is the reason for the continuous search for new medical targets within the human body.

All big pharmaceutical companies are in this race and quite often the same medical target will be the focus of research at a number of companies, each spending millions in the hope that their drug will be better even though, in reality, the difference in safety or efficacy will be marginal in most cases. There is a lot of duplication of effort and resources in pharmaceutical research. This has been a criticism levelled against pharmaceutical companies because this drives up the cost of drug development and obviously the price for the payer.

Drug discovery and development in the pharmaceutical sector is a race, as I said earlier. Whichever company gets the drug out to the market first gets the bigger share of the market. The only exception would be when the first drug in to the market had safety problems in which case other drugs of the same class, often coming from other companies, would be selling more. It is also possible that unsafe drugs would be facing the prospect of withdrawal of their marketing licences, which would be a big blow for the company concerned. Companies are often well aware of the competitor drugs for the same disease treatment that are in different stages of discovery and development within other companies. It is not uncommon for companies to start their own research programs in a particular drug class even when they are aware that other companies have already had good head starts. This often happens even without sufficient evidence that there will be guaranteed improvement in the safety or efficacy profile with the new drugs. This kind of drugs are referred to as 'me too' drugs because they really are not novel. It has been said that pharmaceutical companies often focus their attention on diseases that are likely to have a big market. Diseases like diabetes, cancer, arthritis, high cholesterol etc. often chosen by companies because these diseases are seen more in developed countries with the paying potential. There are quite a few diseases for which there are no effective treatments but the companies often neglect them because the size of the market is small or because these diseases are seen in less developed countries who cannot afford to pay.

Novelty in pharmaceutical research is about identifying new targets. Targets refer to some disease-related molecules in the cell that need to be modified, inhibited or activated to cure the disease. Interestingly, the number of newly identified cellular targets per year has remained constant, between five and six, since the early 1980s. The remaining targets are actually repeat use of previously known ones. Taking advantage of the progress in genome sequencing and advances in computational methods, as well as techniques like proteomics and genomics, companies are of course making improved attempts at finding new targets.

A survey conducted in 1996 suggested that the total number of molecular targets for drug discovery was in the region of 500. This means that, in the opinion of the drug companies, these were the only molecules that were likely to provide medical benefit when targeted. A review titled 'The Druggable genome' published in Nature Reviews on Drug Discovery in 2002 suggested that the total estimate of potential targets in the human genome could be between 600- 1500. We use medicines not only to cure non-infectious diseases but also ones that are caused by microbes. So, naturally, we are interested in finding the targets on microbial genome that can be hit with medicines. If you add these microbial targets as well to the list of targets on human genome one could estimate the total number to around 1700-3000. In other words, potentially, there are up to 3000 molecules in known human and microbial genome that are in some way related to causation of disease and therefore worth pursuing for discovery of new medicines.

If you looked carefully at the types of targets it is very interesting to note that more than 50% of all molecular targets fall under 3 classes - G-protein coupled receptors, nuclear receptors, and Ion channels. As you can see these 3 classes of molecules play vital roles in cell signalling. It is no doubt astonishing that half of all new drugs aim to hit cellular information flow. Doesn't that tell us something? This is the reason behind my claim that the pharmaceutical companies strongly believe that cell signalling can be exploited for medical benefits.

Further analysis of the drug targets reveals that over 60% targets are located at the cell surface, which is an indication that they are all involved in some sort of cell-surface signal transduction. It has been claimed that there are probably more than 1000 GPCRs in the human genome. This could mean that pharmaceutical companies are not going to run out of targets in the near future! Presumably, GPCRs are also occurring in large numbers in other organisms as well. C. elegans, a nematode, has about 19,000 genes of which 5% are GPCRs!

A closer look at the medically interesting targets, from the perspective of the pharmaceutical companies, it becomes even more interesting to note that a large proportion of the remaining 50% targets (those that do not affect the receptors and ion channels directly) also affect cellular information indirectly. Take the case of drugs that directly attack DNA such as most of the cancer drugs. The main mechanism of action of cytotoxics (drugs that are toxic to cells) is by causing deliberate DNA damage in cancer cells so that the cancer cells will not be able to replicate. It is interesting that these drugs actually used information destruction principles. The cancer cells were deprived of their genetic information. Note that these drugs do not mediate their effect through any receptors or ion channels. Yet, they hit the source of cellular information at the very fundamental level.

Some of the newer cancer drugs still employ similar DNA damage principles. It could be by the use of analogues of DNA bases like Cytosine that actually get incorporated in DNA strands during a round of replication. Once incorporated into cancer cell DNA they prevent DNA replication, as these analogues of DNA bases do not allow the copying enzymes to work well. The consequence is that new cancer cells cannot form. Other types of DNA damaging cancer drugs use inhibitors of enzymes like Thymidylate Synthase that is required for synthesis for DNA bases. By doing it we are literally starving the cancer cells of raw materials for making DNA and therefore the cells are starved of the genetic information. Another very commonly used medicine for cancer is platinum. Platium-based cancer medicines damage DNA by intercalating between DNA strands, preventing proper separation of the strands during replication of cancer cells. These drugs are powerful and effective.

Looking at the biochemical classes of current pharmacological targets it is also worth mentioning that a very significant number of them are enzymes, mostly proteases, reverse transcriptases, kinases, polymerase, phosphatases, phosphodiesterases, ribonucleases etc. It is readily apparent that these enzyme classes play vital roles in biochemical signalling. These drugs were not included in the direct receptor or ion channel targets as their mechanism of action is distal to the activation of receptors or ion channels. For instance, the importance of phosphorylation/dephosphorylation in cell signalling was referred to numerous times in previous chapters and it is no wonder that kinases (phosphorylating enzymes) and phosphatases (dephosphorylation enzymes that enable phosphate removal) are scoring high on the list of medical targets. Polymerase is the enzyme that copies DNA and Ribonuclease is the enzyme that degrades RNA. Since they both play crucial roles in genetic information one can see how drugs targeting these enzymes could modulate/interfere with genetic information. Proteases and reverse transcriptases play a role in HIV replication and are therefore inhibitors of these two enzymes are very useful drugs in HIV treatment. Reverse transcriptase is the enzyme that allows integration of the HIV RNA, after conversion to DNA, into the human DNA. By preventing this step what we are achieving is an inhibition of viral DNA from copying and multiplying. Basically, HIV viruses are denied the ability to use their own information.

Receptors, as I said right from the beginning of this chapter, are the most frequent and obvious targets if you wanted to garble cell signalling. This is the age of targeted therapies where you hit the diseased cell with a precision-controlled drug. In other words, these modern targeted drugs act like guided missiles. They hit exactly where you want them to hit. It is not surprising that more often than not we want to hit information transfer mechanisms aimed at the cell-surface receptors. Cancer treatment in the past was very messy. Many of the agents were like crude bombs. You gave these highly toxic drugs to the cancer patients who would unfortunately face side effects that would sometimes drastically lower the quality of the short life that was left. In many cases the dying patient simply wants to be left alone. You would often see people lose hair, have serious falls in blood cell counts, get diarrhoea and malabsorption etc. This was because the old-fashioned cancer drugs attacked not only the cancer cells but also the normal cells, which were caught in cross fire.

Some of the newer cancer agents also work by other interesting ways. They can block information transfer between cells that occur through growth factors and their respective receptors. Growth factors are vital for growth of cells and rapidly dividing cancer cell need more of them. Various growth factors like epidermal growth factor, fibroblast growth factor, vascular endothelial growth factor, platelet-derived growth factor are critical informational molecules in cell growth. Pharmaceutical companies these days have devised inhibitors of the receptors for these growth factors and they seem to do very well in treatment of cancer. Several pharmaceutical companies are actively studying a number of cancer drugs that can inhibit more than one type of growth factor receptors. For example, some of the novel treatments for cancer target epidermal growth factor as well as other growth factors like vascular endothelial growth factor. The number of receptor types that be targeted can be sometimes as many as four. The thinking behind this strategy is to hit at as many signal transfer points as possible to maximise the effects of information garbling.

The growth factor receptors mediate their intracellular signalling using mostly tyrosine phosphorylation mechanism and therefore the drugs of this class are actually tyrosine kinase inhibitors. Herceptin is a classic example of such a Tyrosine kinase inhibitor that actually inhibits cellular information transfer happening through the Epidermal Growth Factor. Herceptin has transformed the way breast cancer is treated these days.

In addition to DNA damage and inhibition of Tyrosine kinase-based growth factor receptors there are other approaches as well that have been employed to kill the cancer cell. One such mechanism is to inhibit specific intracellular second messengers involved in signal transduction other than these tyrosine kinases. There are a few types of kinase inhibitors currently in use and also in development. Example would include inhibitors of Serine/Threonine Kinases such as Mitogen-activated protein kinase, Jun Kinase and Cyclin-dependent kinase. In many types of cancer these intracellular signalling pathways are deranged. They usually get activated at a rate that is higher than usually seen in the normal cells. Interestingly, in many instances, there is a constitutive (permanent) activation of these pathways due to mutations in the receptors or oversupply of relevant stimulatory growth factors that keep these intracellular signal transduction pathways always active.

Cyclin-dependent kinase is a mediator of cell cycle control and is activated by unique cell cycle control proteins called cyclins. A cyclical process, with rigid checkpoints, tightly controls normal cell division. The basic purpose of a cell cycle is to allow a cell to undergo controlled division to produce an offspring cell. This is needed in practically most types of cells in our body except perhaps in the case of nerve cells. Skin cells may need to multiply and form new cells if there is an injury to skin. Hair cells need to multiply to replace lost hair. Many cell types in our body have a finite life span and the dying ones need to be replaced. There are some cell types in our body that divide more often than others. Cancer is the condition where the cells have lost the regulatory control and so divide uncontrollably without regard to need and availability of resources to support the newly formed cells.

Cell cycle itself is comprised of distinct stages, which have to run one after another. The cell cannot move to the next stage before the previous one is completed. The book 'Molecular Biology of the cell' edited by Albert et al compares the cell cycle to the control system of automatic washing machine. A clock, or a timer, turns on each event at a specific time allowing a fixed amount of time for each event. The essential processes in the wash cycle occur in stages: it takes in water, mixes it with detergent, washes the clothes, rinses them, and spins them dry. There is mechanism to initiate events in the correct order and allow them to happen only once per cycle. Sensors detect completion of each step and can delay progression to next step if the previous step is not yet complete due to a malfunction. In our cells the cell cycle is also controlled by such sensors, which put a block on the progression of cell division if a fault is detected. These checkpoints make sure that cell is not undergoing runaway cell divisions. Cancer cells can overcome these checkpoints by making mutated versions of the checkpoint molecules that are no more susceptible to the regulatory action. Therefore, the cancer cells can undergo uncontrolled cell divisions. As one can imagine inhibitors of the Cyclin-mediated signalling are being currently evaluated for cancer treatment.

Our body has some interesting molecules whose role is to suppress tumour development. An example would be the BRCA1 gene that is known to be associated with breast cancer development. Women who inherit one mutant BRCA1 allele have a 60% probability of developing breast cancer by the age of 50. The other tumour suppressor gene known is the APC gene. Mutant APC gene is known to predispose to colon cancer. What do the tumour suppressor genes do? Their role is to prevent uncontrolled cell divisions. They slow down or inhibit the progression of cell through a specific stage of the cell cycle.

A protein called p53 can be termed the ultimate tumour suppressor in our cells. Inactivation of its tumour-suppressor activity is almost an universal step in the development of human cancers. Because it protects the cells from becoming cancerous the p53 protein has also been termed 'the guardian of the genome'. Pharmaceutical companies are trying desperately to exploit p53 as a medical target but no company has succeeded yet.

In some cancers it is well known that the tumour cells need the action of hormones to enable the growth and division of the cells. For example, the breast cancer cells need oestrogen hormone to survive and grow. This is the basis for using Oestrogen antagonists for treatment of breast cancer. A classic example would be Tamoxifen, which revolutionised the treatment of breast cancer. Prostate cancer requires male sex hormone (Testosterone) for its growth and that is why Testosterone antagonists are useful for treatment of prostate cancer. This is curiously different from providing hormones for treatment of some diseases like diabetes. Either way, the final result that is achieved touches upon the theme of biochemical signalling. It has to be pointed out here that women are treated with oestrogen supplements as part of the hormone replacement therapy because, with old age, the ovaries lose the ability to generate oestrogen code. This context is akin to replacement of Insulin in diabetics. The problem with HRT is that oestrogen can produce some unwanted effects that have been highly debated over the years like the risk of breast cancer etc.

Receptor inhibition, and the consequent arrest of intracellular signal transfer, is not limited to treatment of cancer. Pharmaceutical companies have adopted this approach for treatment of a number of disease types. The drugs you take for even common conditions like Hay fever and other allergies are actually interceptors of biological information. Antihistamines block the action of Histamine that gets released by mast cells (cells that play important roles in allergy). Histamine produces dilation of blood vessels and a number of other actions that promote allergy by acting through type 1 histamine receptor. Specifically, these histamine-blocking drugs block the histamine-mediated signalling through this type 1 receptor.

Interestingly, histamine also plays a role in acid secretion in your stomach assisting the digestive process. This effect is mediated by type 2 histamine receptors. Blockers of type 2 histamine receptors are big-time sellers belonging to the class of drugs called antacids. They are very useful for the treatment of peptic ulcer.

Receptor multiplicity is a common biological phenomenon. This is a way of accomplishing multiple cell responses with a single type of signal. From the medical perspective it becomes necessary to target individual receptor subtypes when you want to affect one of these multiple cell responses. I suppose the more important examples of receptor multiplicity, from medical point of view, are dopamine, adrenaline, serotonin (5-hydroxytryptamine) etc. 5-hydroxytryptamine (5-HT) receptors come in at least 14 forms, the highest for any informational molecule! Dopamine receptors occur in 5 types!

Adrenaline receptors are basically of two types - alpha and beta. Alpha and beta adrenaline receptors can occur in more than one form again - alpha 1 and 2, beta 1 and 2 etc. I had discussed adrenaline signal in more detail in an earlier chapter. I will now restrict my discussion to medical applications of these receptor subtypes. Alpha adrenaline receptors mediate constriction of blood vessels. In medical situations where the blood pressure is low, due to blood loss etc. it is helpful to purposely narrow the blood vessel lumen with drugs that can stimulate vasoconstriction. Vasoconstriction raises the blood pressure and enables better circulation of blood. If someone loses a lot of blood the blood vessels do not fill up fully. The heart is unable to keep enough blood in circulation and the blood pressure falls pretty low. What the doctors do, apart from infusion of blood or saline to expand the blood volume, is to use drugs like noradrenaline, which is an alpha 1 adrenaline receptor activator. This will lead to constriction of the blood vessels and an increase in blood pressure. Such drugs are also used in situations like septic shock when the blood pressure falls low due to blood vessels dilating. This is due to release of a number of molecules involved in the immune process. In this disease setting, potentially life threatening, the problem is not loss of blood but a fall in blood pressure due to dilated blood vessels.

As one can imagine, alpha adrenaline receptors become the target if you want to lower the blood pressure as well. But, in this instance, the drugs to lower blood pressure will be inhibitors of the alpha-receptor and not activators. By inhibiting the receptor the vessels are prevented from constricting. Instead, they become dilated thereby reducing the pressure inside the blood vessels.

Beta 2 adrenaline receptor mediates the effect of dilation of the bronchi in your lungs in response to signals coming in the form of adrenaline. This allows us to breathe heavily to meet emergencies. This pharmacological effect is exploited by use of stimulators of beta 2 adrenaline receptor like salbutamol for treatment of asthma. Blockers of beta 1adrenaline receptors come handy when you want to reduce the heart rate in order to lower the effort the heart needs to make towards contraction. Heart muscle contraction is an energy requiring activity and also requires a lot of blood flow through the heart muscle. In situations like heart attack the heart muscle undergoes ischemic damage and struggles to beat with sufficient force. Beta adrenaline receptor blockers come handy by enabling a lowering of the rate of the heart beats and therefore save the heart muscle from over activity. That is why drugs like beta-blockers are widely used for treatment of patients who have suffered a heart attack. They are also used for treatment of people with high blood pressure for the same reason. In fact, they are also used to treat symptoms of anxiety. Anxiety leads to rapid fluttering of the heart and beta-lockers are useful to control this. It is also known that some people use beta-blockers to control symptoms of stage fright. When they have to make a public speech they take beta-blockers before hand to help them to control their rapid heartbeats!

In the case of 5 HT receptors it is curious to note that each type of receptors mediate different effect. Pharmaceutical companies who have discovered specific blockers or activators of sub types of 5HT receptors exploit this. Antipsychotic drugs like Clozapine, used in treatment of Schizophrenia, are a more selective antagonist of 5-HT2A, 5-HT2D and 5-HT6 receptors. Interestingly, these types of newer antipsychotic agents also target dopamine receptors (especially D2 and D4 types). As you can see the drugs have a broad specificity towards different signalling systems in the brain by affecting more than one neurotransmitter signal.

Even more interestingly, 5-HT3 receptors mediate completely different biological process, namely mediation of vomiting response. Antagonists of this 5-HT receptor subtype have been developed by pharmaceutical companies to control severe vomiting seen in seriously ill patients. Particularly cancer patients on treatment with highly toxic cancer drugs have serious vomiting and 5-HT blockers are useful in this setting.

Selective 5-HT1A/1B receptor antagonists are powerful medicines for treatment of a completely different disease \- migraine! Stimulation of 5-HT4 with drugs like Mosapride helps in the treatment of constipation-predominant irritable bowel syndrome! One signal, many receptors, many diseases and multiple drugs!

Another classical example of targeted attack on biochemical signalling is the case of a very successful class of blood pressure lowering medications. Under normal physiological conditions the renin-angiotensin biochemical axis controls our blood pressure to a large extent. To illustrate the complexity of such adaptive responses one could look at what would happen, for example, when there is a fall in salt concentration in the extra cellular fluid.

A fall in salt concentration in the blood will cause a fall in the extra cellular volume, which includes the intra vascular blood volume, which will affect the circulatory system in terms of efficient transport of nutrients and oxygen. To prevent this from happening adaptive responses kick in with an overall objective of bringing the vascular and extra cellular volume back to the original level. Afferent signals captured by arterial baroreceptor cells, atrial stretch receptors, intra-renal baroreceptor cells and intra-thoracic volume receptors trigger the release of renin by the juxtaglomerular cells of the nephrons. Renin is an enzyme that can act on hormonally inactive angiotensinogen released by the liver to produce angiotensin I, which is a deca-peptide originally present at the N-terminal end of the angiotensinogen molecule. Further steps are required to generate information out of this molecule which involves removal of two amino acids from the C-terminal end of angiotensin I, cleaved by the angiotensin-converting enzyme, produced by a variety of cells such as vascular endothelium, lung, liver, adrenal cortex, kidney, and neurohypophysis to synthesise angiotensin II which is information-rich.

Angiotensin II can bind specific receptors on target cells and stimulate the rate-limiting steps of aldosterone synthesis by the adrenal cortical cells to release aldosterone, which is another information-rich molecule. Aldosterone (a hormone) will carry a message to the renal proximal tubular cells, decoded by the aldosterone receptors on these target cells, to conserve salt. Angiotensin II also has other secondary actions on other cells like myocardium (enhanced myocardial contraction), vascular smooth muscle cells (vasoconstriction), intestinal cells (salt and water reabsorption) and neural centres in hypothalamus (thirst and salt appetite) and, as one can see, these actions lead to a common goal of expansion of blood volume and an efficient circulation.

Inhibitors of angiotensin converting enzyme are very successful blood pressure lowering medications widely used in clinical practice. This class of drugs are particularly preferred in treatment of high blood pressure seen in diabetic patients. New generation drugs targeting this biochemical axis include inhibitors of renin as well as inhibitors of angiotensin receptors. Even aldosterone antagonists are useful blood pressure lowering medications in a particular class of patients where there is overproduction of aldosterone in adrenal glands. I guess rennin-angiotensin axis not only highlights the importance of finding suitable targets for achieving medical benefits but also illustrates the complexity of cell signalling itself.

Anaesthetic drugs act by preventing nerve impulses in sensory nerves thereby interfering with conduction of information about the pain. Local anaesthetics, which doctors use for minor surgical procedures like dental extraction etc. act by affecting the sodium-gated ion channels in the nerve endings. By doing so these agents interfere with generation of nerve impulses. You can also block major nerve roots, both sensory and motor conduction, by using certain anaesthetics that can be injected around the nerve plexus or peripheral nerve to be blocked. For example, epidural anaesthesia given during childbirth is one such regional anaesthetisation achieved by injecting anaesthetics into the lower back in the extradural space where it acts on the nerve roots.

General anaesthetics act on the brain, particularly on the reticular activating system. By acting on the GABA and glycine receptors (both inhibitory by nature) the general anaesthetics open up the chloride channels that will make it difficult for generation of nerve impulses in the reticular activating system neurons. As I said earlier, RAS consists of diffuse sensory nerve conduction fibres that relay vital sensory information to the brain. These relay fibres are offshoots from main sensory information conduction tracts coming from the spinal cord when they join the base of the brain. The purpose of this RAS is to keep a person conscious. When the input into RAS is abolished the brain loses the consciousness, which works fine for the surgeons. Sleep is a physiological state where RAS conduction is minimised. Coma is the extreme state where RAS conduction is long lasting and potentially irreversible.

Surgeons also want the muscles to be relaxed when they perform the operations. The anaesthetist helps here by using muscle relaxant drugs along with the anaesthetic agents. The muscle relaxants are also useful when patients are put on electroconvulsive therapy (shock treatment) when excessive muscular contraction can occur. These muscle relaxants work by typically blocking acetylcholine-mediated nerve impulse conduction to the muscles. Acetylcholine is the chemical message sent via the nerves to the muscles to initiate contraction. Neuromuscular blocking agents compete with acetylcholine at the signal transfer point. Naturally occurring substances like toxins and venoms (e.g. botulinum toxin) can prevent the release of acetylcholine at the nerve endings. Drugs that act on the signal interface between nerve and the muscle can be completely paralysing to the extent even the muscles needed for breathing can be paralysed. This means that such patients need mechanical ventilation. The muscle relaxing agents work exactly like Curare, a naturally occurring poison. South American natives use the extract of a tree bark, from which curare can be obtained, to coat their arrows used for hunting. The natives are signal hackers.

Depression is a common psychiatric condition. It is said that in depression there is a deficiency of the neurotransmitters noradrenaline and serotonin in the brain. The antidepressant medications prescribed by doctors rectify the situation by one of the 2 mechanisms: prevention of reuptake of these neurotransmitters at synapses (thereby prolonging the action of these neurotransmitters), or by inhibiting the enzyme (Monamine oxidase) that degrades these neurotransmitters (again with the same effect of prolonged, sustained action of noradrenaline and serotonin). The best-selling antidepressant drug Prozac works by reuptake inhibition mechanism.

GABA is the most important inhibitory neurotransmitter in the brain. Just as stimulatory inputs are important it is even more important to bring some balance in neural signalling by having some form of inhibitory control. GABA and glycine are well known inhibitory neurotransmitters whose job it is to silence nerve cells from firing away. Glutamate is a typical excitatory neurotransmitter. GABA-producing nerve cells are situated all over the brain and spinal cord but not outside these two structures. Interestingly, level of GABA stimulation or inhibition determines much of our brain's mental status and other higher neuronal functions. In the presence of more GABA activity (and therefore more inhibitory output in the brain) there is sedation, amnesia, muscle relaxation, lack of balance and coordination. Nervousness and anxiety are also reduced when GABA's inhibitory output increases which means that these emotions are mediated by stimulatory brain activity. GABA helps to control the feelings of anxiety and that is why pharmaceutical companies have targeted GABA receptor for developing drugs that can control anxiety.

Epilepsy is characterised by excessive neuronal discharges in the brain due to over excitability of the brain neurons. This can be due to localised or generalised hyper excitation of the brain. Medical treatment of epilepsy is aimed at calming the brain electrical activity. Drugs used for treatment of seizures are capable of stimulating GABA release in the brain. As GABA is primarily an inhibitory neurotransmitter this helps to lower brain neuronal discharges that fire signals to muscles indiscreetly. The effect is reduced muscular contraction and relief from the intense muscular contraction seen in many different types of seizures. Some of the drugs used for epilepsy also lower the stimulatory neurotransmitters like Glutamate. Some drugs like Vigabatrin and Valproate act by inhibiting the enzyme that degrades GABA prolonging the action of GABA at the GABA receptors. Drugs like Gabapentin are actually analogues of GABA itself so that they mimic GABA at the GABA receptor and bring about the same signal across the receptor.

As one can imagine many drugs used for neurological and psychiatric diseases are modulators/inhibitors/activators of neurotransmitter receptors. This is hardly surprising. Nerve-nerve communication and nerve-muscle communication are central to the function of the brain and the nervous system in our body.

So far we have been looking at cellular targets present in our own body that are medically manipulated to bring about a cure. We should not forget the fact that many of our diseases are brought on by microbes that infect our body. Such diseases caused by microbes are usually short-lived and in many cases self-limiting too. This is true of many viral diseases such as common cold etc. Bur, there are very serious infections that can be caused by many viruses like Ebola, AIDS, Marburg etc. In such serious forms of viral infection death can often result. Bacterial infections are normally treated with antibiotics and there are quite a variety of antibiotics available in the doctor's armamentarium. With regards to the viruses it is a sad truth that we do not have many effective treatments. The point I want to bring up here is the fact the microbial diseases are treated by drugs that attack the microbes. Ideally these drugs should leave the human cells alone. So, the molecular targets of drugs for infectious diseases are selectively targeted to the virus or bacteria.

Drugs that act against the bacteria work by 3 broad mechanisms: inhibition of bacterial cell wall synthesis, inhibition of bacterial protein synthesis and inhibition of bacterial DNA synthesis. Commonly used antibiotics like Gentamycin, Tetracycline, Neomycin, Erythromycin etc. are information-hacking weapons really. They act by binding to bacterial ribosomes such that the bacterial protein synthesis is affected. Protein synthesis is the process whereby the nuclear code for the protein sequence is used for attaching individual amino acids in the right order. The binding of antibiotic to the ribosome interferes with this step and incorrect amino acids are attached. The protein that is formed is faulty and is unable to execute the required functions. The bacteria die. It is clear that the mode of action of the antibiotics is information-oriented. They prevent the ability of the bacteria to use their own genetic information to make executable molecular codes (namely proteins).

Antibiotics like Ciprofloxacin work differently. They inhibit bacterial (not human) Gyrase enzyme that is used by them for supercoiling the DNA. This supercoiling is needed to compact the DNA and without this the bacteria will not be able to undergo timely cell divisions. Bacterial multiplication is therefore avoided and helps us to curtail the growth and multiplication of the harmful microbes.

The antibiotic Co-trimoxazole inhibits an enzyme called Dihydrofolate synthase essential for making DNA bases, an effect similar to some of the anticancer drugs. The end result is the same.

The most curious point we should not miss when we talk about antimicrobial drugs is the fact that many of them are derived from natural sources. We humans do not own the 'patent rights'. These drugs have been produced in the natural setting by competing life forms that use them as toxins to ward off competition in the ecological niche. For example, a common source of antibacterial agents is the fungus. The fungi produce antibiotic substances for the same reason we produce antibodies and cytokines within our immune system. For the purpose of discussion of the topic in hand it is more than interesting to note that bacterial warfare is also information-based!

I want to sum up finally - information is the very basis of survival in the animal kingdom. Without information transfer life systems cannot exist. Curiously, we find that the motifs used for information handling by biological systems are so much like our own information technology and in many cases superior. The detailed description of all types of medicines used in the modern times clearly point to one single striking fact: they all act by interfering with information transfer of some sort. There is no exception. Those who had the courage to read the entire chapter will agree with me.

Educated readers, including doctors, may have felt compelled to argue with me. How can someone make a sweeping statement such as 'information failure is the basis of all diseases'? Believe me no medical student has been taught about diseases this way. None of the medical texts used in any part of the globe has this conclusion.

For those who fully read and understood what I have said from the beginning to the end of the book will surely start backing me on my novel theory of human diseases.

