Better Prescription

After open source software, it is now the turn of open source drug research. If this unique process can find a new anti-TB drug, it might well become the future of drug research. G.S. Mudur reports
In the temple town of Thanjavur, Aparna Venkatachalam, a final year engineering student, has turned into a foot soldier in a fresh scientific assault on the microbe that causes tuberculosis. After combing through some 200 research papers and spending dozens of hours searching online biological databases, she has assigned functions — biological tasks — to 60 proteins found in the TB microbe. She picked up a reward for her efforts last week — an Acer Netbook.

Venkatachalam is one of a group of 120 students and researchers scattered across India, Dubai, Japan and Germany, who have put together the most detailed map constructed so far to describe the biochemistry of a living organism. The 18-month science project, spearheaded by India’s Council of Scientific and Industrial Research (CSIR), is seeking new drugs against the TB microbe in a manner never attempted before.

“When you want to destroy an enemy, it’s good to identify vulnerabilities,” said Samir Brahmachari, director general of the CSIR. “This map will provide us unprecedented insights into the biochemistry of the TB micro-organism.”

The search for new drugs against TB is the first project of the CSIR’s Open Source Drug Discovery (OSDD) programme, a Rs 150 crore effort to solve complex problems by breaking them into smaller “work packets” open to virtually anyone across the scientific community to solve. The challenges are posed on the OSDD website, and researchers wishing to try and tackle them need only to register and join the effort.

An international consortium of scientists had sequenced the genome of the microbe Mycobacterium TB [MTB] nearly 12 years ago. And over the past decade, scientists have identified 3,998 genes, and assigned biological functions to all but nine of them.

The OSDD effort has now generated a map that places about 3,700 MTB genes and their protein products into a network of biochemical pathways. The network, a web of biochemical reactions, shows how these genes and proteins allow MTB to carry out its myriad life-cycle activities — from invading human cells to evading the human immune system to routine housekeeping.

“It’s a very big and a very complex circuit,” said Hiraoki Kitanu, director of the Systems Biology Institute in Japan, who leads a research team that has contributed significantly to the development of a computer-readable format to display models of biological processes, and who has joined the OSDD effort. “This is a new approach for drug discovery,” Kitanu said.

Scientists believe MTB is an appropriate organism to pit innovative ideas against. This killer microbe claims about 1,000 lives across India each day. The four best anti-TB drugs that make up the first line of therapy were developed in the 1950s and 1960s. Secondary drugs are toxic and expensive. There are now drug-resistant versions of MTB, which pose a new challenge. While clinical trials are under way, a new drug is not expected to be ready for use until 2012.

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All previous efforts at finding drugs to fight MTB involved a laborious trial-and-error method in which researchers exposed the organism to compounds and picked the ones that appeared most effective in killing bacteria or suppressing their growth. Researchers believe that the map of biochemical pathways will now allow them to choose specific regions of the pathway as targets for future drugs. “Instead of shooting in the dark, we’ll be searching for targets in a rational way,” said Anshu Bharadwaj, a scientist at the Institute of Genomics and Integrative Biology, New Delhi, who, among other roles, also assigns work packets to OSDD researchers.

Some 800 researchers — most of them students — joined the effort, but only some 120 who succeeded in assigning functions to at least 40 genes — Venkatachalam among them — were picked to receive the reward. One of them was a homemaker from Dubai who had used her skills in bioinformatics to help build the pathways map. All those who won a reward, however, did not attend the meeting in Delhi — a software engineer from Germany told the OSDD that he doesn’t travel as he is wheelchair bound.

Venkatachalam, a bioinformatics student at SASTRA University in Thanjavur, and her colleague Ahalyaa Subramanian scanned published scientific literature to tell the stories of 60 MTB genes. In all, Brahmachari estimates, the consortium of researchers scanned at least 12,000 research papers on TB and compiled the information in a standardised format to build the map.

Some biologists caution people not to expect a new drug too soon. “I’m very optimistic this is going to have an impact,” said Richard Jefferson, a molecular biologist based in Australia and chief executive officer of Cambia, a non-profit institute seeking to promote innovation. “But it’s important we do not expect too much too soon. It’s going to be a long fight,” Jefferson said at the OSDD meeting last week.

In the drug discovery process, scientists will have to look for “vulnerabilities” in MTB pathways that can be exploited to design a new drug. Researchers say that one of the biggest challenges will be to find compounds that act exclusively on MTB. “We’ll need to find a vulnerability exclusive to MTB that leaves the human system alone,” said Bharadwaj.

Brahmachari himself has ventured to suggest that the effort could lead to a new candidate drug ready for clinical trials within two years. If that happens, said Brahmachari, the OSDD will invite five drug companies to invest four per cent of drug development costs, while the CSIR will provide the remainder 80 per cent. Each company would then get an opportunity to produce inexpensive generic versions of the drug.

If the OSDD does indeed deliver a new and effective drug for TB, it might trigger a paradigm change in drug research.

Source: The Telegraph (Kolkata, India)

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