Epigenetically Programmed Biological Materials
Abstract
Living cells have the ability to make and transmit memories. Traditionally considered a trait of neural cells, there is an increasing appreciation that memory storage and processing is both prevalent and fundamental to non-neural cells across all kingdoms of life. Central to these processes is a form of stable, reversible, and hereditable biological memory that persists without changes to DNA sequence, known as epigenetics. From an engineering perspective, epigenetics offers a number of powerful features, including: (1) reversible state transitions, making it possible to encode adaptive and switchable properties into systems; (2) persistent memory over long timescales, ensuring durability and robustness of engineered traits; (3) sequence memory, generating distinct phenotypes that depend on the history of signal exposure; (4) heritability, enabling an engineered trait to be transmitted to descendants. Collectively, these properties constitute a unique information storage/processing modality that, if understood and harnessed, could drive transformative new capabilities for engineering biology. In contrast to building fragile systems using static predefined components – the current state-of-the-art – epigenetic memory enables isogenic cells to establish distinct and hereditable phenotypic states that cells can switch between when a specialized function or morphology is needed. This paradigm would be particularly transformative for enabling a new class of programmable living materials with organizationally and functionally rich properties. The goal of this project is to discover and establish fundamental engineering principles for epigenetic information storage and processing in living cells, and to use these principles to enable epigenetic programming of self-organizing multicellular structures, yielding biological materials with tailored properties. To achieve this goal, Aim 1 focuses on development of the first epigenetic memory toolkit – a library of mechanistically-diverse epigenetic switches that enable long-term memory storage and recall in eukaryotic organisms – and fundamental studies to define their operation and memory properties. Aims 2 and 3 will develop a modular “synthetic morphology” platform for creating epigenetic programs that drive and control self-organization in cellular populations. Specifically, in Aim 2 we will discover design rules to direct naturally-occurring epigenetic programs that regulate transitions between unicellular and multicellular phenotypes in yeast, developing this into a platform to program microbial materials that exhibit reversible phase transitions, shape memory, self-repair, and epigenetic signal-dependent organizational features. In Aim 3, we will circumvent natural selection and investigate the minimal requirements for creating de novo epigenetic programs that direct selforganization of defined multicellular structures using mammalian cells not naturally capable of this behavior. Collectively, these Aims will produce a new epigenetic programming language that will augment our ability to engineer complex eukaryotic and multicellular systems and structures. If successful, our work will inspire future applications, including in situ fabrication of materials with attributes of living systems, sensing and communication devices utilizing epigenetic encoding/decoding functions, epigenetic switches enabling coordinated control of entire biosynthetic pathways, and the manufacturing of large-scale synthetic materials with precise structures and functions. The program will be led by Ahmad (Mo) Khalil. Dr. Khalil’s team has made pioneering advances in synthetic biology paradigms for engineering eukaryotic systems, using these to advance basic understanding and control of epigenetic regulation. Dr. Khalil has a strong track record of engagement with the DoD, e.g. as recipient of a DARPA Young Faculty Award and performer on 5 DARPA programs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Sep 11, 2020
- Source ID
- N000142012825
Entities
People
- Ahmad S Khalil
Organizations
- Boston University
- Office of Naval Research
- United States Navy