Beyond Bacteria


A Promising New Method for Engineering Mammalian Cells

By Mark Dwortzan

Albert J. Keung (BME), first author on the paper in the journal Cell, describing CoSBi research on chromatin at CoSBi's Synthetic Biology Boston symposium.
Albert J. Keung (BME), first author on the paper in the journal Cell, describing CoSBi research on chromatin at CoSBi’s Synthetic Biology Boston symposium.

At the heart of synthetic biology is the assembly of genetic components into “circuits” that perform desired operations in living cells, with the long-term goal of empowering these cells to solve critical problems in healthcare, energy, the environment and other domains, from cancer treatment to toxic waste cleanup. While much of this work is done using bacterial cells, new techniques are emerging to reprogram eukaryotic cells—those found in plants and animals, including humans—to perform such tasks.

To engineer useful genetic circuits in eukaryotic cells, synthetic biologists typically manipulate sequences of DNA in an organism’s genome, but Assistant Professor Ahmad “Mo” Khalil (BME), Professor James J. Collins (BME, MSE, SE) postdoctoral fellow Albert J. Keung (BME) and other researchers at Boston University’s Center of Synthetic Biology (CoSBi) have another idea that could vastly increase their capabilities. Rather than manipulate the DNA sequence directly, the CoSBi engineers are exploiting a class of proteins that regulate chromatin, the intricate structure of DNA and proteins that condenses and packages a genome to fit within the cell. These chromatin regulator (CR) proteins play a key role in expressing—turning on and off—genes throughout the cell, so altering their makeup could provide a new pathway for engineering the cell’s genetic circuits to perform desired functions.

Using synthetic biology techniques, the researchers systematically modified 223 distinct CR proteins in yeast to determine their impact—individually and in various combinations—on gene expression in yeast cells. Described in the journal Cell in a paper featuring Albert Keung as first author, their findings could provide a new set of design principles for reprogramming eukaryotic cells.

“Albert’s paper is one of the first to show how we can harness chromatin as a pathway for gene regulation,” said Khalil. “This approach represents a new paradigm for manipulating the structure of chromatin for engineering a biological system.”

Among the researcher’s findings was the discovery that selected CR proteins can regulate the expression not only of single genes, but clusters of nearby genes. They also determined that chromatin modifications induced by CR proteins got passed down to new cells once existing cells divided, endowing them with “memory” of specific functions. This memory retention could enable sets of engineered cells to sense a fleeting signal and remember it over a long period of time even as cells divide. Cells within a bodily organ, such as the brain or liver, also require memory of their tissue type in order to maintain their function and avoid becoming cancerous.

“Exploiting the major role that chromatin plays in gene regulation provides us with another layer of control in reprogramming cells to perform specific functions,” said Keung, who envisions the new approach leading to a better understanding of cell biology and a more powerful synthetic biology toolkit.

The study was supported by the National Institutes of Health, Defense Advanced Research Projects Agency, National Science Foundation, Boston University College of Engineering, Wyss Institute for Biologically Inspired Engineering, and Howard Hughes Medical Institute.