It Two years may be a long time to hunt down an elusive killer, but for the seven-member team it was well worth the wait. Identified as SPINK 1, the vicious nibbler had chewed up many a pancreas and had turned into a killer in cases where it had not been stopped in its tracks. So when the joint team from the Asian Institute of Gastroenterology (AIG) and the Centre for Cellular and Molecular Biology (CCMB), Hyderabad, tracked down the gene responsible for causing tropical calcific pancreatitis (TCP), it was cause for celebration.

SPINK 1: HOW THE MUTANT GENE ACTS 1. Pancreas secretes trypsinogen, a digestive enzyme, which is converted into trypsin in the intestine, which helps digest food. 2. If trypsinogen is mistakenly activated in pancreas instead of the intestine, it leads to pancreatitis. 3. Scientists have discovered the gene SPINK 1 which blocks the activation of trypsinogen in pancreas. 4. When SPINK 1 is mutated, it cannot stop the enzyme activation in pancreas, leading to the disease.

The research shows that in patients suffering from TCP, the SPINK 1 gene is mutated, resulting in the release of an enzyme that eats up the pancreas and can trigger diabetes early in life. The pancreas plays two critical roles in the body: helping in digestion and producing the hormone insulin whose deficiency leads to diabetes. It secretes trypsinogen, an enzyme that in the intestines is converted to trypsin, which helps digest food. The problem begins when trypsin is activated in the pancreas itself. The SPINK 1 gene produces a protein called pancreatic secretory trypsin inhibitor (PSTI) which controls the activation of trypsin in the pancreas and thus stops auto-digestion. When the gene malfunctions, it can lead to recurrent pancreatitis attacks.

The symptoms begin in childhood with abdominal pain, followed by diabetes in adolescence and early death by 40. In others, chronic pancreatitis damages the gland and its deterioration can lead to cancer, uncontrolled diabetes and renal complications. All this is set to change with the identification of the gene, opening up opportunities for early diagnosis and scope for gene manipulation or gene therapy and other methods of cure. "It will now be possible to screen patients, treat them at an early stage with medicine, endoscopy, modify the course of the disease and arrest it," says AIG Director Dr D. Nageshwar Reddy. He led the team that detected the gene and included Dr G.V. Rao and Dr P.V.J. Sriram of AIG, and Dr G.R. Chandak of CCMB. Further, by identifying the abnormal gene in childhood, doctors could suggest precautions to avoid the incidence of pancreatitis or diabetes.

The study also suggests that the genetic basis for many Indian diseases is different from that found in Europe and the US, where the commonly occurring pancreatitis is due to alcohol abuse. "This is the first time that the genetic basis of TCP, a disease specific to the tropics, has been established. The gene mutation could also be used as a screening tool for patients as well as unaffected relatives of patients," explains Chandak. This could lead to early intervention therapies, especially in populations susceptible to the disease, and even prevent its transmission to the next generation through genetic counselling. In the long-term, scientists may be able to pluck out the faulty gene from the foetus and provide a correct copy of SPINK1. Currently, however, the doctors are unable to explain why the TCP erupts and persists in a chronic form.

The study has also revealed that the disease is found to be more prevalent in Kerala, Karnataka, Andhra Pradesh and Tamil Nadu and some parts of Orissa, with the incidence particularly high in parts of Kerala like Kottayam and Kollam where one in every 1,000 persons suffers from it. As most cases of chronic pancreatitis were observed in south India, dietary items like cassava or jowar and fuels like kerosene were initially considered the triggering factors. The doctors had been baffled and research papers had blamed the disease on diet, lifestyle, and environment.

The AIG-CCMB study, published in the Journal of Medical Genetics, London, on the presence and role of SPINK 1 is corroborated by independent probes. But much more needs to be done. "Perhaps for the first time, gene mutation has been found to be the cause of gastro-intestinal disease in India," says Reddy, suggesting such diseases need to be investigated in India, not abroad.

For now though, the discovery of SPINK 1 has the medical community intent on providing relief to the suffering masses in India.

— Amarnath K. Menon