UCSF

Creating the tools to build a Human Cell Atlas

If it’s hard to take an accurate census of the 325 million people living in the US, it’s even more daunting to survey the 37.2 trillion or so cells that make up the human body. The brain alone, for instance, contains nearly 90 billion neurons, which can be classified into over a thousand distinct cell types. But these numbers are informed estimates—the true diversity of cells in the brain, let alone throughout the body, remains out of reach.

A collaborative project, backed in part by the research tools and expertise concentrated in the UCSF School of Pharmacy, could soon change that—and enable scientists to home in on both the cells that are responsible for human health, and the cells that are culpable in human disease.

In October of 2016, a group of world-leading scientists met with the goal of creating a “periodic table of cells,” which they dubbed the Human Cell Atlas. This central repository of every known human cell type—grouped by shape, size, function, and life cycle—promises to give scientists a clear view of how multitudes of cells normally operate in tissues and organs. It will also fill in the details of how cells malfunction during disease, and potentially open the door to new and more precise treatments.

structural diagram of liver tissue

An example of the many types of cells in the liver.

The ambitious project, which requires the resources of multiple institutions, similar to the Human Genome Project, has early funding from the Massachusetts Institute of Technology’s Broad Institute and the Chan Zuckerberg BioHub.

A database to hold it all

When you’re dealing with somewhere between 30 million and 100 million cell types—the early estimate for the number of cells that will fill the Atlas—information technology and database management are critical.

That’s where John “Scooter” Morris, PhD, comes in. Morris is a faculty member in the School of Pharmacy's Department of Pharmaceutical Chemistry and a core developer of Cytoscape, a software program that helps create and visualize the complete networks in biological systems.

In March, Morris received a grant for $249,000 from CZ BioHub to apply Cytoscape to the terabytes of data the project will produce. He is tasked with exploring various ways to index the immense datasets destined for the Human Cell Atlas, and designing the Atlas to be useful to scientists of all stripes.

Morris is excited to work on a project with so much potential, and he predicts that the Atlas could lay the foundation for a new generation of treatments.

Getting data

James Wells, PhD, a fellow faculty member in the School’s Department of Pharmaceutical Chemistry and a CZ Biohub investigator, is one of the scientists tasked with collecting information on different cell types—what makes them unique, how they function, and how they can misbehave.

Cells are dotted by thousands of types of membrane proteins. These proteins are responsible for communication and interaction between cells, and for safely shuttling various molecules across the cell membrane. Depending on which membrane proteins are stimulated, a cell might be provoked to grow, multiply, or even change its identity. “These arrays of membrane proteins are the keyboard of the cell,” Wells said.

When cells become cancerous, for example, the assortment of membrane proteins can change dramatically. Some proteins may be added, some may disappear, and entirely new complexes may be created when various proteins regroup with other neighboring proteins.

A grant from the Chan Zuckerberg Institute will allow Wells and his collaborator, Spyridon Darmanis, PhD, a group leader at CZ Biohub, to track changes in the cell surface as different “oncogenes”—the genes that cause cancer—transform normal cells into cancerous ones.

Wells will track these changes using next-generation sequencing, a term that’s a catchall for several new techniques that allow scientists to detect and quantify DNA and RNA sequencing on a very small scale, down to a single cell.

Building and maintaining a successful index of cancer cell identities and interactions could be key to finding new drugs to slow or stop tumors, and even help clinicians prescribe the best drugs for particular cancers.

Wells says the School of Pharmacy has a major role to play in the development of the Atlas. Five other School faculty members are also Chan Zuckerberg Institute Investigators: Bo Huang, PhD, and Zev Gartner, PhD, both in the Department of Pharmaceutical Chemistry; and Tanja Kortemme, PhD, and Adam Abate, PhD, both in the Department of Bioengineering and Therapeutic Sciences.

Assembling this master encyclopedia of the “what, where, why” of every type cell requires far more than a typical census by microscope has ever been able to provide. But the technologies and tools being developed in the UCSF School of Pharmacy and across campus will finally allow us to peer into the proteins being used and produced in each cell, and make the information useful.

“To truly understand our biology and push medicine forward, we need to understand what we’re built of,” said Wells.


About the School: The UCSF School of Pharmacy is a premier graduate-level academic organization dedicated to improving health through precise therapeutics. It succeeds through innovative research, by educating PharmD health professional and PhD science students, and by caring for the therapeutics needs of patients while exploring innovative new models of patient care. The School was founded in 1872 as the first pharmacy school in the American West. It is an integral part of UC San Francisco, a leading university dedicated to promoting health worldwide.