Single-Cell Biology Could Change Medicine As We Know It. Here’s How.


A microscopic view of the villi in the duodenum, finger-like projections that help the small intestine absorb nutrients and water. Photo curtesy of Jay Thiagarajah.

Editor’s Note: This post has been updated as of 7/26/22 with the new name of CZ CELLxGENE (formerly cellxgene).

Every day, biomedical journals publish roughly 4,000 new articles. The vast majority make incremental contributions to the body of scientific knowledge — but a handful signal greater change.

Four such papers were published last week in Science. Each contains groundbreaking insights, and together, they mark a major milestone for biomedicine — one that could signal fundamental changes in our understanding of human biology, and usher in a bold new era in medicine.

While progress has been mounting in recent years, this latest work is momentous in its scale and breadth, demonstrating how far new technologies have come — and that we can be certain of their impact.

To appreciate the significance of the moment, it’s important to know how most biomedical research proceeds today. Generally speaking, scientists who study human tissues have been constrained to sampling hundreds of thousands of cells at a time before analyzing an average across that sample. Or they can use much more laborious techniques to examine, say, just one hundred cells.

Both approaches have serious limitations. Bulk methods are fast, but they fail to capture the extraordinary heterogeneity of different cells within the sample. High-resolution techniques have the opposite problem. And neither approach gives us what we actually want: the ability to measure what happens within and between individual cells — with speed, precision, and scale.

But now that’s set to change. In recent years, scientists, engineers, and mathematicians have developed what amounts to an entirely new toolkit for biomedical research. It’s called single-cell biology, and in a nutshell, it uses advanced methods to sequence and analyze the features — such as gene expression, DNA features, and proteins — within large numbers of individual human cells, at very high resolution.

Each of the four research projects I mentioned earlier relied on single-cell techniques. Collectively, they mark a breakthrough in not only how scientists can use technologies to analyze multiple tissue samples from individual donors, but the biological insight we can gain from doing so.

One group of scientists used single-cell methods to study how 45 types of immune cells are distributed across the body. Their findings tell us a lot about why pathogens — including viruses like SARS-CoV-2 — provoke profoundly different immune responses from different tissues.

A second group characterized more than 400 cell types, including immune cells, across 24 tissues and organs — a survey so vast in scope that they called it the Tabula Sapiens.

A third group looked at a long list of mutations that are linked to genetic diseases, then identified the specific cells and tissues where the genes associated with those mutations are expressed. If you think of the human body as a map, these scientists dropped pins in the precise locations of where diseases are likely to arise and how we might apply new therapeutic interventions.

Meanwhile, a fourth group created an atlas of the developing immune system. The map is the first of its kind — spanning multiple organs and tissues — and will be immensely helpful in advancing in vitro cell engineering, regenerative medicine, and our understanding of congenital disorders.

While each of these projects is a momentous achievement in its own right, the four of them add up to something greater than the sum of their parts. If you’re an immunologist, for example, you suddenly have access to a treasure trove of data about where immune cells are located and how they differ — which could have huge implications for how we study vaccines, diseases, and more.

Importantly, the four papers are mutually reinforcing. Each team operated independently, using a unique combination of single-cell techniques to characterize the immune system. But they all reached similar conclusions about how cell types are distributed in the body. This underscores that single-cell technologies are generating robust biological signals — even as they continue to improve.

Moreover, this kind of finding — where different people take different paths, but everyone uncovers similar biological findings — is a strong signal for truth. It suggests that the discipline of single-cell biology has achieved a level of maturity that many scientists thought was unlikely, if not impossible, just a few years ago.

So, where could it take us?

One of the most exciting applications is called the Human Cell Atlas (HCA). It’s a collaborative, open project to map out all 37 trillion cells in the human body — and create the first comprehensive picture of how our tissues, organs, and systems function and interact at the molecular level. The journal articles above present important steps toward data needed for the HCA, while also providing a framework for the work that’s underway to create detailed maps of each of our individual organs.

In both size and importance, the Human Cell Atlas resembles the Human Genome Project — and even though the HCA is in its early stages, it’s likely that you’ve benefited from it already. Thanks to the combined efforts of 14 separate research teams, the community developed a draft atlas of the human lung. And scientists have used that information to learn which cell types in our airways are most vulnerable to SARS-CoV-2, and most in need of protection. The work helped to clarify the presence of particularly susceptible cells in the nasal airway as the primary route of infection.

We undoubtedly have much more to gain from single-cell biology. To realize its potential, we’ll need to devise better ways to compile and integrate its massive datasets, and to assess cell components, interactions, and lifespans. We’ll also need to ensure that the Human Cell Atlas represents all of humanity — not just a small slice.

The work that I lead at the Chan Zuckerberg Initiative aims to address these challenges. In partnership with other leaders and funders in the field, we’re expanding access to single-cell methods, supporting researchers who recruit diverse groups of study participants, and building tools — like Chan Zuckerberg CELL by GENE (CZ CELLxGENE), which was essential for supporting collaborations like the Tabula Sapiens — to help scientists explore and share single-cell data.

If we’re successful, then we can expect to see a lot more papers like the ones that were published this week — and with time, a cascade of medical breakthroughs that leverage the foundational insights on cellular heterogeneity.

Today, you can take a test to learn your susceptibility to genetic diseases. Tomorrow, single-cell research could tell you how a particular disease would manifest in your cells. That knowledge would, in turn, point toward a targeted therapy. It might take the form of a drug — but it could also take the form of cells as therapy, such as engineered immune cells, or an entire organ grown from scratch.

That future isn’t here yet. But if progress in single-cell biology continues at its current pace, it might come sooner than you think.

Jonah Cool, Program Officer, Single-Cell Biology

Jonah Cool is a cell biologist and geneticist by training, and is currently a program officer at the Chan Zuckerberg Initiative, where he leads the organization’s Single-Cell Biology Program. He was an American Heart Association fellow while completing his PhD at Duke Medical Center, with a focus on the role of vascularization during cell differentiation and organ morphogenesis, and was subsequently a Ruth Kirchstein Fellow at the Salk Institute studying nuclear organization during stem cell differentiation. Dr. Cool previously worked in intellectual property litigation, as well as ran an industry research group working toward therapeutic application of 3D bioprinted human tissue. He has a deep love of cell biology and, in particular, the origins of cellular heterogeneity and how diverse cells assemble into complex tissues.



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