Cell talk, mischief and cancer: What has the boson got to do?

Introduction

When you are in the twilight years of your life there is so much to reflect and you also realize that so much more needs to be said and done. The oft repeated statement, ‘if I had been younger,’ keeps ringing in your ears with predictable regularity! But then you console yourself and say that there is this element of wisdom that allows you to ponder over yet to be discovered concepts and phenomena. It is at this stage of your life when you discuss the meaning of existence and confuse yourself with theology, mathematical physics and what is the origin of man.

Nearly four  decades have gone by since entering the field of Medicine and I see how the practice has changed influenced by technological advances and fragmented by  organ specific therapy and applied therapeutics based of ‘search and kill’ philosophy. Within these two weeks two of my doctor friends died of cancer and both did not discover its existence dying within a few months of diagnosis. I spent nearly 12 years treating cancer in women and went through the rudiments of diagnosis, breaking bad news, operating on many and using a combination of radiation and chemotherapy. A few lived for many years but I saw several who fell by the side, crippled and maimed by the disease. Depression and melancholy was not only experienced by the victims and family but they affected me equally.

Now I re-look at the advances in the understanding of cancer and wonder, have we understood the disease and its origin? I become more sceptical as I view current treatment with some degree of despair.

The scorn of cancer

The patient who had premalignant disease had a good lease of life. Those who had early disease had good prognosis but those with had advanced disease did not thrive for long and it pains me to see how futile attempts are made by earnest oncologist with little respect for dignity and quality of life. This reminds us of medical ethics and the right to make decisions on terminating life! Why does cancer develop in the first place?  When a disease invades to a limited extent would we call that cancer? Endometriosis can be very aggressive in penetrating the adjacent organs but we call it benign disease. Conventional teaching in pathology has categorized cancers based on the organs that are inflicted with the disease. We also have seen that some forms of cancer do not spread so quickly as others. If we take cancer of the uterus, they tend to penetrate the inner layers much more slowly than the cancers of the lungs. Cancers of the ovaries and lungs in fact are at an advanced stage when they are detected. Why is this so? Medical teaching outlines how cancers would spread directly into the neighbouring areas before permeating to the lymph nodes and blood vessels when they become more widespread.

We have been experimenting with various forms of therapy like regional removal of the tumor leaving a wide margin to more radical surgery where the entire tumor is removed  extending the surgery to removing the lymph nodes and other affected organs. If all fails or surgery is not possible then cancer drugs and radiation are employed. Having said that we continue to contemplate if the treatment given is the most appropriate because unlike exterminating infections with antibiotics, killing cancer cells has been less than optimal.

Cell talk, cell adhesion and cell signalling

Organs in the body are made of numerous cells bound together working in harmony, recognising their roles and that of others. However when the harmonious relationship breaks down due various reasons like reduced immunity and aging, the cells grow autonomously and begin to proliferate with little respect for adjacent normal cells.

Current views have moved to molecular biology and cancer biology to determine new ways of controlling and treating cancer. But have we succeeded? A scan of subjects relating to cells talking to each other, how they adhere and work in synergy and how they die eventually and are replaced is still being studied and enormous information is now available on of cell signalling. Apoptosis is regulated suicide. Key proteins cited are p120caterin which entails nuclear condensation, shrinkage of the cell with membrane blebbing and eventual fragmentation of DNA. CASPACES are mentioned as central regulators of apoptosis which play a role in cleaving cellular proteins.

Current concepts of breast cancer reviews cell biology and cell-cell adhesion much of it being related to ErB2; increased proliferation permits motility resisting apoptosis but no invasion takes place. But with loss of yet another protein, E-cadherin invasiveness of the tumor occurs. Spread of cancer to distant sites can be suppressed by amplifying the effects of ErB2 which is now the basis of using newer medication like trastuzumab. Although the explanation for a cancer of the breast remaining at its original site (in situ) or spreading to distant sites (metastasis) is much more complicated than what has been mentioned  above, experimental biologist continue to develop newer drugs to combat cancer based on an understanding of the various proteins that contribute to cell adhesion, cell signalling and apoptosis. 

Other signalling processes involved in the catabolic process are called macroautophaging or autophaging. Nutritional deprivation is inevitable in cancer. A similar but less severe state follows stress, differentiation of cells, neurodegerative disease and infection. Under these circumstances Lyoscyem in the cytoplasm degrade releasing aggregates of abnormal proteins and excess damaged organelles result. The kinase mTOR appears to be critical to autophagy induction.

Cell cycle control is essential for regulated cell growth and the process is essentially maintained in an orderly fashion because of G1/S checkpoints. The whole transition from the G1 phase of the cell cycle to permit entry into DNA synthesis (S-phase) requires different stimuli and checkpoint control (e.g. TGF-beta, replication senescence, growth factor withdrawal). Any or a combination of these factors going wrong will set off a series of misconduct and perhaps will lead to premature cell death or excess cell proliferation.

The cytoskeletal system remains another dynamic site for both regulation and adhesion between cells. The adheren junction structures both strengthen, spread, degrade and reform using various proteins establishing connections between its counterparts and adjacent cells. In what has been described as the stable model complex of cadherin, beta – cadherin is bound to actin skeleton. A whole bunch of adaptor proteins are involved including kinases and phosphatases. Key proteins cited are p120caterin. Breakdown of this process clearly upset the whole equilibrium between and within cells with disastrous consequences.

Can we stop this cancerous growth?

The destruction of cancer cells through gene modification and gene transfer has been the basis of viral oncolysis (i.e the destruction of cancer cells) using viruses that replicate themselves. Thymidine kinase coupled with herpes simplex virus has been seen to infect cancer cells killing them. This has been possible by affecting the spatial control of transcription.  

How has all this contributed to cancer biology and cancer treatment? Essentially we are beginning to get a microcellular picture of the complex array of action of proteins within the cytoplasm, nucleus, and cellular membrane, between cells and how the harmonious relationship can be maintained or destroyed.

The basis of drug development to fight disease is derived form the understanding of the functioning of normal signalling pathways. Angiogenesis is common in cancer. New blood vessels are formed in the process of cancer cell proliferation. This is not unlike what normally happens when there is an infection of when a wound is inflicted. In cancer the inductor is hypoxia, a lack of oxygenation. The hypoxia inducible factor (HIF) is a transcriptor factor that is sensitive to changes in oxygenation delivery to the cell. Normally, when the HIF is hydroxylated and acetylated (with normal concentrations of oxygen) it is transported to the nucleus where it induces expression of targeted gene products. Several growth factors like VEGF, FGF, TGF, which are growth factors will induce a cascade of signalling pathways which are responsible for several further activities which are involved in growth of blood vessels like the proliferation of endothelial cells and changes in permeability of the endothelium and cell migration. Such dynamism is coupled with changes that are induced to occur in yet another set of proteins, the extracellular matrix proteases. Several regulators will induce the tissue matrix to remodel so as to prepare to receive the migrating endothelial cells from existing blood vessel so as to form new blood vessels.

This whole process is bizarre in cancer. Host susceptibility, some abnormal trigger in perpetuating the process of cell division to take on a different pathway from that of the norm and unbalanced host-tumor relationship may contribute to abnormal proliferation and cancer. The resultant lack of cell-cell adhesion principle and bizarre cell signalling mechanisms have been implicated in an abnormal growth becoming aggressively invasive and eventually destroying the organelles and ultimately the organism.

Current treatment and are we on the right path?

Current strategies of chemotherapy is  based on cell biology; ionizing radiation appears to be rather non-selective in destroying cancer cells and to some extent normal cells leading their ability to arrest the growth of cancer cells albeit temporarily . The use of radioactive iodine in treating thyrotoxicosis and short lived radioactive substances to produce three dimensional coloured images of functioning tissues in the body in positive emission tomography have opened novel approaches to cancer treatment. The use of biomimicry principles has made it possible to  fox abnormal cells to undergo early ‘suicide’ but its extensive use in treating disease may be limited in view of the complex signalling processes in the organelles of the cell making this approach rather non-directive.

My current views are that scientists are unravelling the secrets of the goings on in cell biology at a molecular level and knowledge derived from the numerous engagement of cell metabolic pathways are being used  to direct therapy to control division of abnormal cells. However, the complexity of the pathways appears to override the fundamental steps as the simplicity of using the principles in killing bacteria with antibiotics do not seem to work in cancer biology. At this point in time we will continue to understand the numerous substrates involved in metabolic pathways and the discoveries will continue without end after the chapter on DNA was first revealed by Watson and Crick.

We got to go subatomic!

I am of the opinion that gene therapy and ionizing radiation will not be the ultimate answer in treating cancer. I can see that newer diagnostic tools will continue to be developed as we discover and understand the processes of organelle functioning but there will be huge gaps in putting the pieces together for many decades. Cancer treatment will continue to be targeted at ablative surgery, chemotherapy and radiation therapy for years to come. We will be dwarfed by the lack of understanding of cell biology and will need to take a new approach. Just as we see the role of the radiologist changing to become imaging specialist and intervention specialists, I see that the roles of physicians will become less distinct. The radiologist will eventually become therapist as they would be holding the key to tools that will target control of subatomic particles in the cell that would eventually be the point of attack in treating disease, whether it is cancer, inflammation, degenerative disease or mere senescence.

This brings me to the uproar in scientific circles of Particle Physics. Quantum physics changed our thinking and then we got confused if light is a wave! Do protons have weight? Particle physics (high energy physics) appears to be derived from the fundamental elements of earth, fire, water and air. They form the basic building blocks of matter. We learnt that the nucleus has protons and neutrons. Electrons have negative charges and there is a balance within the particle to keep the spin in place. Then sub particles were discovered in quarks, again there are u-quarks and d-quarks. More than 200 subatomic particles have been discovered forming the basis of what is called the ‘standard model’. All the particles interact with forces keeping them in harmonious motion.  Subset of second and third generation particles came into our knowledge pool (CHARM and STRANGE) and counterparts of electrons like MUON and TAU were discovered. To add on the understanding of the strange ways particle physics work, it is now agreed that each quark and lepton family has an ANTIMATTER partner (a mirror image). When particle and antiparticle get too close in this ‘double act’ they lead to annihilation. They burst with release of enormous energy (High Energy Physics). This is the basis of Einstein’s e=mc^2.

It has been over five decades that mathematical physicists have been trying to understand the origin of the universe. Since the times of the discovery of gravity, knowledge of the molecule and subatomic particles has increased to a very large extent. The Standard Model of Particle Physics does not seem to explain all the forces including that of gravity. The superstring theory remained a hypothesis with its own limitations.  

Several scientists have been throwing more light to explain the gaps we have in the knowledge of Particle Physics. Higgs in Edinburgh, Scotland theorized more than four decades ago about field points with no push or pull factor. In 1964 he put forth the idea about how massless particles acquire mass. It was then plausible to accept his views as if there was no Higgs field, quark particles would ‘flit past each other at the speed of light’. Hence some ‘invisible field ‘was present to keep all in place. It was Leon Lederman, a Nobel prize winner’ who referred to Higgs Boson as the ‘God Particle’. The acceptance of  Higgs Boson  and that all the elementary particles interact with each Higgs field hence slowing down their motion (inertia) was announced recently in CERN in Geneva. The Large Hadron Collider measuring 17 miles in length has been in in the news for the last several months illustrating the fundamentals of particle collision energy.

Why am now confusingly yarning about a multitude of areas with little coherence? I started to talk about cancer treatment I was involved in and the despair I have encountered when managing advanced disease. I went on to talk of the modalities of treatment available in surgery, chemotherapy and radiation. Then I introduced the discoveries of the goings on within the cell and cell biology. I touched on the need for cell-cell talk, cell adhesions and cell signalling. I then despondently talked about how rudimentary our tools are for treating cancer. I alluded to the role of subatomic particles when we developed newer imaging tools like PET. The standard model of particle physics could not explain everything and now we know about Higgs Field that has no pull or push factor like the other subatomic particles.

Personal Views

What I now opinionate is that cancer treatment would not be successful if we do not take it further down molecular biology to subatomic levels. Ablative surgery would not be the ultimate. Chemotherapy would be close to stagnating cell division but would not contain the cancer cells forever. Causing cell suicide and cell destruction as in radioiodine therapy would be closer to our goals.  Radioisotopes will work if we could deliver it in such a way that the difference in rate of cell growth between normal and abnormal cells could be determined with accuracy so as to deliver the exact dose. We are fully aware of the role proteins play in both normal and abnormal cells. We are also cleat that all these subcelluar material are formed from atoms. Hence  we need to  down the subatomic pathway and use the principles of Particle Physics. An environement needs to be created ,in all probabilities the Higgs Field, around potential 'mischief cells , so as to keep cells in a state of suspension and evetually control cancer. This would require very early detection  or deviation from normal cell growth. Micro nanotechnology  would be the possible approach in introducing the appropriate subatomic particle to detect  cells who have the potential to behave abnormally!

New approaches are essential as although cancer drugs have been novel in attacking programmed and abnormal cell growth, they are not good enough to cure disease in the long run. Results from years of  use of  a combination of surgical treatment, chemotherapy and radiation have not shown us the perfect way to manage cancer patients..

Conclusion

A close relation between scientist and physician is inevitable if we want to combat cancer. The way cells respond to stimuli will follow predictable pathways irrespective of conventional pathological classification. We need new taxonomy that would classify disease according to subatomic particles since all matter are related to the atom and its sub particles. Treatment of disease should be directed to the stereochemistry of proteins by developing fields of low energy which could keep cancerous cells in a state of suspension. In time to come all one needs to do is to swallow a treated sub particle which would find its way to the subatomic boson within the protein that’s gone wary so as to induce a state of suspension or impotency!

Sivalingam Nalliah

25 July 2012

DEVILS, DRUGS, DOCTORS and HISTORY

Introduction

Devils, Drugs and Doctors; what’s the association, you may wonder. This book was given to me by an Australian Academic with whom I stayed for a week back in 1991. The author of the book, Howard W. Haggard explains that it is a story of ‘Science of Healing from Medicine-Man to Doctor'. Printed in 1929 by William Heinemann (Medical Books Ltd), I am hoping it will fetch a princely sum from Christie’s! The reason for bringing up the contents of this book is to illustrate the rapid evolution of Medicine today and how it has changed from being an art depending on wisdom and experience to a huge degree of fragmentation of the approach to the sick with the development of medical technology, imaging and super-specialization. I pray common sense will prevail and the holistic care of the patient will become the order of the day.

History of Medicine is  a wonderful field that portrays the works of great healers from the East and the West. Ironically, the title of the second chapter in Haggard’s book is 'Saiy Gamps and The Midman' and begins with ‘Medicine declines and fanaticism rises'. It refers to the death of civilizations. The Roman Empire declined and Greek Medicine deteriorated. The Christian religion was in ‘ascendancy, and under the influence of theology, spirituality reigned superior to the physical aspects of disease'.  While the teachings of the religion of the day were relevant, there was a replacement of rational medicine by superstition. As medical knowledge ground to a halt with resurgence of religion, the great teachings of Hippocrates and Soranus were buried and not available to the public in the Middle Ages. Ignorance and barbarism dominated daily life. The author explicitly quotes about the ‘birth of caesarean operation done without anaesthesia by the executioner and barber and not by physicians as it was below their dignity to perform such procedures'.

The beginning of Midwives

Albert Magnus (1193-1280), a clergyman, wrote a book for midwives not for the good of the childbearing mother but to ensure the baby is born and lived long enough to be baptized! Safer maternity care was encouraged by a manual written by Eucharius Roslin in 1513 which highlighted the works of the Greeks including the inclusion of the superstition of medieval medicine and fumigation with dove’s dung. The title of Roslin’s book was ‘The Grade of Roses for Pregnant Women and for Midwives’. ‘The Byrthe of Mankynde’ was a version derived from Roslin’s book.  Men could never be involved in Midwifery in the Middle Ages. A story is quoted in this chapter that a certain Dr Wertt of Hamburg , Germany, was very keen to see a birth of a child and had dressed in women’s clothes to see the event. He was caught and burnt to death!

When we talk about medical men of the 1500s one would come across Ambroise Pare’ from France who described podalic version for the child who was not in the normal position in the pregnant uterus. He opposed Caesarean deliveries and preferred internal podalic version , as he felt by inserting the hand into the uterus and pulling on the legs of the unborn child, the results would be better.  During his time a School of Midwives was opened at Hote Dieu in Paris. This school lead to qualified midwives as safer persons for caring pregnant mothers. Pare’ also encouraged the physicians be called in when midwives could not handle difficult pregnancies, something that was thought to be a blow  to the ‘dignity of physicians of those days'.  Several scientific achievements of the 16^th century  and  radical changes in Medicine were taking place during that time and are worthy of note. Copernicus revealed that the planets were revolving around the sun and Galileo talked about the ‘law of falling bodies’. Vesalius was introducing the foundation of human anatomy and syphilis was named by Girolamo Fracastoto (he wrote a poem in which appears the term- ‘Syphilis sive Mobus Gallicus’) . History has much to say about this disease which was not scorned upon till late in the 18^th century. Moses is said to have attacked this problem by associating it with immorality though.

Biblical Times and Morality

In the times of Moses (Old Testamount) it is said that , not unlike the times of today where the vice trade thrives worldwide, foreign prostitutes called ‘strange women’ were not allowed into the larger cities but could set up booths and tents along highways where they ran a combination of providing their ‘services’ together with selling their wares. In Rome of the old days (Roman empire) it is said that prostitutes could be identified as women who were elegantly dressed with a huge number of ‘admirers’ around them . It is also recorded in Ancient Greek times that prostitution was a ‘social institution’ (reference: Medical Thread in the Moral Snarl. Devils, Drugs and Doctors’).  While courting prostitutes was an act of adultery in Rome, the Greeks did not consider such an act as unacceptable. Gender bias is obvious in that  sexual contact with a prostitute was a ‘male privilege’ whereas in Rome it became a practice of both sexes!

What is perplexing is that the principles of healing have not changed over the years from time immoral. The basic tenet of treatment recorded stems from three aspects i.e. faith healing, hygienic therapy and drug cure. Today we use the same principles. While faith healing varies, we have to bear in mind the importance of treating the psychological elements of disease which is amenable to a variety of therapeutic strategies varying from suggestion, hypnosis and plain explanation of the course of disease. Western Medicine reigned high but now we are becoming comfortable with ‘alternative and complementary medicine’. There was white magic and black magic then, such practices prevail to this day!

Therapeutics and Drugs

The modern use of drugs based on theory of disease is often referred to as the ‘Galenic system’. Galen, a physician of 159 AD appeared to be have based medication for illness on more robust principles compared to that of Hippocrates. Galen’s theory looked at the human body as the universe in that it had all four elements;, fire, water, air and earth. All four had to be in equilibrium to be healthy. Heat and cold were balanced. Should there be an imbalance as manifested by symptoms and signs, then various therapies had to be instituted. Cooling, moistening and drying were vital therapeutic measures. The use of medication assisted in the process. The use of herbs persisted as a form of treatment long after he was dead but till today we see the importance of his theories in treating disease. The term ‘cool as cucumber’ is drawn from Galen’s practice of medicine. Ego continues to hound physicians even up to now. Galen, unlike Hippocrates, was said to be very egoistical and his intellectual honesty was suspect because it is said that he did not record his failures, only his success. Today, we see the same malady. Scientists, physicians and journals often report the successes, not the failures!

Historical perspectives bring back to us several reminders that there are periods of success and phases when there is deterioration and decline. While scientific principles were known to be used other factors influenced their application. Today we see a combination of advanced technology in Medicine and invasive investigations intertwined with herbal medicine and faith healing. Is that why they say the ‘word is round’?

Hippocrates said, ‘some patients, though conscious that their condign is perilous, recover their health simply through contentment with the goodness of the physician (Precepts IV).  He also states that a physician who is a lover of wisdom is the equal of GOD.  A Japanese proverb, on the other hand aptly states that ‘better go without medicine than call in an unskilful physician'. But is it not true that ‘a doctor is a man who is licensed to make grave mistakes’? (Quote: Leonard Louis Levinson).

Conclusion

Reading about history permits comparative studies and to reflect. We have made huge strides in medical advancement but the principles laid down from the times of Hippocrates and his likes remain. Benjamin Franklin said that ‘he’s the best physician that knows the worthlessness of the most medicines'. So it cannot be wrong when one says that a miracle drug is any drug that will do what the label says (Eric Hodgins). Life span has increased and health is a bonus. So do we look forward to becoming old because we live longer now?  Oddly a Chinese proverb states that ‘man fools himself; he prays for a long life, and he fears an old age!.

Sivalingam Nalliah

5^th July 2012

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