Medical explorer

Dr S.S. Sriramachari. The medical research community lost a crusader.-S. Siva Saravanan

COMMITMENT is too much of a cliche to describe the perseverance and the passion with which Dr Samavedham Srinivasa Sriramachari tackled a medical problem until he unravelled it to the utmost detail. The attendant cost and discomfort to himself did not concern him.

On December 3, 2009, the 25th anniversary of the Bhopal gas tragedy, Sriramachari was scheduled to give a talk at the Institute of Pathology of the Indian Council of Medical Research (ICMR) on the histopathology work that he had been doing over the past two and a half decades on the tissues of the victims of the gas disaster. (He was the founder-director of the ICMR and was an Indian National Science Academy (INSA) honorary scientist.) But only a few days earlier, he had been admitted to the intensive care unit (ICU) of the Vallabhbhai Patel Chest Institute (VPCI), Delhi, because of chronic obstructive pulmonary disease.

He had been in and out of hospital for some time owing to this disease, which he most likely contracted as a result of the hundreds of biopsies he had carried out on tissues affected by methyl isocyanate (MIC) poisoning in the immediate aftermath of the disaster. But the subject was close to his heart. He would immediately get worked up whenever there was any discussion on the topic and always wanted to tell you about his new findings.

And so it was this time. His condition had improved enough for him to summon the strength to actually get out of the ICU and make the scheduled presentation at the VPCI itself. But his health began to deteriorate, and he passed away on December 25. The medical research community lost a crusader.

Born on June 25, 1925, Sriramachari had an outstanding career as a medical scientist. In the words of V.M. Katoch, the Director General of the ICMR, Dr Sriramachari was a rare type of person who, until his last hour, kept on thinking about newer and unexplored scientific research aspects relating to the Bhopal gas disaster in addition to his keenness for sharing it with us.

Indeed, his recent research was related to the possible role of the chloro-derivatives of MIC, resulting from the interaction of chloroform with MIC, in the mechanism of chronic or recurrent cyanide toxicity in Bhopal victims. He was carrying out this work in association with the Gwalior centre of the Defence Research and Development Organisation. The perpetual question, Sriramachari said in an interview about two years ago, even now unresolved is about the risk of cancer in Bhopal victims. The story is not yet over, but it seems unlikely that it has caused an increased incidence of cancer. He had suggested a study of survivors and their next of kin for two generations to characterise genetic abnormalities, if any.

His central finding in the case of the Bhopal tragedy was that the cause of the immediate death of or morbidity in the victims as well as the chronic and recurrent morbid conditions, which have been greatly in evidence, was cyanide toxicity, a finding that went against prevalent medical wisdom and belief. Actually, Sriramachari was about to leave for Belgaum in Karnataka to carry out studies on fluorosis and the protective role of tamarind when the deadly gas leak occurred. He cancelled his trip and wanted to head for Bhopal immediately. But the bureaucracy of the ICMR delayed him by taking about a week to sanction his trip. On the basis of initial autopsy findings, in particular the cherry red discolouration of organ tissues, Sriramachari, along with the late Dr Heeresh Chandra of the Medico Legal Institute of Bhopal, postulated cyanide toxicity as the causative factor. This was also corroborated by Max Daunderer, a German toxicologist who had visited Bhopal in the wake of the massive gas leak. This view stirred up a great deal of controversy soon after the tragedy, with Union Carbide Corporation asserting that there could not have been any cyanide toxicity.

Twenty-one very ill patients who did not respond to conventional treatment dramatically improved on being administered the cyanide antidote, sodium thiosulphate (NaTS), and 12 were fully cured of their respiratory symptoms. Correspondingly, Sriramachari also found increased excretion of sodium thiocyanate in their urine, an indication of clearance of the cyanide pool in the body. Controlled double-blind trials demonstrated his hypothesis conclusively, following which the ICMR recommended widespread use of NaTS as a therapeutic measure. That his findings were initially ignored perhaps resulted in many deaths that could have been prevented.

Follow-up studies found that nearly 30 per cent of patients had clinical relapses, with pulse and respiratory rates that did not match the observed degree of pulmonary damage. In all these cases, too, the patients responded positively to NaTS therapy. This, he found, was because of increased levels of hydrogen cyanide in the patients blood arising from chronic cyanide poisoning. To explain this, Sriramachari hypothesised that MIC somehow was bound chemically to blood.

A study of blood samples and several cryo-preserved tissues of post-mortem organs demonstrated the binding of MIC (to the amino acid of the amino-terminal valine residue of haemoglobin) by a process of N-carbamoylation. He argued that MIC could directly alter the oxygen affinity of blood by this carbamoylation. He also postulated that MIC could also bind to blood through S-carbamoylation of the chemical glutathione and enzymes such as rhodanase, esterase and alsolase in the blood. Sriramachari argued that while the former served as an exchange pool for isocyanate in the body, the latter resulted in the functional impairment of the enzymes, leading to repeated episodes of muscle weakness, increased pulse rates and respiratory problems. In a paper that he wrote in Current Science in April 2004, he pointed out that while the cherry red discolouration was because of the immediate acute toxicity caused by exogenous hydrogen cyanide that may have been produced by the thermal decomposition of MIC, the continued endogenous liberation of cyanide, and the resultant morbidities, were because of the functional impairment of rhodanase and other enzymes caused by S-carbamoylation of the MIC in blood.

These and other findings of the decade-long Population-based Long-term Epidemiological Studies carried out during 1985-1994 were published as the first technical report of the ICMR on the Health Effects of the Toxic Gas Leak from the MIC Plant in Bhopal, which, ironically, was published a decade later on the 20th anniversary of the accident in 2004 (Frontline, February 25, 2005).

While Sriramacharis research on Bhopal victims has become widely known among the general public, his research in diverse facets of pathology, which he raised to a level beyond mere diagnosis and therapy, is widely recognised in the medical community. He had earlier worked on a range of areas including hepatic pathology, nutritional pathology, neuropathology, osso- and muscle pathology and clinical toxicology. Whenever the country required specialised pathological opinion, Sriramachari was sought.

Born into an Andhra-based Tamil family, Sriramachari was denied a seat in a medical college for being under age and did his B.Sc. in Vizianagaram. Keen on doing medicine, he joined a medical college in Visakhapatnam and took his degree in 1943-48. With the help of a teacher named Dr M.D. Ananthachari of KG Hospital in Visakhapatnam, he did his postgraduation in medicine as well. But he could not get a house job because of his political affiliations and had to leave. But having now got interested in research in medicine, in particular on liver function and liver structure in malnutrition, a condition that he had come across in many cases during his postgraduate days, he joined Andhra Medical College on Ananthacharis advice. As he desired, the college principal, Dr N.G. Pandalai, allowed him to pursue his work on the liver with Ananthachari. His proposal fetched him the Lady Tata fellowship. He was the first to get the scholarship in 17 years after the pioneering Dr M.V. Radhakrishna Rao got it for Indian childhood cirrhosis , a subject that Sriramachari would return to later.

When he started, Sriramachari was the first to do liver biopsies in India. To train himself, he took the help of a mortuary assistant and did biopsies on unclaimed bodies. In those days, Sriramachari recalled in his interview, it was very difficult to get laboratory reagents. So he used to go to the abattoir and collect sheep brains and prepare cephalin-cholesterol emulsions. He did over 200 cases of liver biopsies and liver function tests as part of his research work. He and his supervisor Ananthachari published the results in 1954 in the Indian Journal of Medical Sciences.

His work on liver biopsies fetched him a job as an assistant research officer at the Nutrition Research Laboratories (NRL) in Coonoor, Tamil Nadu, where he joined Dr V. Ramalingaswami, the well-known medical scientist and a former Director General of the ICMR, in his department of pathology.

According to Sriramachari, in the post-War period, malnutrition was rampant among the children of plantation workers in the Nilgiris. They were afflicted with kwashiorkor, a condition which results in swollen feet and bodies and reddish discoloured hair. Sriramachari carried out liver biopsies on such patients and carried out tests using his new histochemical methods, which resulted in the first research paper on the disease from India, by Ramalingaswami and Sriramachari. In fact, the method of demonstration of fat in the liver that he had developed at Visakhapatnam was published in the British Journal of Clinical Pathology.

He also demonstrated using his techniques that fatty liver in alcoholic cirrhosis was different from the fatty liver of kwashiorkor, which had no cirrhosis but only mild fibrosis. In fact, he showed, on the basis of experiments on rats, how fat is released from the liver and how by modifying diets he could generate both kwashiorkor fatty liver and alcoholic cirrhosis liver in rats.

After this stint at the NRL, Sriramachari went to the U.S. to be trained in neuropathology at the Armed Forces Institute of Pathology in Washington, DC, the mecca of pathology, where he worked under Webb Haymaker, a world famous neuropathologist, and his colleague Leo Krainer. He returned after six months and registered himself for an M.D. degree in Visakhapatnam and later for a D.Sc. degree as well. At this time he also got a job at the All India Institute of Mental Health (now the National Institute of Mental Health and Neuro Sciences, or NIMHANS) in Bangalore. The country, according to him, had very few neuropathologists at that time, and he was the second person in India to be trained in the field.

At this time, he also completed his work on the reversibility of fibrosis and cirrhosis, a phenomenon that he had discovered during his work using rats, and the work was greatly recognised by world experts in the field. Sriramacharis notable work in neuropathology is related to neurolathyrism on which he has published an original piece of research in the journal Nature. His work fetched him a WHO fellowship to study at important centres of neuropathology in England and Germany.

It was around 1953 that he got interested in Indian childhood cirrhosis, on which pioneering studies had been done by S.T. Achar and others. Only two years ago, Sriramachari completed an authoritative report on the subject. It is a caste- and community-based regional disease, unique to India for over a century, he pointed out. What drew his attention to it was that there was cirrhosis only in the better-fed communities, such as Brahmins, Vaishyas and Khatris, in India. Over 50 years, he carried out over 2,500 liver biopsies to study the disease.

His research led him to conclude that the condition arose from metal toxicity in indigenous domestic therapeutic remedies in traditional homes. Indeed, the disease has drastically declined as the use of such potentially harmful remedies has given way to more modern medicines.

In 1962, he was summoned to the ICMR by Dr C.G. Pandit to initiate high-altitude research projects in the wake of the Sino-Indian conflict. At this time, he was invited by the All India Institute of Medical Sciences (AIIMS), New Delhi, which had no department of neuropathology at that time, to help it in the diagnosis of brain tumours. It was at this time that Sriramachari got interested in muscle pathology and worked with Indira Narayanan and Virmani. He has also carried out neuropathological research on the topo-optical properties of glial filaments of brain tumours as against other biofilaments such as collagen and reticulin. A controversy arose at that time about children dying in summer months, and there was a spurt of cases in Nagpur. The argument was whether the deaths were caused by encephalitis or hyperpyrexia or any other factor.

Along with the noted neurologist Baldev Singh and N.K. Patoria of Nagpur, Sriramachari, as the chief pathologist, found that the brain autopsies showed no encephalitis infection but showed oedema similar to the classic heat hyperpyrexia found by his mentor Haymaker. To prove the point, he simulated the condition in primates by subjecting them to increased temperatures in incubators.

Sriramachari also studied head injuries in a systematic way through simulation in primate models and showed that besides compression, concussion, haemorrhages and swelling, there were severe oedematous changes. He also evolved methods to correct the condition and restore normalcy. Sriramachari was also invited to investigate the Kanishka aircraft disaster of 1985 through autopsies and the death of Sivarasan, who was involved in Rajiv Gandhis assassination.

Besides his research work in histopathology and neuropathology, with which he was occupied until his last days, Sriramachari had a long-lasting and passionate interest in microscopy, photomicrography and photography. In fact, he had a collection of all kinds of microscopes and was interested in establishing a museum. Apart from his medical research work, his main interest was the study of Indian politics. He owned a large collection of books by Indian political leaders. He often expressed his concern about making medical education affordable and the need for low-cost educational aids.

Sriramachari served the ICMR from 1982 to 1987 as the Additional Director General. He won several national awards for his medical research including the Shakuntala Amir Chand Award, the Basanti Devi Amir Chand Award, the B.C. Roy National Award, the B.C. Guha Oration Award of the Indian Science Congress Association, the Jagdish Chandra Bose Award in Life Science and the Baldev Singh Oration of the Neurological Society of India. He was conferred the Padma Shri in 1985.