New project aims to systematically map billion cellular interactions

Multicellular life depends on remarkable acts of cooperation. Every cell in the human body must sense what is happening around it, interpret signals from its neighbors and respond in ways that support the larger tissue. These chemical, physical and electrical messages help determine when cells grow, repair damage, fight infection or quiet down after a threat has passed - and tissue health depends on how well those parts come together.

You have many different cells playing different parts. A healthy tissue emerges when those parts are coordinated - when cells listen and respond to one another in the right way."

Dr. Dino Di Carlo, the Armond and Elena Hairapetian Professor and Chair of Bioengineering, UCLA Samueli School of Engineering

But when those signals are misheard or go out of sync, the results can be devastating. In fibrosis, a misfiring message drives cells into a scar-producing overdrive, stiffening lungs, hearts and kidneys. In cancer, tumor cells can distort the score, sending molecular signals that suppress or misdirect immune attack. What sounds like harmony in health can become discord in disease.

Now, in a perspective published in Nature Biotechnology, Di Carlo and colleagues from UCLA, USC and Caltech are calling on the scientific community to join the Billion Cell×Cell Project - an effort to understand the cellular symphony one duet at a time, by systematically mapping how individual pairs of cells influence one another.

The project aims to generate nearly 1 billion measurements of controlled interactions between pairs of human cells, creating a foundation for understanding how cells communicate in health and disease - and how scientists might one day restore, block or rewrite those signals to treat disease.

From cell atlases to cellular conversations

Over the past decade, single-cell technologies have transformed biology, allowing scientists to catalog the many cell types that make up the human body and identify which genes are active in each of these cells. Spatial biology has added another layer, showing where cells are located within tissues and which other cells surround them.

But these approaches still leave a major gap: They often cannot reveal which cell caused another cell to change, when that influence occurred or whether the interaction produced a meaningful biological outcome.

"You can look at a tissue and identify all the players that are involved," said Di Carlo, lead author of the perspective and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "But that's only a snapshot."

The Billion Cell×Cell Project would focus on characterizing the cellular dyad, a controlled interaction between two individual cells. Standard co-cultures can show how groups of cells behave together, but they often blur the individual encounters that drive those outcomes, Di Carlo said. By isolating defined cell pairs, the dyad approach allows scientists to determine which cell influenced which partner, when the interaction began and what changed as a result. The rationale behind the approach, Di Carlo said, is that one of the most relevant ways to understand an individual cell's function is to watch how it changes another cell.

A technology whose time has come

The project builds on advances in single-cell sequencing, spatial profiling, synthetic biology and micro- and nanotechnology. A key enabling technology is the nanovial, a "lab-on-a-particle" platform developed in part by Di Carlo's lab at UCLA.

Nanovials are tiny hydrogel particles that can capture individual cells - or defined pairs of interacting cells - in self-contained microenvironments. They allow researchers to bring two cells together, control when their interaction begins, measure what they secrete and profile how their gene activity changes, all while remaining compatible with widely used tools such as flow cytometry, cell sorting and single-cell sequencing.

That broad compatibility is central to the project's vision.

"If we want this to be scalable, we want any lab with standard tools to be able to contribute," Di Carlo said. "The goal is to make this something the broader scientific community can build together."

The initiative would unfold in stages. The first would map how defined cell pairs alter one another's gene expression. The second would add genetic and biochemical perturbations to identify the molecules and pathways that drive those changes. The third would connect molecular interactions to functional outcomes.

Together, these layers could help scientists understand cell-cell communication in enough detail to engineer it more precisely. That knowledge could inform the design of emerging therapies - including CAR T cells, bispecific antibodies, engineered T cell receptors and checkpoint inhibitors - that already work by altering how cells recognize, influence or attack one another.

"Many of today's most exciting therapeutic strategies act at the interface between cells," said Dr. Owen Witte, founding director emeritus of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA and co-director of the UCLA Parker Institute for Cancer Immunotherapy. "A deeper map of those interactions could help us design therapies that redirect cellular communication with far greater precision."

A call for the scientific community: Joining the effort to map billions of cellular interactions

The long-term vision for the project is to help train computational models that simulate how cells behave together in tissues.

Such models - sometimes described as virtual cells or virtual tissues - could eventually allow scientists to test therapeutic ideas "in silico" before moving into laboratory experiments. This could make drug discovery faster and less expensive while reducing reliance on animal models.

For now, Di Carlo and his colleagues frame the Billion Cell×Cell Project as a call to arms - one that will require collaboration among biologists, engineers, computational scientists, clinicians and drug developers.

The team has launched cellxcell.org as a hub for updates and opportunities for others to get involved. The ultimate goal, Di Carlo said, is to transform a field that has long studied cells in isolation into one that can finally hear how they communicate.

"For years we have been listening to cells play their lone melodies," Di Carlo said. "Now we want to understand how cells play off one another to create the whole symphony."

Additional UCLA authors include Heather J. Wright, Mohamad Abedi, Sean Yamada-Hunter, Jason Zhang, Keriann Backus, Thomas Rando, John K. Lee and Owen Witte. Leonardo Morsut, Megan L. McCain, Eunji Chung and Yingxiao Wang of the University of Southern California and Long Cai, Matt Thomson and Michael Elowitz of the California Institute of Technology also contributed to the perspective.

This work was supported by the Chan Zuckerberg Initiative. The perspective was shaped in part by joint activities, discussions and technology demonstrations enabled through this CZI-supported consortium and the Cell-Cell Symposium convened on April 16, 2025, at UCLA.