THE STORY OF PENICILLIN

Let me, at the very outset, introduce you to this wonderful story-teller. Prof. H.S. Adenwalla is in his late eighties and is one of the most senior Plastic Surgeons in India. He is the Head of Charles Pinto Centre of Cleft Lip, Palate and Cranio-facial Anomalies in Jubilee Mission Medical College & Research Institute in Trichur, Kerala. The learned professor is an encyclopedia of knowledge and yet an epitome of modesty. Trained under the famous Plastic Surgery Guru Charles Pinto in K.E.M. Hospital, Mumbai, when the octogenarian professor chooses to walk down the memory lane, you are distinctly lucky if you are accompanying him! This is one of hise several stories which I am going to share with you all from time to time!

In the history of the growth of science it is difficult to lay any clear watersheds, but we can say that the era of modern medicine roughly started with 1880’s- many good things had happened before, for instance Jenner had begun his war on Small Pox, and Louis Paster had conquered the horrors of Rabies. Dogmack had synthesized salvarsan which was a sulphoamide. But otherwise medicine consisted of purging, bloodletting and starving and more people died of the treatment than the disease. There were a few useful drugs which became the physician’s carthorse, digitalis for the heart, Quinine for malaria, salicylates for fever, sarol for intestinal infections, hexamine for urinary tract infections and opium for pain. Insulin for diabetics, thyroxine for myxoedoema and salvarsan (arsenic) for syphilis, came later.

Our story of Penicillin begins with a young Scottish student of Medicine who wanted to be a surgeon. In 1906 he took a temporary job in the bacteriological department of the St. Mary’s hospital, London under Sir. Almroth Wright, his intention was to stay on the hospital’s rifle shooting team. That as Udwadia says in his book “The forgotten Art of Healing” was a quirk of destiny for both Fleming and the world.

His first discovery of importance was that he proved that there was in tears an enzyme called lysozyme which destroyed organisms that existed in the nasal tract. It showed why the eyes resisted infections so effectively. He then turned to the study of staphylococcus a common organism which infected wounds and caused fatal septicaemia and death.

Now starts a Cinderella story never surpassed in the annals of medicine. Fleming retiring from a holiday found that one of the Petri-dishes that he had left open by chance had been contaminated by a mould, and the bacteria round the mould had been destroyed. He presumed that this mould may have floated up the stairs or through an open window from a laboratory where a research worker was studying fungi. The genius of Fleming was that he did not just throw away the Petri-dish. He was intrigued by the pneumonia and so he studied what lay before him and found that a powerful substance had emanated from the mould that had killed the bacteria. What was this substance? He believed that the mould was Penicillium rublem. It was really Penicillium notatum and hence he called the lethal substance Penicillin. His further research showed that this Penicillin destroyed a whole range of gram positive cocci and a few gram negative ones too. He also showed that Penicillin did not affect healthy tissue or the leucocytes in blood. Why did not Fleming try Penicillin on infected animals? This was because he found that if Penicillin was mixed with blood it lost its potency. He failed to realize that what happens in vitro does not necessarily happen in vivo. Disappointed at this road block he turned to other areas of research. Strange to say other workers who thought Fleming had given up too easily could not duplicate Fleming’s observations. When they dropped penicillium mould on to an agar plate full of colonies of staphylococcus nothing happened. A year later Robert Hare solved the riddle. Robert Hare consulted the meterological records for London at the end of July 1929. When Fleming was away, London had a very cold spell of a week, which favored the growth of the penicillium mould. After that the temperature rose which favored the growth of the staphylococcus. Robert Hare succeeded in duplicating Fleming’s experiment in conditions of controlled temperature. But there the research died. It must be noted here that without that cool period when Fleming went on leave he would not have discovered penicillin at all.

For six years no one spoke or heard of penicillin. In 1935 Howard Florey a brilliant Australian who headed the Dunn School of pathology at Oxford hired a German Jew who had just escaped from the Nazis in Germany, he was a biochemist, they both set out to find a powerful antibacterial substance. By chance they stumbled upon a paper by Alexander Fleming on penicillin but they just could not isolate the active substance from the mould. It was Norma Heatley another biochemist on the team who succeeded. On Sunday the 25^th of May 1940 Florey’s team inoculated 8 mice with lethal doses of streptococci four were then put on penicillin. By 1.45 AM the next morning the mice who were not treated with penicillin died the other four survived. Florey exclaimed “This gentleman looks like a miracle.”

The Second World War was going badly for Britain. France had already capitulated. Florey then made a desperate decision, he decided to convert his department into a manufacturing plant for penicillin. Heately was put in-charge and he at last had enough penicillin for a human trial. A police man Albert Alexander had developed septicaemia following a scratch while pruning roses. Dr. Charles Fricher on the 12^th of February 1941 administered penicillin three hourly to the patient. By the fourth day the patient’s temperature dropped and he became lucid but unfortunately they ran out of penicillin and Alexander died. They had no doubt that if they had enough Penicillin Alexander would have lived.

Florey appealed to the British pharmaceutical industries for help but they said they were too busy due to the war, so in July 1941 Florey and Heatley flew to the USA to get the help of Andrew J. Moyer. Moyer it is said sapped Heatley of all his knowledge but gave nothing in return. Moyer succeeded in manufacturing penicillin in large amounts.

Now in 1942 Fleming asked for some penicillin for a dying friend, he has given the drug and his friend survived. This was reported in the Times. It was then that Almroth Wright wrote to the Times giving credit to his pupil Fleming for the discovery of Penicillin. Fleming, Florey and Chain shared the Nobel Prize for Medicine. As often happens in life Norman Heatley and Robert Hare were forgotten. Penicillin became the wonder drug which opened up the phenomenal era of antibiotic therapy. For a moment man thought that he had conquered diseases caused by infective organisms but it was not to be, nature always has the upper hand and as Udwadia says “Microbes like man evolve, when threatened they mutate to form resistant strains. And so the battle for survival goes on.”

CAN WE OVERCOME THE TWIN TROUBLE OF CASTE AND RELIGION?

The largest state of India, Uttar Pradesh, goes to the poll next year. Political parties have started preparations, but what preparations you may ask. They are trying their level best to get the caste equation right. For a majority of the voters the performance or the non-performance of the government does not matter and the performers / non-performers know this pretty well. 

The ‘caste’ unfortunately influences political activity in our country from Panchayat right up to Parliament. While the Caste System is breaking down in social and cultural fields; conflicts between castes are intensified by party politics. Numerically large castes have become important pressure groups in local as well as state politics. Political Parties in India sponsor candidates having social base, which is nothing but the numerical strength of a caste of candidate in the constituency. Their service to the society is unimportant and their criminal background usually does not matter.

U.P is not the only state which suffers this malady. In Karnataka state politics there is rivalry between Okkaligas and Lingayats, the two leading present castes. In Andhra Pradesh the chief contesting castes are Reddies and Kamas, in Bihar, Bhumidars, Kayasth and Rajput. Dravida Munnetra Kazngam (D.M.K) emerged as a non-Brahmin party of break the Brahmin cal dominance in Tamilnadu state politics. Bihar and U.P. are champions of caste based politics. The traditional caste rivalry between the Rajput, Kayastha and Bhumindar is found today among the political parties in Bihar. The emergence of Kanshi Ram and Mayawati as Dalit messiah and that of Mulayam as the benefactor of Yadavs have polarized the post Mandal politics in U.P. and will continue to do so till a charismatic leader emerges who can, more by his deeds and less by his words offer employment, progress and prosperity across the caste divide.

Political parties utilize the support of caste for their functioning and seek their support in winning elections. The involvement of these castes organization in politics has changed their position in hierarchical pattern of Hindu society. Caste solidarity and political power have helped them to achieve higher social, economic and political success and become one of the most formidable elements of group formation within political parties in India.

 Incidentally political process has a dual effect on the caste system. To the extent that caste and sub-caste loyalties are consistently exploited, the traditional structure is strengthened and to the extent that it leads to new alliance cutting across caste, it loosens the traditional structure. Caste enters the political process by making appeals to caste loyalties and thus engineering power shifts from one dominant caste to another or one caste/sub caste combine to another by articulating caste interests in an organized manner. From Kanshi Ram and Mayawati for the Dalits to the new kid on the block Hardik for the Patidars the pattern has remained unchanged.

Religion too enters the political chess in a very unique way and with almost one out of five votes belonging to a Muslim, they can be expected to be wooed by all and sundry. Appeasement of a particular caste and religion combine may lead to a winning combination and every political party will strive for this divine match making. But in the midst of all this the state of Uttar Pradesh has swung like a pendulum between corruption and lawlessness since almost last three decades. Much is expected from the aspirational India of today but in states like Uttar Pradesh and Bihar the thought process is still medieval and so the situation notoriously remains status quo.  Whether this is good for the nation or not only time will tell. But if good and honest politicians fall victim like Abhimanyu to this chakraview of caste and religion and I wonder how it can be good for our future.

KIDNEY TRANSPLANT ………..HOW DID IT ALL START?

In the late 40s, during the ward rounds at this Boston hospital, the residents were very concerned at the young comatose patient who had been wheeled in. The consultant looked at the patient at her and said "the only thing that can save her is a new kidney. Else she will not last more than a day or two"

During the evening after the consultant had gone, another patient in the ward died and the young residents took his words seriously. They felt that they could try to give her a new kidney. They went to the mortuary and removed the kidney, brought it back to the ward and using a wick lamp worked till late at night stitching the renal artery and vein to the most easily approachable vessels - Brachial artery and cephalic vein in the ante-cubital fossa.

At the end of the anastomosis they realized that the ureter was hanging free. Too tired they just placed it in a kidney tray and covered the donor kidney with a wet gauze and headed back to sleep.

Next morning when they came back the patient was awake, sitting up. The kidney tray was full of urine and had dripped all over the floor.

Obviously there is no mention about long term survival and the kidney must have been rejected later but the ball was set rolling. Joseph Murray, a Plastic Surgeon did the first proper kidney transplant. It needs a Plastic Surgeon to think out of the box!

Experimental studies to transplant a kidney in animals started in 1902 in Vienna Medical School in Austria. In 1909 the first kidney transplant experiments were performed in humans in France using animal kidneys – a brave surgeon inserted slices of rabbit kidney into a child suffering from kidney failure.  Although “the immediate results were excellent” the child died about 2 weeks later. Scientists blamed such failures to unknown ‘biochemical barriers’. The first human to human kidney transplant was attempted in 1933 by Yuri Voroniy from Kherson in the Soviet Union but the donor kidney never produced urine and they blamed it to the fact that the donor had a different blood group!

On June 17, 1950 a successful transplant could be performed on Ruth Tucker, a 44-year-old woman with polycystic kidney disease, at Little Company of Mary Hospital in Evergreen Park, Illinois. Although her transplanted kidney was rejected eventually as there were no immuno-suppressants available then, before rejection it gave sufficient time for her own remaining kidney to recover and she lived for another five years!

The first kidney transplants between living patients were undertaken in 1952 at the Necker hospital in Paris by Jean Hamburger although the kidney failed after 3 weeks of good function. However, by now people knew that new approaches were needed to prevent the body from fighting off a “foreign” donor kidney. Sir Peter Medawar at the University of London was experimenting with the immunologic basis of organ rejection in the late 40s and in early 50s Cortisone like medications were used to protect the donor kidney from the recipient’s immune system!

Two days before Christmas in 1954 Joseph E. Murray and his colleagues J. Hartwell Harrison, John P. Merrill performed the famous Boston Transplantation, which changed the course of history. The procedure was done between identical twins Ronald and Richard Herrick to eliminate any problems of an immune reaction and so was done without any immunosuppressive medication. For this and later work, Dr. Murray received the Nobel Prize for Medicine in 1990. The recipient, Richard Herrick, died eight years after the transplantation. More importantly, this opened the door to many more kidney transplant between identical twins, both in Europe and in America.

After scientists more accurately understood why our bodies fight off foreign organs, they experimented with ways to combat these defenses.  Surgeons used X-ray, bone marrow infusion, immunoparalysis, donor-recipient matching, and drugs to stop rejection. The 60s came with rapid advances and better techniques for matching donor and recipient blood and tissue types. Improvements in preserving cadaveric (from recently deceased donors) kidneys, were developed and today’s solutions and cooling methods can be safely preserve kidneys for up to 48 hours, there were times when surgeons rush organs from decapitated prisoners!

A procedure, which today is practiced with effortless ease in almost every country, has developed because of the determination and dedication of countless men and women of medicine who were not happy with status quo, and challenged the prevalent norms.

THE HISTORY OF THYROID SURGERY

I am once again back with an outstanding account of history of medicine from the pen of my senior colleague Dr. H.S. Adenwalla. Besides being one of the most respected senior Plastic Surgeons of our tme Dr. Adenwalla is Head of the Charles Pinto Centre for Cleft Lip, Palate and Craniofacial Anomalies in Jubilee Mission Medical College and Research Institute in Trichur, Kerala.

Physicians hundreds of years ago had learned by observation that eating roasted sponges sometimes reduced goitrous swellings. In 1820 the Swiss scientist Jean Francois Coindet had discovered that iodine was the effective component of sponges and ever since then iodine became the sheet anchor of all therapy for goiters. It was rubbed into the gland, taken by mouth and even injected into the gland. The treatment had some effect and is still used in iodine deficient areas to prevent goiters. But it did nothing for the large goiters that either killed their victims with asphyxiation or, in cases of toxic goiters, with ultimate heart failure. A tracheostomy was performed as a last resort for asphyxiation. No one really knew as to what was the function of the thyroid gland, which unlike other glands had no duct to carry away its secretions. Scientists made the most fantastic speculations about its function.

The Roman physician Celsus had written an account of his experience with thyroid surgery. He enucleated the nodules and most of his patients either died of sepsis or severe hemorrhage.  Two hundred years later Galen described an operation on a child. The patient survived the hemorrhage but lost the ability to speak. Galen described a nerve behind the thyroid gland, the slightest disturbance of which would affect speech. This nerve was later called the recurrent laryngeal nerve which controlled the vocal cords.

A thousand years after Galen, Paracelsus issued dramatic warnings against a surgical solution of the thyroid problem. Roland, a noted surgeon, burned holes with hot iron and drew threads of horse hair to tie off chunks of thyroid tissue hoping that those parts would necrose and die. Desault and Dupuytren tried surgery but with no success. Until by 1877 some hundred and fifty operations were performed on the thyroid resulting in death due to haemorrhage or pyaemia and the few that survived lost their speech.

Then came the work of Semmelweis, Pasteur and Lister and the advent of antiseptic surgery, anaesthesia and the creation of the artery forceps, the stage was now set for the epic speech delivered by Edmund Rose, a fourty year old surgeon from Zurich at the annual congress of German surgeon in 1877. Rose said that “total extirpation of the thyroid was the only remedy for this condition and it could be done without undue haemorrhage and without  damaging the vocal nerve if the surgeon took pains to study in detail the anatomy of the thyroid gland.” Rose’s lecture focussed the attention of European surgeons on the thyroid gland. In his talk, he acknowledged the work of Theodore Billroth of Zurich and Theodore Kocher of Berne both of whom had successfully done total thyroidectomies as early as 1872, a good five years before his presentation. Both Billroth and Kocher described a method whereby they systematically tied off the major vessels that supply the thyroid gland, and carefully avoided touching the recurrent laryngeal nerve. However, there came up at the time a few reports of the patients developing spasms, no one knew why and no one knew what to do for them. This neglected “tetany” killed a few patients due to severe spasm of the thoracic muscles. We know today that this was due to the inadvertent removal of the parathyroid glands and all that one has to do is give calcium to control it, but no one knew anything about the parathyroids at that time.

Theodore Kocher was now at the height of his fame. The world was talking about how he had mastered the operation on the thyroid gland, and how he had saved hundreds of young women from a ghastly death and then suddenly his world came tumbling down. It  was Reverdin who first pointed out to Kocher that one of his fourteen cases on whom he had done a total thyroidectomy had become a cretin and he suspected that the cause was the total removal of the thyroid. Kocher made Roux his assistant write to everyone of his patients to come for a checkup, and when they came, it was the saddest day for this great surgeon. He realised that he had created a generation of Cretins. Roux reports that he found the Professor sitting in his room with his head in his hands and when he looked up at me he said, “Roux have you ever known the moment when God suddenly hurls you down from a peak of self-complacency and lets you recognize what small bungling creatures we are?” The history of Medicine has given a full account of what this meant for the new born science of thyroid surgery. They described the nature of the mistake, how it came to be made and what its consequences were and how it was gradually amended. But they did not name the victims and they do not tell you what Theodore Kocher felt when he first recognized the terrible thing he had done by totally removing the thyroid gland. So what did this great surgeon and scientist do? He went before the Congress of German surgeons in Berlin on the 4^th of April 1885 and told them what he had done and the result of his mistake. He strongly advocated that the total gland should never be removed otherwise they would have many of their patients end up with what he called “cachexia strumipriva” later on labeled as myxoedema or cretinism.

Kocher was not the type of man to accept defeat. He went back and experimented on animals and ultimately came to the conclusion that if a small portion of the gland was conserved the horrible complication would not occur. Many surgeons without proper training took to doing thyroid surgery. They did not have the dexterity and expertise of men like Kocher, Billroth and Reverdin and so many complications kept occurring until the great Lahey at the Lahey clinic wrote his monumental paper on thyroid surgery and the recurrent laryngeal nerve. The complications of damage to the parathyroid was recognized and surgeons learned the use of calcium to treat tetany. In 1891 George Redmayne Murray in England extracted desiccated thyroid extract from pigs. Edward Calvin Kendall of the Mayo clinic extracted the pure form from hog thyroid glands. The hormone was synthesised by Charles Robert Harrington and George Barger British chemist in 1927. In 1960 Levothyroxine was synthesised and with these advances total thyroidectomy for cancer became a safe operation and both myxoedema and cretinism if detected early could be treated.

Today when we race through a subtotal or total thyroidectomy we little realise what the great surgeons of yore went through to give us simple answers to our problems in this, and other fields of surgical endeavor. 

A FRIEND FOR LIFE …..AND EVEN BEYOND!

Today was my friend, Mohan Chand Pant's varshik shradh. We, his batch-mates, friends and relatives, gathered at his home in Lucknow remembered what a wonderful friend he was and met his lovely family.

At Mohan's home today: Mukul, Veneet, Atul, Vinay and myself

We were batch mates in King George’s Medical College and so knew each other since our first day in college in the hot summer of July, 1975. Freshers, as we were then called, we were the easy target for ‘activity’, which was a politically correct name given to ragging. Mohan was a clean shaved lad who had not yet lost his baby looks and in the hostel he was paired off with another baby faced boy from the hills, Mukul. They were both very studious but Mukul was an accomplished sports person too. And they were very sporting and Mukul was crowned the T.G. Queen, an age old custom in which a boy is dressed up as an ‘Apsara’ every year!

Roommates Mohan and Mukul in S.P. Fair

After completing his M.B.B.S, Mohan chose to do his post-graduation in Radiology. This was when, for the first time he realized that life is going to be tough. He hailed from a very modest background and there was no hope of being supported by parents while doing post-graduation, and to his horror he found that this department had no paid residency posts! His professor told him that despite his best efforts he had not been able to convince the government about this demand for paid residency scheme. Mohan took it up as a challenge and pursued the losing cause all by himself. Every day he would go to the Secretariat or the Medical Directorate with applications and documents and request everyone –chaprasis, babus,  clerks, officers, ministers…..whoever he could reach to help him out. He would make them realize that Radiology is much more than taking X-Rays and perhaps for the first time the people in power understood that Radiology was a vast subject with two wings – investigative or Radiodiagnosis and therapeautic or Radiotherapy. Now with this understanding and new vigor he managed to convince the people in power that a residency scheme was very vital for the success of this branch of medicine and the residency scheme was sanctioned. Needless to say, this struggle made him very popular with everyone in the government and the hill people in particular adopted him as their future pride! Mohan never disappointed them.

The door at the beginning of the corridor led to Mohan’s humble room in the Department of Radiology  in his early days

The struggle for financial existence also taught Mohan a very important lesson – the art of man-management. He knew how to convince people and get things done. He would dream a future and make others believe in his dreams. His persuasive skills were so genuine that one was easily convinced by his simplicity. Dreaming big was his passion; he never asked for a job for himself, he insisted on a residency scheme!  His efforts were so selfless that right from that time and that early age he was in ‘Institution building’ mode!

Mohan never forgot those who helped him and even if a peon fell sick he would personally see to it that he or she would get the best treatment in the Medical College. A small hand written note from a friend or a batch-mate to a patient, with only his name scribbled on it was enough for Mohan to get up from his office chair, personally escort the patient to the concerned department, get an out of turn appointment from a busy consultant and ensure that the sick person is fully satisfied! I have been at the delivering end on many such occasions, and when I saw the concern on Mohan’s face for a complete stranger I could never gather the courage to say no, no matter how busy I was.   

Mohan was a big name in the field of Radiotherapy and he had students chairing many premier Radiotherapy departments all over the country, but he was never satisfied with what he was doing. He would often ask me why was it that our patients were coming to us so late when the cancer had spread so much that neither he nor I were able to be of any help. He was of the firm opinion that we needed to prevent cancer and all our efforts should be aimed at prevention and early detection. How do we do this was our next concern. Not to be undaunted Mohan thought of a multi-pronged approach:

1.       Write chapters for text books in regional language for school children, making them aware of cancer and its association with tobacco and chemicals

2.       Conduct audio-visual presentations in the village panchayats and village schools and make people understand the ill effects of tobacco – smoked, chewed or sniffed

3.       To use every available public platform – school function, social and cultural functions, drama festivals, Ramleelas and talk about cancer prevention and early detection.

4.       To use media – radio and television and in simple and understandable language talk about these issues

5.       Write newspaper articles, preferably in regional language to spread the message of early detection and prevention of cancer

Today when I look back, I am amazed at the passion with which he went about doing all this, and that too without ignoring his students, his staff members, his friends and family! There have been evenings when we have met in marriage functions and I have seen 7 more gift envelopes in his pocket and a list of ten destinations to visit that evening with only 3 ticked till then! Not only did he befriend people easily but he had a passion to cultivate friendship, garden it, nurture it and give it back in his own unique way.

Mohan with batch-mates

My mother was 79 years old when she was diagnosed with a urinary bladder cancer. She was investigated and was offered the best treatment that was possible and as we had made an early diagnosis she recovered completely to live for another three pain free years. Mohan was with me all throughout this ordeal and that was a big help. With my younger sister however we were not so lucky. She neglected her breast lump and when we diagnosed her she had an advanced disease. Mohan was very angry with her and asked her whether she had ever thought what would people think….he could not make an early diagnosis in the case of his own sister? She was operated and later Mohan planned radiotherapy for her under his guidance in his own institute, of which he was then the Director. During all this my brother in law was very uncomfortable with one issue which he found strange. In Delhi, where they lived, he was told that the therapy will cost Rs. 2 lacs and here no one was asking him to make a deposit. He asked me where was he supposed to make the payment, and how much? I told him to ask Mohan directly. So next day he went to Mohan’s chamber and asked him. Mohan conveniently ignored the question and flooded him with a ton of other questions of his own about my sister’s health and how my young nephew and he were coping. But my brother in law was insistent; he needed to make a payment. So when refused to let his query be brushed aside Mohan looked into his eyes and said ‘ jis din meri behen se tumhari shadi hui thi us din ye hisab kitab ho gaya tha.’ My brother in law was stunned and he returned home to tell me the story. It took me quite a bit of persuasion thereafter to repay Mohan – two trips to his office and 7 cups of tea to be exact!

A crusader against cancer and a champion of early detection, nothing could be more ironical than the fact that on December 25, 2014 when he was diagnosed for the first time with cancer, the disease was already advanced and incurable. It was a bolt from the blue and though he fought bravely till the last it was all over in eight months! That evening with a very heavy heart when I was sitting in front of his mortal remains though there are hundreds of his other friends and well wishers all around him, in the same somber mood as I was, I could feel his gaze penetrating the glass case and smiling at me as he had always done in the last forty years. Mohan was my friend, a friend for life. It was only then, when the eternal sole had left his body that in his smile he told me death was just a milestone that our friendship had to cross; we were not just friends for life but even beyond! May his aatma rejoin with paramatma and rejoice for some time but promptly return to earth because his fight against cancer is incomplete and Mohan never left things half done!