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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.

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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Detect Blood Cancer, the Calcutta Way

Discovery by Scientists at the Saha Institute of Nuclear Physics :-


Ten years ago, when biophysicist Abhijit Chakrabarti started looking at telltale proteins in the red blood cells of children suffering from leukaemia, there weren’t many takers for his research.

Chakrabarti, professor of biophysics at the Saha Institute of Nuclear Physics (SINP) in Calcutta, believed that the intriguing protein signatures might, some day, help doctors identify blood cancer at an early stage and customise cancer therapy for each patient, instead of relying on a one-size-fits-all approach.

“Even experts couldn’t relate to the study of proteins for clinical application,” says Chakrabarti. “Those were the heyday of gene discoveries.” Now things have changed dramatically in favour of proteins, the body’s workhorse molecules. Scientists as well as drug makers have realised the limitations of gene-based data.

A series of publications by Chakrabarti and his team in international journals such as the British Journal of Haematology and the European Journal of Haematology is testimony to how quickly the young field of large-scale analysis of proteins — known as proteomics — is growing. The nascent field of research involves efforts at developing methods for sifting through thousands of different proteins in the blood. The goal is to identify the trace proteins — called markers — that are leaked by tumours into the blood, to be subsequently used for early and more accurate diagnosis of cancer and other diseases.

If all goes well, Chakrabarti hopes their work will some day yield simple tests that will allow for early diagnosis of childhood cancers like acute lymphoblastic leukaemia (ALL) — diseases that can prove fatal if not detected at early, and more treatable, stages.

“It is very important, both to diagnose childhood leukaemia as early as possible, and to determine what type of leukemia is present so that treatment can be tailored for the best chance of success,” says Dr Debasish Banerjee, haematologist at the Ramakrishna Mission Seba Pratisthan, Calcutta. “At present the therapy is based on genetic changes in leukaemic cells, which helps in classifying patients into specific risk categories. This is known as risk-based stratification therapy,” he adds.

Haematologists usually deploy gene chips or DNA microarrays to gauge the changes. One big problem with the strategy, however, is that the genetic chips offer a ‘global’ view of cancerous changes, not the ‘ground level’ view in the proteins. “Another very important issue is monitoring the response to a therapy of the diseased cells,” says Banerjee. He believes that the current diagnostic tests fail to tackle these problems. “Proteomics can not only take care of both the problems but also diagnose minimal residual disease (MRD) responsible for a relapse after therapy is complete.”

Chakrabarti’s recent foray — presented at an international symposium on Complex Diseases: Approaches to Gene Identification and Therapeutic Management, in Calcutta — is critical in the search for marker proteins among a vast sea of proteins in blood serum. “It’s like looking for a needle in a haystack,” says Sutapa Saha, a co-researcher. “Blood serum is an extraordinarily complex mixture of thousands of proteins,” she adds.

What’s more, any two proteins may exist in concentrations that differ more than a billion-fold from one another. “Systematically searching for the potential candidate proteins from thousands of others is extremely painstaking work,” says Dipankar Bhattacharya, another researcher involved in the project. After years of persistence the SINP team has been able to hunt down 80 such proteins. The study is scheduled for publication in the journal Proteomics – Clinical Application.

To guide their search, the Chakrabarti’s lab uses instruments like mass spectrometers, which can sort mixes of proteins, based on size, weight and electric charge. Since every protein is different, each has an equivalent of a molecular “barcode” to distinguish itself. The goal, Chakrabarti says, is to find proteins that are present only in the blood of people with cancer or are at detectably higher levels in people with cancer than in healthy individuals.

Chakrabarti is pursuing another approach too in finding cancer-specific markers, based on the immune system’s ability to act as a “biosensor” of disease. “It’s well known that the immune system can recognise cancer cells as abnormal and react against proteins made by tumours,” he says. “One of our approaches in finding proteins made by cancer cells is to see what antibodies or immune cells are produced by the immune systems of people with cancer but are not made by healthy systems.”

Despite the stiff challenges the team faces, drug designers have concluded that protein-based diagnostic tests hold greater promise than those exclusively based on genes, which are the DNA blueprints that cells use to make proteins. Proteins are more relevant to the biological functioning of the cell and most drug targets are found in them. Above all, proteomics assays, or protein-based diagnostic measurements, can be applied to readily available biological samples like serum and urine. “ The current dogma is: to understand genes better you need to read the proteins too,” says Chakrabarti.

Sources: The Telegraph (Kolkata, India)

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