DNA is the fundamental molecule to all living things. The genetic sequences embedded in its double-helical structure contain the instructions for producing proteins, the building blocks of our cells. When our cells divide, DNA readily unzips into two strands and makes a copy of itself for each new daughter cell. In a Nature Communications report this week, researchers at Northwestern University describe how they have harnessed DNA’s elegant design, which evolved over a billion years ago, to engineer a programmable set of on/off instructions to mimic the dynamic interactions that cells encounter in the body. This nano-sized toolkit could provide a means to better understand stem cell behavior and to develop regenerative therapies to treat a wide range of disorders.

Instructing cells with programmable DNA-protein hybrids: switching bioactivity on and off Image: Stupp lab/Northwestern U.

While cells are what make up the tissues and organs of our bodies, it’s a bit more complicated than that. Cells also secrete proteins and molecules that form a scaffold between cells called the extracellular matrix. Though it was once thought to be merely structural, it’s clear that the matrix also plays a key role in regulating cell function. It provides a means to position multiple cell signaling molecules in just the right spot at the right time to stimulate a particular cell behavior as well as interactions between cells. This physical connection between the matrix, molecules and cells called a “niche” plays an important role for stem cell function.

Since studying cells in the laboratory involves growing them on plastic petri dishes, researchers have devised many methods for mimicking the niche to get a more accurate picture of how cells response to signals in the body. The tricky part has been to capture three main characteristics of the extracellular matrix all in one experiment; that is, the ability to add and then reverse a signal, to precisely position cell signals and to combine signals to manipulate cell function. That’s where the Northwestern team and its DNA toolkit come into the picture.

They first immobilized a single strand of DNA onto the surface of a material where cells are grown. Then they added a hybrid molecule – they call it “P-DNA” – made up of a particular signaling protein attached to a single strand of DNA that pairs with the immobilized DNA. Once those DNA strands zip together, that tethers the signaling protein to the material where the cells encounter it, effectively “switching on” that protein signal. Adding an excess of single-stranded DNA that doesn’t contain the attached protein, pushes out the P-DNA which can be washed away thereby switching off the protein signal. Then the P-DNA can be added back to restart the signal once again.

Because the DNA sequences can be easily synthesized in the lab, it allows the researchers to program many different instructions to the cells. For instance, combinations of different protein signals can be turned on simultaneously and the length of the DNA strands can precisely control the positioning of cell-protein interactions. The researchers used this system to show that spinal cord neural stem cells, which naturally clump together in neurospheres when grown in a dish, can be instructed to spread out on the dish’s surface and begin specializing into mature brain cells. But when that signal is turned off, the cells ball up together again into the neurospheres.

Team lead Samuel Stupp looks to this reversible, on-demand control of cell activity as means to develop patient specific therapies in the future:

Samuel Stupp

“People would love to have cell therapies that utilize stem cells derived from their own bodies to regenerate tissue. In principle, this will eventually be possible, but one needs procedures that are effective at expanding and differentiating cells in order to do so. Our technology does that,” he said in a university press release.