Scientists program cells to carry out gene-guided construction projects

Stanford researchers have developed a technique that reprograms cells to use synthetic materials, provided by the scientists, to build artificial structures able to carry out functions inside the body.

“We turned cells into chemical engineers of a sort, that use materials we provide to construct functional polymers that change their behaviors in specific ways,” said Karl Deisseroth, MD, PhD, the D. H. Chen Professor and professor of bioengineering and of psychiatry and behavioral sciences.

A paper describing the research was published March 20 in Science. Deisseroth shares senior authorship with Zhenan Bao, PhD, the K.K. Lee Professor and professor of chemical engineering. The lead authors are former postdoctoral scholars Jia Liu, PhD, and Ariane Tom, PhD; graduate student Yoon Seok Kim; and research scientist Claire Richardson, PhD.

In the paper, researchers explained how they developed genetically targeted chemical assembly and used the new method to build artificial structures on mammalian brain cells and on neurons in the tiny worm called C. elegans. The structures were made using two different biocompatible materials, each with a different electronic property. One material was an insulator, the other a conductor.

Changing neuronal properties

Bao said that while the current experiments focused mainly on brain cells or neurons, genetically targeted chemical assembly should also work with other cell types. “We’ve developed a technology platform that can tap into the biochemical processes of cells throughout the body,” Bao said.

The researchers began by genetically reprogramming cells they wanted to affect. They did this by using standard bioengineering techniques to deliver instructions for adding an enzyme, called APEX2, into specific neurons.

Next, the scientists immersed the worms and other experimental tissues in a solution with two active ingredients — an extremely low, nonlethal dose of hydrogen peroxide, and billions of molecules of the raw material they wanted the cells to use for their building projects.

Contact between the hydrogen peroxide and the neurons with the APEX2 enzyme triggered a series of chemical reactions that fused the raw-material molecules together into a chain known as a polymer to form a mesh-like material. In this way, the researchers were able to weave artificial nets, with either insulative or conductive properties, around only the neurons they wanted.

The polymers changed the properties of the neurons. Depending on which polymer was formed, the neurons fired faster or slower, and when these polymers were created in cells of C. elegans, the worms’ crawling movements were altered in opposite ways.

In the mammalian cell experiments, the researchers ran similar polymer-forming experiments on living slices from mouse brains and on cultured neurons from rat brains, and verified the conducting or insulating properties of the synthesized polymers. Finally, they injected a low-concentration hydrogen peroxide solution along with millions of the raw-material molecules into the brains of mice to verify that these elements were not toxic together.

Tools for exploration

Rather than a medical application, Deisseroth said, “what we have are tools for exploration.” But these tools could be used to study how multiple sclerosis, caused by the fraying of myelin insulation around nerves, might respond if diseased cells could be induced to form insulating polymers as replacements. Researchers might also explore whether forming conductive polymers atop misfiring neurons in autism or epilepsy might modify those conditions.

Going forward, the researchers would like to explore variants of their cell-targeted technology. Genetically targeted chemical assembly could be used to produce a wide range of functional materials, implemented by diverse chemical signals. “We’re imagining a whole world of possibilities at this new interface of chemistry and biology,” Deisseroth said.

Deisseroth is a Howard Hughes Medical Institute investigator and a member of Stanford Bio-X and the Wu Tsai Neurosciences Institute at Stanford. Bao is a senior fellow at the Precourt Institute for Energy, a member of Stanford Bio-X and Stanford ChEM-H, and an affiliate of the Stanford Woods Institute for the Environment. 

Other Stanford co-authors are Kang Shen, MD, PhD, professor of pathology and biology; Sergiu Pasca, MD, PhD, assistant professor of psychiatry and behavioral sciences; laboratory director Jeffrey Tok, PhD; Lief Fenno, MD, PhD, a resident in psychiatry; Lydia-Marie Joubert, PhD, life science researcher; postdoctoral or visiting scholars Xiao Wang, PhD, Cheng Wang, PhD, Toru Katsumata, PhD, Huiliang Wang, PhD, Yuanwen Jiang, PhD, and Fikri Birey, PhD; former graduate student Shucheng Chen, PhD; and life science research assistant Charu Ramakrishnan.

A researcher at Lawrence Berkeley National Laboratory’s Advanced Light Source also contributed to the work.

The research was supported in part by the National Institutes of Health, the National Science Foundation, Stanford Bio-X, Life Sciences Research Foundation, the Gordon and Betty Moore Foundation, the Wu-Tsai Neurosciences Institute and the Kwanjeong International Foundation.