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MIT Better World

By Catherine Caruso

Some three decades later, he is back in that same building, gesturing excitedly at protein models arrayed in his office along with books and travel mementos. As he discusses his research, the “Brass Rat” class ring on his hand provides a tangible reminder of where he began. And, it’s clear he is just as interested in chemistry and biology as he ever was.

Raines, who joined the MIT faculty in 2017 after a long career at the University of Wisconsin–Madison, serves as the Firmenich Professor of Chemistry at MIT—a professorship with a distinguished 40-year history. He leads a lab pursuing projects at the interface of both fields that are poised to have a major impact on medicine and society.

“I’ve always liked tangibility, I’ve liked science I could touch, and chemistry and biology are both sciences that I can touch,” Raines explains. “I love projects that span from very fundamental science all the way to a clinical outcome—that’s the goal.”

One such project that has occupied Raines’s lab for the past five years started with a straightforward concept: Proteins are complex molecules that carry out many key tasks in cells, but mutations in the DNA blueprint used to build them may result in dysfunctional proteins—and when these damaged proteins are involved in how cells grow or divide, it can lead to cancer. So, Raines thought, what if you could overcome such cancer-causing mutations by simply replacing dysfunctional proteins with working versions?

Unfortunately, there’s a snag. Proteins are large and have negative charges, which makes it basically impossible for them to pass through a cell’s protective membrane—a dense, negatively charged lipid bilayer. “[This layer] is very difficult to cross—it has evolved to keep the outside out and the inside in,” Raines explains. “There are very, very few proteins that can naturally enter human cells, and even those do so inefficiently.” What was needed, Raines realized, was a way to smuggle proteins across this protective membrane undetected.

Enter what Raines has dubbed “ghost proteins.” Adapting a process used in medicinal chemistry to move drugs into cells, Raines and his lab have developed a technique that creates an invisibility cloak for proteins. The basic idea is that a protein undergoes a chemical reaction that turns its negatively charged, acidic carboxyl groups into neutral ester groups, thus allowing it to sneak into a cell. Once inside, the cell’s enzymes convert these ester groups back into carboxyl groups, removing the protein’s invisibility cloak and restoring its function.

“We’re very excited about this; we’ve demonstrated this with a handful of proteins, and we are seeking to expand this to many, many proteins, including ones that can be used in new therapies,” Raines says. Developing new cures is the biggest and most interesting research challenge, the “gold ring on the merry-go-round,” Raines says, but he views the therapeutic potential of these ghost proteins more broadly—as an untapped territory brimming with possibilities.

Raines’s lab, which consists of almost two dozen postdoctoral researchers, graduate students, and undergraduates, is also working on myriad other projects at the intersection of chemistry and biology, including creating artificial collagens to treat wounds, developing cancer drugs from enzymes called ribonucleases, and establishing a process for fabricating biofuels. “An advantage of having a group that’s broad in its interest… is that people talk to each other about ideas that are seemingly far afield at the outset, but can often be merged to create a whole that is bigger than the sum of the parts,” Raines says.

Being at MIT is also an advantage, he adds. “It’s so exciting. It’s so vibrant. It’s on the cutting edge in every field that interests me.”