Quantum Science, One Picoliter Drop at a Time

A single drop of water may not seem very large. Now imagine shrinking it until it holds just one trillionth of a liter and then put a quantum sensor in it.

It may seem almost impossible, but researchers supported by the UC Noyce Initiative are doing just that.

Exploring quantum biology

Led by Assistant Professor Ashok Ajoy at UC Berkeley, with Professor Adam Abate at UC San Francisco, Professor Nicholas Curro at UC Davis and Professor Peter Burke at UC Irvine, the team is building an innovative toolkit that includes fluorescent nanodiamonds, magnetic particles, molecular sensors and advanced imaging. Their goal is to detect minute biological changes — from signs of cellular stress to shifts in how cells use energy — inside microscopic droplets and living cells.

“Quantum sensors are incredibly sensitive and traditionally they’ve been limited in how and where we can use them. What we are doing is trying to find ways to make them mobile and programmable. This could eventually allow us to search for extremely rare molecular signals or even approaching the detection of a single molecule,” Ajoy said. “That opens up exciting possibilities for bringing quantum sensing into real biological systems.”

At the heart of the work are reactive oxygen species, short-lived molecules that play an important role in regulating cells but can cause damage when produced in excess. Existing methods have difficulty quantitatively measuring these signals inside individual cells or extremely small samples. The researchers hope their quantum sensing innovation can help change that.

Making the invisible easier to detect

At UC Berkeley, researchers have created a platform that places fluorescent nanodiamond quantum sensors inside tiny droplets and tracks their movement. Magnetic fields organize specially designed magnetic beads into chains and send them moving through the droplets. The researchers are working to use molecular binding to transfer that motion to a nanodiamond, effectively turning an otherwise difficult-to-detect molecular interaction into a movement researchers can see and analyze.

A machine-learning system developed by the team distinguished random motion from magnetically driven motion without error in a held-out validation dataset. The approach provides a potential pathway toward detecting rare molecular targets and, ultimately, individual molecules.

That matters because quantum sensors can be extraordinarily sensitive, but they typically operate one at a time and in fixed configurations. By making the sensors mobile and programmable and placing them inside large arrays of tiny reaction chambers, the researchers are exploring a way to bring that sensitivity to biological testing at a much larger scale. As the sensors move through the droplets, they may have a better chance of finding rare targets, potentially paving the way for tests sensitive enough to detect even a single molecule. As the sensors move through the droplets, they may have a better chance of finding rare targets, potentially paving the way for tests sensitive enough to detect even a single molecule.

Four campuses, one system

Achieving that vision requires far more than a sensor, which is where the collaboration across four UC campuses becomes particularly important.

At UC San Francisco, Abate’s team developed technology to repeatedly image, measure and sort droplets. The system includes two-color imaging and real-time processing, along with three-dimensional imaging that can distinguish objects at different depths within a droplet. Ultimately, these capabilities could allow researchers not only to detect an interesting signal, but also to identify and recover the particular droplets containing it.

At UC Davis, Curro’s team advanced techniques for controlling diamond-based quantum sensors and developed molecular sensors that can report mechanical strain. The work expands the kinds of physical signals that quantum sensors may eventually be able to measure.

At UC Irvine, Burke and his collaborators demonstrated a pulsed quantum microscope capable of manipulating and imaging two different types of quantum sensors within the same living cell. They also developed a genetically encoded sensor that tracks changes in mitochondria — the structures responsible for much of a cell’s energy production — and can distinguish metabolic responses in cancer cells and heart muscle cells.

Together, the pieces form what the research team describes as an “end-to-end architecture:” UC Berkeley converts molecular binding into programmable motion; UCSF provides repeated measurement, three-dimensional imaging and sorting; UC Davis advances quantum control and strain sensing; and UC Irvine brings quantum sensing into living cells and probes mitochondrial metabolism.

UC Noyce Initiative brings new possibilities

“UC Noyce support made it possible for us to establish a genuinely integrated four-campus program, bringing together expertise in quantum control, microfluidics, machine learning and cell biology,” Ajoy said.

The funding also helped open a new research direction in trajectory-based quantum bioassays at Berkeley while supporting complementary technologies across the other campuses. It provided interdisciplinary training opportunities for graduate researchers as well, including three doctoral students at UC Davis.

The team is already considering what comes next. Researchers are planning a larger National Institutes of Health proposal building on the project as interest grows in the emerging area of “quantum biology.” In the near term, the researchers see potential for high-throughput droplet-based assays. Longer term, their work could provide new ways to detect rare or even individual molecular events in biologically relevant environments.