Bangalore: One of the revolutionary discoveries in biology in the past decade has been gene silencing, the discovery of a molecular switch that can silence the disease-causing gene or mechanism in human cells.
The technique, called RNA (ribose nucleic acid) interference, or RNAi, has spurred a new class of specific and long-lasting drugs and diagnostics, galvanizing the global pharmaceutical industry to either acquire or fund this research.
Now, an Indian scientist in the forefront of global RNAi research, who in 1997 showed for the first time that genes could be silenced in fruit flies, is trying to use this technology to develop better diagnostics for cancer, moving, as it were, up against the stream as most of the global patents are held by just two companies.
“It’s very difficult to develop new therapeutics with RNAi as most of the patents are owned by US-based Sirna Therapeutics Inc., and Alnylam Pharmaceuticals Inc.,” said Utpal Bhadra, a senior scientist at the Centre for Cellular and Molecular Biology (CCMB) in Hyderabad. Sirna, a small biotechnology company, was acquired by Merck and Co. for $1.1 billion in 2006 while Alnylam signed a $1 billion alliance with Roche Holding in July 2007, signalling that the big pharma was throwing its weight behind RNAi, a discovery that bagged the Nobel prize for medicine in 2006.
Thinking big: Utpal Bhadra, senior scientist at the Centre for Cellular and Molecular Biology in Hyderabad.
Global patents have restricted Bhadra but, in some ways, have also propelled him to be innovative. With at least four major milestones in the basic science of RNAi since 1997 to his credit, Bhadra is now trying to modify the technique to bypass the patents. In close collaboration with a local biotech company, whose name he doesn’t want to disclose, Bhadra is developing an “easy-shot” diagnostic kit which will use microRNA (miRNA) profiling as a molecular marker for predictive diagnosis of cancer.
The tiniest entities in the human genome, miRNAs, have been lately found to be involved in regulating almost a third of all human genes. In other words, these tiny single-stranded molecules, estimated to be about 1,000 in number, control the turning on and off of a gene. Complementing it is RNAi, a naturally occurring process in the cell for silencing specific genes.
Bhadra says his diagnostic programme will be a complete, packaged test, ranging “from testing the susceptibility of the disease to its sub-classification and stage detection”. The technology is set to enter clinical trials in three months and “if it’s successful” Bhadra will file for a global patent.
Along with his wife and close collaborator at the Indian Institute of Chemical Technology Manika Pal, Bhadra says he is also trying to use this machinery to try prevent HIV, Japanese Encephalitis and cancer.
He wants to generate RNAi-based screens for HIV which would also be a sort of library to screen for genes involved in nearly any process of scientific interest.
These are of course long-term goals and Bhadra is already acting as a chief technology officer, of sorts, for a company, iBrain Life Sciences, which intends to develop RNAi-based therapeutics as well as use this technique to “artificially engineer stem cells”.
“We have acquired land for a hospital where our clinical research in cell therapy will be carried out,” said Shravan Rao, chief operating officer of iBrain.
Enormously potent as this technology is, scientists believe laying down basic infrastructure for cell-based therapies is the responsibility of state-funded institutions. “You cannot expect the industry to invest in such areas,” said Lalji Singh, director of CCMB, who is setting up a “high throughput screening” facility for RNAi.
“Just a handful of such facilities exist in the US and we are trying to set it up here so that if one needs to diagnose cancer, the RNAi can be screened against all 25,000 genes (the approximate number of genes in the human genome) to check which one is effective in silencing the defective gene,” said Singh. He thinks only then will RNAi become useful for commercial purposes.
In fact, commercial opportunities of the study extend to agriculture as well. RNAi can be used to make transgenic crops, which are not controversial such as the traditional genetically modified crops because they are made by a natural process inbuilt into cells to combat viruses.
“Genetic engineering is an artificial process, but RNAi is already present in higher organisms ranging from plants to mammals,” said Sunil Kumar Mukherjee, a scientist at the International Centre for Genetic Engineering and Biotechnology in New Delhi. Mukherjee is currently engineering artificial miRNA genes to fight tomato leaf curl viruses, the deadly pathogens of tomato.