Biologist Ram Sasisekharan was teaching in an MIT undergraduate program at the Chulabhorn Research Institute (CRI) in Bangkok, when he began hearing news reports that the bird flu that had swept through Asia a few years earlier had resurfaced — and it was deadlier than before.
“It was quite troubling,” Sasisekharan recalls. “We were hearing stories about farms where every chicken died.” Scientists worried that the avian flu would jump species, causing a global pandemic on the scale of the catastrophic 1918 Spanish flu. “As the data was coming in, a big question that became obvious was: ‘What will be the mutation that could produce the switch’” that would enable the virus to infect humans. “The quest was on to figure out how the virus (known as H5 to the U.S. Centers for Disease Control) would mutate,” said Sasisekharan, the Edward Hood Taplin Professor of Biological Engineering and Health Sciences and Technology, who is on the faculty of the David H. Koch Institute for Integrative Cancer Research at MIT. He is also director of the Harvard-MIT Division of Health Sciences and Technology at MIT.
By 2007, avian flu had killed dozens of people, mostly those in close contact with sick poultry, and the disease remains a threat to birds in 60 countries, including Egypt, Indonesia, Nigeria, Bangladesh, Vietnam, and China. But thanks to Sasisekharan’s work, it may not endanger human lives in the future.
Sasisekharan studies large, complex carbohydrates called glycans to develop new drugs aimed at glycan-mediated diseases, including cancer and autoimmune diseases. Understanding these ubiquitous molecules could also aid doctors with disease progression and diagnosis — changes in sugars, for instance, are correlated with changes in human tumors.
“If we can figure out whether the sugars around cells are normal or altered, this yields practical applications for disease diagnosis and treatment, as well as answers fundamental questions,” he said. Sasisekharan’s laboratory helped uncover the chemical culprit responsible for the contamination of the anticoagulant heparin manufactured in China that caused 62 deaths in 2007 and early 2008. Heparin, like many modern drugs, comprises a complex string of sugars.
DNA has four basic building blocks; amino acids have 20. Carbohydrates’ long, branching molecules are made up of 48 possible different combinations of simple sugars. At MIT, Sasisekharan has developed the world’s largest glycomics databases. This utilizes an array of analytical techniques to decode carbohydrates’ convoluted makeup.
Researchers used to think that carbohydrates were no more than extracellular scaffolds, but carbohydrates are now known to influence the biology of underlying proteins, acting as catalysts for chemical reactions. They look, Sasisekharan said, “like a fur coat enveloping the skinny protein underneath.”
At the center of flu transmission are receptors in the human body. Carbohydrate molecules are displayed on the surface of vulnerable cells like beacons, signaling a host of molecules, viruses, and bacteria — some beneficial, some deadly — to recognize and bind to the cell.
TRANSMISSION OF FLU
The viral hemagglutinin (HA) protein binds to glycans on the surface of skin cells in the nose and throat. “Previously, the glycan diversity of the upper airways was poorly understood, which is ground zero where the transmission of flu viruses happens,” he says.
Sasisekharan realized that it was not just mutations in the sequence of genes in the HA proteins that were key, but also the shape of the glycans that are effectively shouting “bind here” to a passing virus. The glycan receptors come in both cone-like and wider umbrella shapes. The MIT team found that to infect humans, flu viruses must bind to the umbrella-shaped receptor.
“This work enables researchers to look at flu viruses in an entirely new way,” said Jeremy Berg, director of the National Institute of General Medical Sciences, which funded the research. “Now that we know what to look for, this could help us not only monitor the bird flu virus, but also further development of potentially improved therapeutic interventions for both avian and seasonal flu,” Sasisekharan said. “These findings could permit development of new drugs and vaccines against flu viruses of all kinds.”