At the Speed of Light 

Lightcast controls microdroplets with light to create a fast, flexible experimental platform. 

Based in Cambridge, England, Lightcast is developing a benchtop instrument that delivers detailed information about how individual cells function in varied environments. The platform could provide new insights into how cells interact with each other and respond to drugs, toxins, pathogens, and other factors, providing more comprehensive information than single-cell omics alone. 

“Lightcast has created a new tool that will soon help labs investigate single-cell, functional biology, something that has never been done before,” said Wouter Meuleman, Partner at Illumina Ventures. “Current approaches generally query the molecular drivers in cells, but investigators can only infer what they mean. These micro assays allow scientists to witness how cells actually respond in real-time.” 

 

Moving Droplets with Light 

Lightcast’s technology takes the 384-well plate to the next level (and perhaps the level after that) with tiny, automated, massively parallel, and more precisely controlled inputs. To manage reactions, the platform uses thousands of picoliter-sized droplets (one-trillionth of a liter) arrayed in specified rows. Each droplet could contain a single cell, reporter beads, pathogens, antibodies or other soluble input.  

“Imagine loading hundreds of thousands of droplets with specific content into an experimental array, each one acquired and precisely controlled by a beam of light,” said Lightcast Chief Commercial Officer Paul Steinberg. “Droplets can be merged, queried, down-selected, perturbed, or incubated throughout the experiment.” 

Orchestrated by a complex machine-learning algorithm, the Lightcast system precisely mixes ingredients across thousands of droplet combinations. One droplet row might contain T cells (one cell in each droplet). A second row could house reporter beads programmed to detect and quantify specific cytokines, fluorescing when activated.  

The light beams (called light sprites) move the rows together – a choreographed parallel merge. The combined droplets are then screened for the appropriate fluorescent signal, demonstrating which T cells are producing the desired chemicals. A third row, containing cancer cells, can then be merged to investigate which of the now-characterized T cells are active and demonstrating cell-killing behavior. 

“In a short period, we can understand complex cellular function across thousands of single-cell combinations,” said Steinberg. “In this example, we can see what the T cells are secreting, if they recognize the target cell, and how effectively they engage and kill that cell. Further experimentation could evaluate cell targeting specificity and whether the T cell becomes a serial killer or lapses into exhaustion. Droplet recovery and downstream molecular profiling can then elucidate the complex mechanisms that drove the observed behavior.” 

The system can continuously add new droplets, with unique experimental payloads, and sequentially merge, assay, and down-select the contents to answer specific questions. Once this process is complete, droplets of interest can be dispensed individually, or as functionally-selected pools, into 96 and 384-well plates for expansion or molecular profiling.  

 

Accelerating Drug Discovery 

The platform offers virtually endless opportunities to investigate how single cells function in dramatically different environments. Labs could test multiple drugs or drug combinations to understand how well cells take in the molecule(s) and how they respond. The reporter beads provide continuous, precise information about each cell’s fate. 

“We could set up an experiment with ten dose regimens and watch the differential responses,” said Steinberg. “Or, we could gradually add and examine dosage over time.” 

These insights could provide invaluable information on many therapeutics. Researchers could follow CAR-T cells to precisely track their pathways. Are they being recruited to target cells? Avoiding off-target cells? Exhibiting the necessary killing efficiency? 

The platform could also advance antibody discovery. Labs must scale enormously to test multiple antibody formulations against chosen targets. They can now conduct those experiments directly, with single-cell granularity, across a large portion of the B cell repertoire, leveraging the immune system’s natural diversity. 

“When it comes to biologics-based drug development, we can address the workflow in two key areas,” said Steinberg. “The first is compound discovery. Whether they be monoclonal antibodies, multi-specifics, antibody-drug conjugates, or another engineered cell type, we can accelerate the ability to find hits and understand which clones produce the right functional outcomes. Further downstream, the system can help choose the appropriate producer cells to test for and optimize things like titer and manufacturability at scale.” 

Lightcast has already delivered beta and early access units to major academic institutions and pharmaceutical companies and has launched its Luminary Program to expand access. The company plans to fully launch in the second half of 2024.  

“Single-cell and spatial biology techniques have generated some major advances in how we understand and apply biology, but only infer function at the single cell level,” said Steinberg. “We believe these massively parallel, functional readouts complete a trifecta of single-cell methodologies, providing a discovery toolbox that will greatly accelerates translational research and drug discovery.”