You probably shouldn’t compare a carefully engineered protein — one that made it to the pages of Nature not long ago — to a peanut M&M. Still, that’s how I started my interview with two of the lead authors on the Nature paper: Marc Lajoie, Ph.D., and Gabe Butterfield.

“Yeah, okay, maybe I would step that back,” said Butterfield kindly.

Butterfield is a Ph.D. candidate at the Institute for Protein Design (IPD) at the University of Washington; Lajoie is a post-doc. They both work in the lab of David Baker, Ph.D., and they and other researchers at the IPD design new proteins, not found in nature, to solve intractable problems in medicine and other fields.

In their case, the intractable problem is delivering drugs — especially drugs with terrible side effects, like chemotherapies — to target disease more precisely and effectively, and with less harm to the patient.

“Drug delivery, in general, is a major limitation for medicine. Eight out of 10 of the top-selling drugs are biologics — made out of proteins. And all of them focus on extra-cellular targets,” said Lajoie. Getting the drugs into cells, he says, is another thing entirely.

“If you could do that very well, that could change the world of drug development,” Lajoie said.

But back to the beginning: to candy. I was trying to create a mental picture of a protein with the capacity to surround and package its own genetic material. It turns out that this protein does not look at all like an M&M. Rather, it has icosahedral symmetry — much like a soccer ball.

Making an icosahedral protein assembly was still a fairly new idea when Lajoie and Butterfield took on their project. Former student Jacob Bale, Ph.D., had recently figured out how to push enzymes together to form the shape. What interested several researchers at the IPD was that this newly manufactured icosahedral protein resembled something found in nature.

“It’s the shape of the most basic viral shells,” said Butterfield.

Viruses are expert at attaching to cells, breaking into them and taking them over. Which led to the question: could you take a protein shaped like a virus and make it act like a virus? Could you borrow certain properties — surviving in blood circulation, getting into a specific cell, delivering cargo — that could work in drug delivery?

These are complex traits that are still difficult to rationally engineer. So Lajoie and Butterfield did it by creating a protein with the capacity to evolve.

“My old advisor used to use this analogy to smart phones,” said Lajoie. “They’re great because you can engineer every aspect of them, but they’d probably be a lot better if you could evolve them. Because the engineers can only make one of them. But, if you can make millions of them with evolving designs, you’re going to get one that’s faster and better.”

I asked them to break down the steps of their project for me, and Lajoie jumped up and started writing on the white board.

First, Bale used Rosetta software developed in Baker’s lab to design an icosahedral protein assembly from inert enzymes. Second, Butterfield and Lajoie introduced mutations so it would package its own genome. Third, they manipulated the protein to make it evolve into something tougher, with a stronger protein shell, capable of resisting degradation in blood and circulating for a longer time in mice.

A protein that can package its own genome, that can evolve — as a non-scientist, I couldn’t resist asking the pair to explain what differentiated their protein from something alive.

“That’s a loaded question,” said Butterfield. “Most scientists would say that viruses aren’t alive, and these proteins aren’t even viruses. They don’t have mechanisms to get into cells, they don’t have mechanisms to get out of cells, and they don’t have mechanisms to replicate on their own.”

So, these researchers stopped far short of creating a virus. And this protein is decidedly not alive. But they did create something special.

“That we were able to take these otherwise inert proteins, and create this autonomous system that can evolve with part of its life cycle inside a living mouse? That’s crazy,” said Lajoie.

This project took only three-and-a-half years. Or about eight-and-a-half years, when you count the truly foundational work done by IPD researchers Neil King, Ph.D., Will Sheffler, Ph.D. ’09, and Bale.

“We made this thing that can package cargoes, and it can circulate in mice,” said Lajoie. “So the next step that we’re really excited about is delivery.” To package therapeutic cargoes. To target specific cells. And to deposit therapeutics inside those cells.

“To create something that has never existed before, that’s pretty cool. And the idea that it could actually solve medical problems one day is really exciting,” said Butterfield.

“I live to work,” admitted Lajoie. “The thing is, what else would I enjoy doing more? You get to discover new things that nobody ever knew, and then those new things can be useful for humanity.

“This is the best job in the world,” he said.

By Delia Ward
Photos: Anil Kapahi

Read More Learn more about the evolving protein in Nature.