Innovative synthetic receptors for advanced cell therapies

By introducing new functions into mammalian cells, Makri Pistikou developed a synthetic communication system capable of producing biologically relevant responses by interacting with both natural and synthetic cells. The ability to incorporate such functions into mammalian cells is an important pillar in current biomedical research, with great influence on the development of cell diagnostics and cell therapies.

Mammalian cells have the capacity to perceive and respond to their environment, requiring constant control of the intracellular and extracellular milieu for optimal cell survival and function. Intracellular cell signaling often begins across the cell membrane, with receptors forming the hub of cellular communication. Scientists began creating synthetic receptors because it was recognized that the functionality of these membrane proteins could be exploited to detect and target diseases. Synthetic receptors, engineered membrane proteins, are designed to recognize specific inputs and generate specific outputs. Thanks to their modular architecture, these receptors can be continuously developed and modified for new functionalities.

Synthetic Communication

Engineering communication pathways within mammalian cells represents a significant advancement with profound implications for both basic research and applied biomedicine. Makri Pistikou's research describes the development of a synthetic communication platform in mammalian cells based on synthetic receptors and coiled-coil peptide heterodimers that bind exclusively to each other. This orthogonal, scalable and modular platform is specifically designed for synthetic communication in mammalian cells.

One of the challenges Makri Pistikou addresses is towards the creation of effective communication between mammalian and synthetic cells. Synthetic cells, which function like DNA-based computers, are designed to transmit signals that can be processed by natural cells that have the capacity to produce biologically relevant output.

Engineering autonomous control in mammalian cells

The development of synthetic receptors for cell therapies has dramatically changed the mammalian synthetic biology field, yet continues to face challenges such as adverse effects due to overactivation of synthetic receptors. Makri Pistikou introduces an innovative strategy to introduce autonomous control over the activation of synthetic receptors using microRNAs, small RNA molecules that control gene expression. She developed a system in which the activation of synthetic receptors causes the expression of a synthetic microRNA specifically targeting the receptor itself. This approach was inspired by natural processes, in which microRNAs are routinely used to regulate activation of receptors.

Through her research, Pistikou is contributing to the advancement of synthetic biology and opening new avenues for basic and applied biomedical research, with potentially revolutionary implications for cell-based therapeutics.

The development of a synthetic communication system in mammalian cells, described in this dissertation, resulted in publication in the journal Nature communications in 2023.

Title of PhD thesis: “Engineering synthetic receptor systems for mammalian cell-based therapeutics”

Supervisor: Tom de Greef