India: Poor expression

Despite administrative efforts, financial resources and almost 10 years of research, Indian genetic engineers have been unable to come up with a recombinant DNA product that is commercially viable.

The department of biotechnology (DBT) was set up in 1986 when policy makers realised biotechnology had the potential to address the country's health and food security problem. "Having missed the industrial revolution, there (was) a sense of urgency that if India did not move fast, it would miss the biotech revolution as well," says biochemist G Padmanabhan at the Indian Institute of Science in Bangalore, who is associated closely with DBT.

In the Seventh Plan, more than Rs 140 crore were allotted to biotechnology. And, Indian scientists have been trained in genetic engineering in more than 30 institutions in the country. But most experts agree that an Indian recombinant product is unlikely before the end of the century. Explains Padmanabhan, "This is not due to the lack of expertise, but due to lack of commitment and application."

Says D Balasubramanian, director of the Centre for Cellular and Molecular Biology in Hyderabad, "When biotechnology started out in India, any molecular biology project was interesting and received funding. But now, we need to consolidate what we know and push to develop products to meet the country's needs."

Indian genetic engineering is at least 10 years behind the rest of the world. Most scientists work on problems that are of a theoretical interest and only now have they begun to think of products. "Today it is the fashion to clone genes and express them in various vectors like viruses and bacteria," said one expert, "but merely producing proteins in laboratories is no guarantee of a product."

Genes for human growth hormone, bovine growth hormone, hormones that have potential applications as contraceptive vaccines and epidermal growth factors for treating burn victims have been cloned and their proteins produced in Indian labs. But the yields are too low to be commercially attractive.

To increase yields, it is essential to improve cells into which DNA is inserted to produce proteins. These recipient cells are known as expression systems. Says Padmanabhan, "In the US, companies try to express the same protein in 8 or 9 systems to see which is a commercially ideal producer. But we are clearly not equipped to do that because scientists here work only in systems they have experience with."

Moreover, Indian scientists are not sufficiently experienced in downstream processing techniques, which are necessary to extract the protein from a cell and purify it once it is expressed. "Downstream processing consumes 80 per cent of the cost and effort of developing a recombinant product," says Padmanabhan, "but we haven't even succeeded in cracking the 20 per cent effort required to get the molecular biology correct."

There is a need to train people as downstream engineers, stresses Kunthala Jayaraman, a molecular biologist at Anna University in Madras. Four recombinant DNA products -- insulin, interferon, erythropoietin and hepatitis B vaccine -- are imported by India. The DBT set up a task force in medical biotechnology to develop recombinant insulin, among other products. Says DBT director P K Ghosh, "It is unlikely foreign producers will part with their technology in the next five years, so we must have our own product."

Scientists in Delhi and Bangalore are trying to produce insulin but so far, no one is even close to developing the product, which was first cloned in the US in 1978 and approved for sale more than ten years ago.

However, the private sector seems to be succeeding. Scientists at the Bangalore-based Vithal Mallya Research Foundation claim they are close to an insulin product. Says C Ramdoss of the Foundation, "Not only have we overcome problems associated with expressing the hormone in commercially viable quantities, but we have found a way to overcome glitches in downstream processing and should be able to have a product fairly soon."

Another Bangalore-based private sector research lab, the Astra Research Centre India set up by the Swedish pharmaceutical giant AB Astra, claims to have also had success in producing several recombinant products. These are primarily reagents and bacterial enzymes essential for genetic engineering research.

The scene on the agricultural front is not much better. Says director general of the Indian Council for Agricultural Research V L Chopra, "(Recombinant DNA technology) is in its infancy". Efforts are under way to set up genetic engineering facilities in several ICAR labs, but most are still standardising procedures.

Some preliminary efforts, however, have yielded fruit. Asis Dutta of JNU has identified a gene from amaranth that clones for a protein which is nutritionally ideal. He intends to incorporate this gene into other cereal crops to enhance their nutritional value. Scientists at the Indian Agricultural Research Institute in Delhi have isolated a gene from a bacteria that neutralises the toxin produced by kesari dal (Lathyrus sativus). The toxin causes lathyrism -- a debilitating nervous disorder that affects the limbs. S L Mehta, head of IARI's biochemistry division, hopes to incorporate the gene into kesari dal.

To consolidate recombinant DNA research and make it more product-oriented, Balasubramanian moots the idea of a national consortium of agencies like the Indian Council of Medical Research, Council for Scientific and Industrial Research, DBT and DST. He says the problems must be addressed to ensure India is not left behind in the international race to develop genetically engineered products.