A happy accident with real purpose

Rich in iron and a critical component of hemoglobin, the molecule heme is essential for life. When bound to a protein partner, heme is critically important to our health. For example, heme binds itself to oxygen so that it can be delivered via red blood cells to our tissues. Free heme, however, is a menace, contributing to a wide range of life-threatening conditions, from sickle cell anemia and malaria to cancer, kidney disease, and intestinal parasites. While engaged in his 40-year study of the symbiotic relationship between legumes and bacteria, Graham Walker, an American Cancer Society Professor of Biology at MIT and HHMI Professor, unexpectedly discovered a plant peptide that could be used to sequester and eliminate free heme.

The reason why certain plants, such as legumes, can grow without nitrogen fertilizer is because they develop a symbiotic relationship with bacteria that are able to take nitrogen gas from the atmosphere and turn it into ammonia, the form of nitrogen that plants can use. Legumes do this in part by producing hundreds of peptides that can manipulate their bacterial partner. Dr. Walker and his colleague Siva Sankari had been focusing on one particular peptide, NCR247; as part of their studies, they fused NCR247 to a protein and produced it in bacterium. Typically, proteins are colorless, so they were surprised when it turned reddish. They suspected—and later proved—that this peptide had drawn heme from the bacterium and bound it to itself. This accidental discovery prompted Dr. Walker to question whether NCR247 could be used to address a range of challenging medical issues.

Little experience and even less chance for funding

Like a person with limited knowledge of how to swim suddenly thrown into the deep end of a pool, Dr. Walker found himself with an exciting discovery in an area in which he had little experience. “I’m pretty well known in the areas of DNA repair and symbiosis,” he says, “but I have no connections to sickle cell or malaria or intestinal worms. So I immediately started talking to people about it.” After doing a lot of reading on heme and assembling a collaborative multidisciplinary team, Dr. Walker is ready to explore a number of avenues that would have been impossible without a Bose Fellows grant.

“Angela Koehler of Biological Engineering uses a term—‘the valley of death’—for small molecules that look to have an intriguing clinical application but you can’t do anything with them because you don’t have the preliminary data that traditional funders require,” he says. In fact, when he discussed his discovery with the scientific officer of his NIH symbiosis grant, Dr. Walker was reminded that that funding could not be used for human biology projects. “More than anything else, the Bose grant gives us freedom: the freedom of unfettered exploration to try different ideas.”

Many directions, one destination

Though NCR247 is the smallest and most extensively studied of the more than 700 peptides produced by this particular species of legume, its newly revealed heme-binding ability offers a range of possible applications for improving human health. Not only can this research open the door to novel ways of studying the many critical roles that heme plays in sustaining life, it could also one day lead to developing a first-in-class small molecule drug that sequesters and disposes of potentially toxic free heme. Says Dr. Walker, “After 46 years at MIT, I wasn’t looking for a new research direction, but this is what can happen when you do basic research. With this project, my MIT colleagues and I will be pursuing a number of different directions, which is very exciting. The Bose grant is a gift from heaven that is re-energizing both me and my work.”