Randall Platt engineered cells to record their own history using CRISPR, turning the immune system into a molecular memory device. His lab built recorders that capture gene activity over time, reconstruct cell lineages, and store digital information like movies. The next step: sentinel cells in the gut that track human health biomarkers.
Chapters
The cell, the minimal building block of life, is profoundly complex and evolved to execute the programs written in DNA, enabling incredible feats of form and function, such as the development of a human being from a single cell, or the creation of a distinct milieu of cell types such as red blood cells and neurons. So how scientists address this problem today is we perform time-point experiments in which we break open cells at different times and measure the intracellular contents—RNA, DNA, protein—and we get a snapshot of what's occurring at that very moment in time. And the clear limitation to this is you're only seeing what's occurring at that snapshot and nothing else. So how do we as people remember our history? We take notes, we write books, we build museums, we create documentaries and film. The idea I want to share with you today is how can we coax cells to write down what is happening to them? How can we engineer cells to be their own biographers, transcribing the molecular and cellular world around them into a medium that we can understand and use to reconstruct facets of human health and disease, enabling us to look into the past? It turns out, hidden in nature, the fundamental components of such a recording system have already evolved. And that system is called CRISPR. And in nature, this is a microbial adaptive immune system that endows microbes with the capacity to remember and defend against foreign invaders. This functions somewhat analogously to yours, your immune system, where you can also remember and defend. And how CRISPR functions is CRISPR proteins physically excise pieces of RNA or DNA and physically integrate it within their own genomes, where they preserve this information in a defined location called a CRISPR array. And it's like a fossil record. The information is stored continuously and chronologically such that through sequencing, we construct the molecular order of events that gave rise to the present moment. Again, allowing us to look back into the past. And so scientists have already started leveraging this process, these natural recording proteins. General class of technologies are called molecular recorders, and they allow us to reconstruct the entire cellular lineage tree of organisms such as mice. They allow us to quantify the amount of chemicals or materials in the environment, and they also allow us to encode digital information such as movies.. And my laboratory at ETH Zurich fueled progress in this area by developing a CRISPR molecular recorder that has the capacity to continually record RNA inside of living cells. And RNA, as you know, is transcribed from DNA, which tells us about which genes are being expressed, the quantification of which tells us seemingly everything about the cell. And in sum, we've created a cell with gene expression memory.. And in my lab, we're now using it to create microbial sentinel cells that can interact with the human body and record objective biomarkers of human health and disease via the gastrointestinal tract. There are a few hurdles that stand in front of us from realizing the full potential in the world today. And those hurdles include an unclear regulatory path to approval in humans, the efficiency of the system, and how these cells will perform in at-risk individuals. Such as child— children with malnutrition. Additionally, the type of data we're generating is fundamentally new, requiring new computation. Fortunately, due to advances in computer science, machine learning, synthetic biology, protein engineering, over the next few years, we are very close to executing all these scientific aims. As for the regulatory path, this is clearly more uncertain, and is going to require a concerted effort from scientists, clinicians, law and government. And some scientists have been trying to understand the world with snapshots, and they've just been handed a molecular video camera, taking off the proverbial blindfold, and they can now continuously monitor their world, the cellular world, in real time. So my final— with this molecular video camera, we can now start to imagine an interesting future, a future with cells with memory which we can use as a biotechnology platform to record the molecular and cellular world, including our bodies, including the planet, the soil, air, and ocean. We can monitor them for contaminants. So with my final slide, I want to leave you with a question. With such a molecular video camera allowing you to look at the molecular and cellular world, what would you do? Would you replace the world's data centers, which consume 70% of the world's energy, With DNA recording microbes that could contain all the world's movies in the size of a sugar cube? Would you create a non-invasive diagnostic to interact with the human body? Would you develop a molecular recorder which you can reconstruct entire lineage trees of species? So thank you for your time and attention.
