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Germ of a promise

More than 30 years ago, biochemist Gursaran “Pran” Talwar was studying bacteria isolated from the throat fluids of tuberculosis patients from across India when he noticed an organism that appeared to pose a puzzle and a promise.

The bacteria belonged to the family called Mycobacterium — a group of organisms that includes the germs that cause leprosy and tuberculosis. But this bacillus was harmless to humans. Instead, it could dramatically stimulate the human immune system and it cured patients on leprosy treatment faster. Talwar code named the bacillus “Mw”, but its place on the family tree of Mycobacterium remained unclear.

Mw has now become the first and only organism so far to have its full genome sequenced by a consortium of Indian scientists. And for the first time since its discovery in the 1970s, biologists have acquired insights into its lineage. A research team led by biologist Syed Ehtesham Hasnain in Hyderabad has shown that Mw is among the earliest ancestors of disease-causing Mycobacteria.

“Mw appears to be a great, great, great… grand-daddy of Mycobacterium tuberculosis,” said Hasnain, Distinguished Research Professor at the Institute of Life Sciences and vice chancellor of the University of Hyderabad. Mw is what scientists call a generalist organism, capable of infecting anything from cockroaches to humans and surviving in soil and water, in contrast to specialist Mycobacteria that cause leprosy or tuberculosis.

The study by Hasnain and his colleagues, published last week in the journal Public Library of Science One, suggests that Mw is an ancient organism that evolved in time into specialist disease-causing organisms. With the sequencing effort, Mw also has a new name — Mycobacterium indica pranii (Mip), the “nii” for the National Institute of Immunology (NII), New Delhi, where Talwar had done much of the research on Mip.

Researchers believe a detailed analysis of the full sequence of Mip will help them address a key question about Mycobacteria. “It’s an intriguing question — how and when did M. tuberculosis become pathogenic to humans. Mip has survived for perhaps millions of years. But during its evolution, a harmless Mip turned into M. tuberculosis which causes disease.

“A comparison of the genomes of M. tuberculosis and Mip may allow us to understand the changes in genes in this transformation,” said Hasnain. Scientists believe the sequencing effort might also lead to new therapies using Mip.

Through the 1980s and the early 1990s, Talwar and his colleagues at NII conducted clinical studies to show that the addition of Mip to leprosy treatment can accelerate cure. In 1998, Cadilla, the private Gujarat-based pharmaceutical company, acquired the technology for a formulation based on Mip and began to sell it as an immunotherapy product against leprosy that would reduce cure time by several months.

Mw also encountered some controversy. Some scientists weren’t happy with its unusual nomenclature. “What exactly is Mw' If it’s a Mycobacterium, it should be classified as such with a formal name,” one senior microbiologist at the All India Institute of Medical Sciences, Delhi, and a former colleague of Talwar, had said. The health ministry turned down suggestions that it should be used in the national leprosy eradication programme as an immune-boosting agent along with the standard drug therapy for leprosy. One health official simply said that when drugs were working, what was the need for an immune booster'

But the success with Mip against leprosy has prompted research efforts to evaluate it against several other illnesses, including tuberculosis, HIV and even bladder cancer. “This has become a fairly large research programme now… the hope is that Mip will kick off some compartment of the immune system,” said Maharaj Kishan Bhan, secretary, Department of Biotechnology, New Delhi.

The proposal for picking Mw for genome sequencing came from Hasnain. “It was a natural choice… a bacteria isolated in India, extensively studied in India, and used as a therapy in India,” Hasnain told KnowHow.

The Department of Biotechnology agreed to support the project. Researchers Anil Tyagi and Akilesh Tyagi of the University of Delhi, South Campus, who had earlier participated in an international rice genome sequencing effort, decided to use their infrastructure to unravel the Mip genome. “The follow-up work — the comparison of the Mip genome with other organisms is important,” Bhan told KnowHow.

The early studies suggest that Mycobacterium avium paratuberculosis (Map), an organism that causes a virtually incurable gastroenteric disease called Crohn’s disease — has also descended from Mip. The studies also suggest that Mip and Map bacilli initially lived in water and infected marine organisms predated by fishes, and finally arrived on soil through bird droppings.

“The genetic similarity between Mip and Map opens up the possibility that we may be able to evaluate Mip as a treatment option against Crohn’s disease,” said Hasnain. In the coming months, scientists also hope to use Mip genomic data to gain a better understanding of how this organism stimulates the human immune system, bolstering a response against leprosy and perhaps other infections.

Now retired, Talwar is still taking an active interest in the research on the organism that he almost nurtured. “I’m delighted… it appears as if Mip has more value that we thought it did,” Talwar said.

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