Features | Discoveries

A Cellular Skeleton Key

by Eric Eyges

Fall 2019/Winter 2020

Balance is a central concept in medicine. When the body fails in its ongoing mission to maintain homeostasis, disease creeps in. Medicine’s goal is to tweak, to make minor adjustments. If medicine were a politician, it would be a balance-of-power realist, working hard to make sure that no one biological actor upsets the prevailing order, a goal that requires precision.

AUB alumna and Kuo Family Endowed Professor at UC San Francisco Hana El Samad (BEN ’98) and her colleague, University of Washington’s David Baker, have made a significant stride in the direction of precision with the creation of a synthetic protein that makes cells “smart.”

In the first of two papers published in the journal Nature, El Samad and colleagues discuss LOCKR, a fully synthetic protein having no analogues in nature, yet made from the same chemical building blocks that nature relies on.

Shaped like a barrel, LOCKR can be programmed to interface with a cell in innumerable ways. The barrel remains closed until it encounters a specific protein that acts as a key to open the barrel. Once open, a molecular arm springs out, grabs hold of cell circuitry and makes adjustments. The arm might steer molecular traffic, break down specific proteins, or cause the cell to self-destruct. “It’s like a Swiss Army knife, a tool that has many different functions,” says El Samad.

Researchers can program LOCKR to open and close as they see fit in response to the surrounding cellular environment. In that sense, LOCKR is like a switch, the building block underpinning modern electronics. A system of LOCKRs operating inside a cell can function like a complex circuit or nanorobot, balancing out functions and maintaining human health, reminiscent of the fictional technology found in the popular video game franchise Metal Gear Solid. El Samad sees this kind of functionality as the means to medical precision.

LOCKR has been tested in living cells. “We hacked a cellular pathway in yeast cells and turned their mating signals—they secrete pheromones—on and off in a regulated way,” says El Samad.

In the second paper, El Samad and colleagues describe using a system of LOCKRs to regulate cellular activity in response to cues from a cell and its surroundings.

Cellular engineering is currently in use in modern medicine. The FDA recently approved the use of engineered T cells as a means of fighting certain blood cancers. El Samad sees LOCKR as a potentially transformative tool with limitless potential that folds seamlessly into this branch of medical treatment. She cites traumatic brain injury as being particularly suited to treatment with a LOCKR-like smart cell. Brain injury causes inflammation, which is necessary for healing; however, the amount of inflammation triggered is often far greater than what’s needed and may result in permanent brain damage. LOCKR-style proteins could help cells maintain precise inflammation levels, kicking on and off at certain thresholds.

“The idea that you can take cells from our own body, engineer them and then put them back to be like little living robots that fight diseases such as cancer and neuro inflammation, this is the future,” says El Samad.