The Telegraph
Sunday , June 29 , 2014
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Spunk and struggle behind Indian-led science feat

(From left) Babylakshmi, mother of two young children; Nazia, who turned down marriage proposals to pursue her PhD; Sneha, who chose microbiology over engineering; and Santosh, who packed incense sticks to supplement his parentsí income when he was a schoolboy

New Delhi, June 28: The most comprehensive map yet of proteins in the human body, the result of a 30-month research effort driven by a team of Indian scientists, wouldn’t have emerged without some defiance, some daring and some struggle.

A 72-member team with over 40 Indians last month released a draft map of the human proteome, a catalogue of 17,294 proteins that could help scientists unravel many of the body’s mechanisms and search for new strategies to treat myriad diseases.

Without a pinch of defiance, team leader Akhilesh Pandey might have been an Indian army doctor instead of a biologist in the US who, as a pilot and certified flight instructor, flies a four-seater aircraft for fun twice a month.

India’s protein mappers worked out of Pandey’s lab at the Johns Hopkins University School of Medicine, Baltimore, and the Institute of Bioinformatics (IOB) in Bangalore, a private institution he set up 12 years ago using his credit card and borrowing money from his parents and brother.

The researchers have catalogued 84 per cent of human proteins already predicted and discovered about 200 new ones too.

Team leader Akhilesh Pandey flying an aircraft

Without some daring, the draft human proteome map might not have emerged from this Baltimore-Bangalore collaboration. For, Pandey’s team has pulled off what some might call a scientific feat on a shoestring budget, beating research groups across the world trying to put together the proteome map for over five years.

Pandey said the idea of plunging into the race for the human proteome occurred to him at a scientific conference in Sydney in September 2010 where he heard that China was about to pour millions of dollars into an effort to map the human proteome.

“I saw a window of opportunity and thought we could do it before others,” Pandey told The Telegraph. “I knew a little about the inside workings of proteomics activities in China and I thought they were not really ready — we had a chance to get to the finish line first.”

He flew back to Bangalore’s IOB, called a meeting of research scholars and asked how many thought it would be a good idea to take on the proteome task. The scale of the task, everyone knew, would be daunting. But all hands in the room went up.

Without some struggle — either with circumstances or with themselves — several members of the team might have been doing something quite different.

Biologist Harsha Gowda from Channarayapatna, a town near Hassan in Karnataka, lost his father when he was seven and could complete school only with the help of a scholarship for bright students.

Gowda helped design the protein-mapping study, laid out a work plan for data analysis and supervised tasks assigned to younger team members.

Santosh Renuse, from a village near Pune, also bagged a school award for outstanding students that brought him uniforms, books, stationery, even shoes. He is a PhD student at the IOB and helped extract proteins from the liver, pancreas and the breast.

Renuse recalls that when he was in Class VI, he had to pack incense sticks to supplement his parents’ income.

Nazia Syed from Lucknow — with backing from her parents — turned down marriage proposals because the prospective grooms’ families wanted her to quit pursuing her PhD.

Sneha Pinto, from Bangalore, chose to study microbiology in college, resisting parental pressure to pursue engineering.

Babylakshmi Muthusami, who had joined the IOB in 2002 and then quit to have babies, returned to the lab leaving a two-year-old son and a four-year-old daughter in day care.

And Raja Sekhar Nirujogi had to tear himself away from his seven months pregnant wife — his university sweetheart — for mapping tasks that could be done only in Baltimore.

Syed, Pinto and Nirujogi contributed to proteogenomic analysis — the task of finding connections between the 200 new proteins the team discovered and sections of the human genome that produce those proteins.

Syed analysed proteins in the liver and ovaries, while Pinto identified proteins in the adult heart and foetal brain and the retina. Muthusami helped analyse and build an interactive web portal — — to serve as a resource for the global scientific community.

“This is a very significant advance, not just for the work done but also for building capacity and confidence among young researchers to push the boundaries of scientific enquiry in India,” said Saman Habib, a senior scientist at the Central Drug Research Institute, Lucknow, who was not involved in the protein-mapping effort.

India didn’t play any role in the international human genome sequencing effort that was completed in 2003 and has led to the identification of over 20,680 genes.

But genes merely provide the blueprint for proteins. Almost every biochemical action in the body, during both health and disease, involves direct action by proteins.

A proteome map could improve knowledge of the mechanisms underlying virtually all diseases — from cancers to cardiovascular diseases, from infections to brain disorders — and contribute to the design of new strategies to treat them.

While an international research consortium had developed a plan to assign each human chromosome to members of the consortium to map all proteins on each chromosome, Pandey decided to directly extract all the proteins from all human cells, tissues and organs.

The Baltimore-Bangalore team extracted proteins from human blood cells, 17 adult tissues or organs — including the brain, colon, lungs, kidneys, ovaries, pancreas and the spinal cord — and seven foetal tissues, including the placenta.

The scientists sliced the proteins into smaller units called peptides and used an instrument called the mass spectrometer to identify each peptide with its unique signature. Then, using computational methods, they compared their observations with a database of proteins and put together a list of proteins expressed in each tissue.

Scientists had estimated that the human proteome-mapping effort could cost anywhere between $200 million and $1billion and take up to five years. The mapping effort by the Baltimore-Bangalore team didn’t get direct funding.

Instead, the researchers took time and a bit of resources away from other projects at the IOB and the Johns Hopkins University and worked extra hours to pull off what Pandey calls “a side project”, spending, he estimates, only about $700,000.

“This is a landmark result,” said Albert Heck, a senior scientist involved in proteomics research at the University of Utretch in the Netherlands. But Heck and others cautioned that the functions of proteins in each of the tissues needed to be determined to understand their role in the body.

This wasn’t the first time Pandey had decided to follow his intuition.

Thirty years ago, he had stood first in the National Defence Academy entrance exam but chose to study medicine at the Armed Forces Medical College in Pune. He enjoyed medical school but thought medical practice would be somewhat repetitive.

After graduation in 1988, he told his parents he wanted to become a researcher and discover knowledge rather than practise what others had discovered.

His father, an air force officer, appeared unhappy with that decision. But his mother convinced his father through several post-dinner talks to let the 21-year-old Akhilesh follow his urge.

“Thank God, my dad agreed,” said Pandey. His father sold the family’s new Maruti 800 to raise the Rs 75,000 required to allow Pandey to breach the bond of a permanent commission in the defence services that all Armed Forces Medical College students have to sign.

Pandey moved to the US for doctoral research and training in pathology around the time the global biology community began sequencing the human genome. When the genome sequence was completed in 2003, Pandey was a research scientist in Denmark.

But a tug to establish something of his own had pulled him to Bangalore in 2002 where he established the IOB, investing Rs 1 crore of personal and family money.

Most researchers at the IOB are PhD students, receiving government-sourced stipends from institutions such as the Council of Scientific and Industrial Research. “Many could have earned a lot more in software or engineering,” said Pandey.

When Pandey isn’t in his laboratory or at home with his Danish wife Annette and daughters Maya and Leena, he likes to fly. He got a pilot’s licence while in Boston in 1998 but went ahead to get himself certified as a flight instructor.

“A flight instructor’s task demands greater proficiency. I just wanted to get there,” he said. That attitude may have pushed him into the race for the proteome map.

Another research group led by Berhard Kuster, a biochemist at the Technical University in Munich, Germany, also last month independently presented evidence for proteins for about 18,000 genes, with a core set of 12,000 proteins from different tissue.

Both draft maps were presented in the journal Nature.

But scientists say much work remains to be done. “Seeing evidence of a protein tells us little about its functions,” Heck said. “The functions depend on the protein’s micro-environment, its interaction partners, and tissue-specific versions.”