Ram Sasisekharan, whose wife is an oncologist, admires doctors in that medical specialty. “They know they’ll lose some battles,” he notes, “but they have to be optimists, and they are.
“The more we can understand about cancer,” he adds, “the more we can support them.”
Sasisekharan, an associate professor of biological engineering at MIT, may be on the verge of giving these doctors a big assist. Earlier this year he made an astonishing discovery: a substance that’s found on most of the 100 trillion cells in our bodies, if structured in one way, boosts tumor growth — and if in another, sharply inhibits such growth. What is this molecular Jekyll and Hyde? It’s a carbohydrate, also known as a sugar (though sugars in our bodies are typically far more complex chemically than ordinary table sugar.) Called by the tongue-twisting name of “heparan sulfate glycosaminoglycan,” it’s a close cousin of the blood-thinner heparin. And the fact that in certain forms it combats cancer raises intriguing possibilities, including drugs that make tumors self-destruct. (The agent of destruction, explains Sasisekharan, would be a heparan sulfate that “activates the switch which leads tumors cells to commit suicide.”)
At the time of his discovery, the scientist already knew a lot about heparin and its relatives. He had shown, for example, that they help control the growth of new blood vessels. This was one of several tantalizing indicators that cells’ “sugar jackets” have a big impact on our systems. But since no one knew the exact make-up of the sugars involved, such findings had little practical effect.
“I draw an analogy with DNA and proteins,” says Sasisekharan. “Things didn’t really blossom in terms of applications until we learned how to sequence these molecules and make them in the lab.”
That pointed to an obvious strategy: figure out how to sequence complex sugars. But if it seemed obvious, it must have seemed implausible, too.
The components of sugars, and the way they connect to each other, can vary greatly. You can put together just six of the socalled building blocks for a sugar like heparan sulfate in 12 billion different ways –– far more than either DNA or proteins.
But, notes Sasisekharan, “one thing about being a scientist is that you get to think outside the box.” He decided to take a stab at sequencing sugars. And with the aid of tools that included a base-16 numbering system –– an exotic variation on our tried-and-true base-10 system –– he and his co-workers managed to break the “sugar code” within a few months.
Being able to sequence heparan sulfates let Sasisekharan probe the sugar-tumor connection, which has been known for many years but is poorly understood. Using cancer-afflicted mice, the researchers injected two types of “molecular scissors” –– enzymes –– that clip heparan sulfate molecules at different points in their structures. In one group of animals, the tumors grew faster. In the second, growth stopped almost completely.
“It was phenomenal,” says Sasisekharan. “We expected some effect, but we were amazed that nature exercises such exquisite control over these tumor cells.” Sasisekharan later showed that anti-tumor sugars on tumor cells can actually reverse cancer growth.
A near-term next step will be toward agents that can be tried in patients. Sasisekharan says he’s having conversations with various biotech companies, and adds that “there’s real interest in translating our work into clinical applications against cancer.”