MEMOIR enables the histories of cells to be recorded in their genomes and then read out using microscopy. Here, MEMOIR cells were variably activated, as seen by the bright cyan nuclear fluorescence in some cells. The cells recorded information in response to this signal with the help of a DNA-editing system called CRISPR. This recorded information was then read out using a technique called seqFISH to visualize certain RNA transcripts in the cells (red dots).
Credit: Elowitz and Cai Labs/Caltech
The Allen Discovery Center for Cell Lineage Tracing
A new collaboration between Caltech, the University of Washington in Seattle, and Harvard University aims to develop new in-cell recording technologies to produce genomic maps of multi-cellular development
Three researchers from Caltech—Michael Elowitz, professor of biology and bioengineering, Howard Hughes Medical Institute Investigator, and executive officer for biological engineering; Long Cai, research professor; and Carlos Lois, research professor—have received funding to create the Allen Discovery Center for Cell Lineage Tracing in collaboration with the University of Washington in Seattle and Harvard University. Support for the establishment of the center comes from the Paul G. Allen Frontiers Group, which will provide $10 million over four years with the potential for $30 million over eight years.
The goal of the Allen Center will be to use newly developed technologies to create global maps of cellular development, tracing cells as they divide, move, and differentiate throughout an organism’s development, and revealing the relationships between the vast number of diverse cells that make up a single organism.
Last year, Elowitz and Cai collaborated on a gene-editing technique called MEMOIR, which allows cells to record information in their own genomes, in a format that can be read out by microscopic imaging.
“The goal is for each cell to be able to tell us its own individual history, including its lineage and the specific molecular events it has experienced during development,” says Elowitz. “To do this, we decided to team up with groups from the University of Washington in Seattle and Harvard University who were developing related technologies, and work together to map lineage and developmental histories of cells.”
“One of the fundamental questions in biology is to understand how a single-celled embryo gives rise to a complex animal with hundreds of different cell types organized into highly complex organs and tissues,” says Lois, who will be one of the center’s principal investigators. “A critical step to solving this problem is to be able to track the progeny of cells—that is, their lineage. The funding from the Allen Discovery Center will allow us to develop new methods with which to reconstruct lineage trees over many generations. In addition, we will develop new strategies so that cells can write in their genomes a record of the molecular signals that control their fate. With these methods, the cells will, in a sense, keep a ‘journal’ of what is happening to them, and we will be able to read that journal in the genomes of their progeny many generations later. With this kind of information, we will be able to understand the molecular signals that determine, for example, that a single stem cell will give rise to two daughter cells, with one becoming a neuron that processes visual information while the other processes auditory information.”
“Michael and I had this crazy idea over coffee to use synthetic biology to engineer a circuit to record the ‘memoir’ of a cell,” says Cai, who will also be a principal investigator of the center. “My lab had just gotten a proof-of-principle experiment working to sequentially read out mRNA levels in the cell. So, we thought it would be good to apply that method to read out the recorded ‘bits’ in the cell. That was 2013 and the project has worked beyond our initial conception of the idea. We owe all this to the creativity and the hard work of the people in our labs. The Discovery Center will allow us to answer fundamental questions about cell fate decision-making, which like real life involves many dimensions and is context dependent, by reading out the MEMOIR of those cells.”
Written by Lori Dajose