Bangalore scientists to unravel schizophrenia puzzle
SHARITA RAI

BANGALORE, MARCH 18: In one of India's most ambitious and exciting genetic research projects yet, the Bangalore-based National Institute for Mental Health and Neuro Sciences (NIMHANS) is heading a multi-institute study to understand the complex nature of man's susceptibility to Schizophrenia through "establishing an uniquely Indian base". This, even as it seeks to join scientists in the UK, Germany, US, Scotland and France who are already in the race to take on the "intellectual challenge" that might eventually help man understand how the "human brain works".

With funding from the Science and Technology Ministry's Department of Bio Technology, the project -- led by Dr Sanjeev Jain, Additional Professor of Psychiatry at NIMHANS -- is already underway, with an identified sample population of a 100 families collected over the last year. Another 200 families will be identified over the next two years to meet the diverse requirements of the project, which aims to understand the peculiar nature of the susceptibility to the disease -- known to depend on a whole range of complex gene-environmental interactions. But even this is a mammoth task, because only 10 per cent of Schizophrenics have "first degree relatives" or rather affected siblings or parent.

Dr Jain, on NIMHANS faculty since 1986, has been mainly working on the biology of Manic Depression, a mental disorder that manifests as "mood swings". But since his return from UK in 1994 following a Commonwealth Fellowship to University of Cambridge, England where he specialised in molecular genetics, the scientist has been doing molecular studies on both Manic Depression and Schizophrenia.

Schizophrenia is one of the most complex genetic diseases. And not just because it is polygenic -- caused by more than one gene. "Our technical knowledge of genes has so far been used for a static evaluation. But here there are no known physiological defects. So it has to do with qualitative changes that occur in the way a person deals with the realities in the environment" says Dr Jain. Most Schizophrenics develop it before the age of 25. So there is a "great role of puberty, hormonal changes and stress" involved. Like Diabetes one may carry the disease gene, but never have it expressed, because of environmental factors like dietary control.

It is not surprising therefore that Schizophrenia continues to be one of the great puzzles before the world scientific community. In fact, as far back as 1988, within years of the Human Genome project being initiated, the very first paper using sequencing and gene mapping techniques was published, following a UK-Iceland collaboration. But within two years the paper had to be withdrawn as the findings could not be replicated.

Since then there have been positive results from Germany, US, Scotland and France. But not one finding "was repeated in any country". In India, the attempt is to establish a uniquely Indian base through which to understand the myriad gene-environmental interactions that cause the disease to manifest. What makes the task more compelling is that a World Bank report anticipates that by the year 2005 Schizophrenics will rank 4 or 5 among the global burden of diseases, above cardio-vascular diseases and after cancer. The World Bank estimates the levels of social care to be of a stupendous dimension considering the fact that it implies taking care of a person for a good 50 years -- under-25 to over-75 in a given life span.

Of the 1,40,000 genes in the Human Genome being sequenced, half are in the brain, of which a large proportion are expressed only before birth. So understanding the biology or genetics of the brain is one of the most challenging tasks for the geneticist, even as mental diseases are by far the commonest. In India, nearly 2 crore of its 100 crore population suffer from Schizophrenia. This, as against epilepsy which accounts for a one per cent incidence and mental retardation, another one per cent. Together, not including Parkinson's and Alzheimer's, they account for an incidence nearly three times that of heart diseases and diabetes, both genetically predisposed. Then again Schizophrenia is more than a "bit different" from epilepsy because it cannot be classified and narrowed down to specifics. Also because "we have no idea what Schizophrenia is, in absolute terms" adds Jain.

What the project is therefore looking at, are large sample families and ethnic groups that are sub-culturally and biologically distinct populations, so as to "compare and contrast" the findings -- something that is not possible in Europe, says Jain. But the downside of that is that since multiple genes are involved in the study -- the sequencing information being dealt with is "too much" requiring a "highly complex computational task". So the first stage of the study would be to look at "particular chromosomes - two or three and do a linkage map" within the sample families and population.

There are also advantages to this kind of research. Off-shoot findings that provide a better understanding of the human diversity. For instance, the "triplet repeat genes" are a part of the DNA that repeat itself. When it repeats over 40 times it causes various mental disorders like the Fragile X Syndrome.

At NIMHANS, the approach has already paid dividends. "We have looked at certain of these genes in Schizophrenia and have reported that in general, Schizophrenics have unequal repeat gene sizes than normally" says Jain. But "nobody has been able to pinpoint a particular expanded triplet in Schizophrenia". Though subtle variations in these genes may be contributing to the risk of Schizophrenia, they vary from person to person.

At one of the repeat genes for instance, it has been found that the distribution of that gene in the South Indian population is similar to the German but different from the Japanese. Certain other genes similar to the Japanese are not similar to the Germans.

The diversity of India's population is becoming a unique tool to understand these mechanisms. After all, perception of the reality, thought processes and mood swings -- the susceptibility factors of Scizhophrenia and Manic Depression -- "covers most of what makes us human" adds the scientist.

The Collaborators:

Partho Majumdar, Director, Indian Statistical Institute, Calcutta will consider the population genetics aspect.

Dr Samir Brahmachari, Director, Centre for Bio Chemical Technology, New Delhi will look at how the triplet repeat gene works in Schizophrenia.

Clinical studies will be done by a team led by Dr P Kulhara, Head of Psychiatry, Post Graduate Institute, Chandigarh.

Dr Sanjeev Jain will do the linkage experiments with the neuro-transmitter related genes.

Dr Anuranjan Anand, Head, Genetics Lab at the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, will study the specifics of drug responsiveness, so as to contribute towards the design of new drugs.

Copyright © 2000 Indian Express Newspapers (Bombay) Ltd.