FOR LONG, SUGARS HAD LONG BEEN THOUGHT TO be mere energy- yielding molecules: food for cells, if you will. They were seen as structural elements, sometimes often a nuisance to working out the mysteries of the protein. Moreover, scientists were stymied by the lack of tools to actually decode the structure of sugar molecules that coated each cell. But later new research found sugars to be at a very interesting point vis a vis the cells. They were discovered to actually have an effect on regulating and influencing protein functions and actually influencing their functions. But how they did it, scientists had no way to know. Until now.

At a time when most scientists were busy trying to unlock the mysteries of proteins and DNA, Ph.D. student and itinerant researcher at the Massachusetts Institute of Technology, Ram Sasisekharan, decided that he wanted to do something more esoteric. And that led him through a path of discovery that would, twenty20 years down the line, lead to one of the most exciting discoveries in healthcare. And in the process, he threw the lid off a $2 billion drug industry.

It all started in the late 80s, when Sasisekharan, an associate professor of Biological Engineering, began to hunt for a project for his doctoral studies at the department of chemical engineering laboratory of the redoubtable Prof. Robert Langer of MIT. The medical world in the 80s was warming up to the potential of proteins and sequencing it to produce new and ever more exotic cocktails of drugs. But Sasisekharan chose to investigate what was then the poor cousin of proteins, the third biopolymer called polysaccharides—or, in layman’s terms, sugars.

In order to study polysaccharides, Sasisekharan first needed to determine the sequence of building blocks that make up this sugar. Convinced of the potential value of sequencing complex sugars, Sasisekharan, in turn convinced a fellow research associate, Ganesh Venkataraman, to devise a way of converting the complicated chemistry into a string of numbers. To do this, Sasisekharan’s graduate student, Rahul Raman, utilized computers to keep track of the possibilities. The computer would compare and contrast sequences, showing where they were the same or different. In essence, the numbering system and computation let the scientists determine every possible sequence for a sugar.

Having found a way to determine every possible sequence of the sugars, the duo needed to break them into smaller pieces that would be easier to analyze. For that, Sasisekharan developed a collection of other enzymes and chemicals that act as biological scissors. He and Venkataraman cut up the sugar molecules with scissors, determined how many pieces it made—which depends on the specific scissors and where it cuts the sugar being tested—and used a mass spectrometer to weigh each piece.

The computers then identified which, of all the possible sequences, would produce a number of pieces that weigh this much when exposed to different sugars—cutting tools or enzymes? That, again, eliminated some of the possibilities leading to a process of elimination strategy for sequencing. The scientists then used a different pair of scissors and repeated the process until they narrowed down the possibilities to one.

Eventually, only the exact sequence remained. Sasisekharan and published that work in 1999 and patented the technique. Thus, in the course of over a decade of research, they came up with a practical tool to decode the sequence of sugars on cells. What he found startled the clinical community.

He and his team decided to test a sugar-based molecule that was already in the market. They settled on Heparin and low molecular weight heparins, one of the world’s largest selling anti-coagulants (anti-clotting agents). The drug was used the world over for cardiac treatments. But Heparin was also one of the few drugs,, which was described in terms of what it did and not how it did it. Little was known about it apart from its anti-coagulant properties. Sasisekharan delved into the secret of Heparin’s anti-coagulant properties.

“Once we had a method to sequence sugars, various applications for clinical use were just waiting to be found,” says Sasisekharan.

Sequencing Sugars
Sasisekharan’s sugar sequencing tool helped him and his team co-relate Heparin’s structure with its anti-coagulant properties. And, in the process, discovered a way to tailor the drug to the exact requirement of clinicians.

“We went to cardiologists and clinicians and asked them, ‘what would your ideal Heparin or low molecular weight heparin molecules be?’. And it turned out that the present Heparin low molecular weight heparins molecules could not be monitored or neutralized effectively. So, our goal was to make these drugs safer by being able to neutralize them on demand. We used our sequencing technology to study the structural activity and showed that we could not only make the drug more potent, but also monitor it because there are some sequences that enable it to be monitored, and also we could neutralize it with the current techniques.”

Sasisekharan’s research on sugars also unearthed a cascade of other potential applications that could significantly improve outcomes for patients undergoing major operations such as heart bypass surgery and impacts a multibillion-dollar drug industry. In the year 1999 alone, there were approximately 600,000 Coronary Artery Bypass Graft (CABG) surgeries worldwide.

A Cure for Cancer
A cure for cancer is just one of the many applications of Sasisekharan’s landmark discovery. “Cancer cells have a sugar coat on them that influences whether these cancer cells stay dormant or become active. And exchanging the sugar coats, you can make the cells more active or inhibit them,” he says.

The sugar tested by Sasisekharan was one of a family of molecules called heparin sulfates commonly found on cell surfaces throughout the body. Sasisekharan’s team found that different forms of heparin sulfate had sharply different effects on tumor cells. One form of the sugar actually speeded up the growth of the tumors and caused the cancer to spread throughout the body. Another related sugar, by contrast, slowed the growth of virulent skin and lung cancers.

A Momentous Discovery
So excited was Sasisekharan with his findings that, to explore its commercial potential, he founded a company, Momenta Pharmaceuticals (initially christened Mimeon), along with his former professor Langer, and Venkataraman.

The closely held company applied for and won the intellectual property rights for the technique and drugs made by using it. Momenta also completed a coup when it attracted industry veteran Alan Crane as chief executive officer. Alan Crane has made his bones as a vice president of corporate development at Millenium Pharmaceuticals, bringing in more than $2 billion in alliances to the pharma company.

Says Sasisekharan, “Sequencing DNA led to the biotech revolution and we think that sugars are at that juncture now. The next revolution will be in terms of really being able to have an impact in new drugs and also more importantly, being able to understand the drugs that are already available in the market and make them more potent and more effective and reliable.” Sasisekharan reckons that Momenta is very aggressively poised to do just that.

In fact, so great is the opportunity in the field of glycomics that Momenta currently focuses only on that field. “Our goal is to be in the top ten companies associated with glycomicsbiotechnology companies. The biggest thing in the current market scenario is “products” and Momenta already has a few products in the pipeline,” Sasisekharan reveals. In the near future, however, Momenta will focus on heparin and low molecular weight heparins, already a market of more than $2 billion and expected to grow at 10 percent per year to a $4 billion industry by 2009.

Exciting Time Ahead
Sasisekharan agrees that feels it is a time for exciting discoveries. “The National Institute of Health has funded a large effort to the tune of $35 million over the next 5 years to get the thought leaders and the key people from the U.S. and Europe to come together and understand the sequencing of sugar and how it affects the biology, and how to profile cells and leverage the information thereof glycomics.”

Sasisekharan himself is part of the consortium that spans universities and industry across the U.S. and Europe and heads the bio-informatics core of the consortium. With their help, he hopes to discover more applications that may eventually benefit millions around the world.

Sasisekharan emphasizes the need for a close working relationship between industry and academics in order to make the most use of technological advances. “It is very important to do science not just for the sake of doing science but also to see what one cancan you translate into in terms of practical value. To be able to do something that has a lot of practical significance was very important to me. I always look at any technology and see how it can be applied to a particular situation and look for the practical value of the application. That’s one of the reasons I went down the Heparin path.”