SEATTLE – As it enters its third year, the Human Cell Atlas project has mapped 100 million of 100 billion cells, and by comparing gene expression profiles of normal and aberrant cells and building networks of cellular interactions, is leading to breakthroughs in understanding of disease at a molecular level.
One example is the discovery of a previously unknown cell type in the trachea which expresses the CFTR gene that lies at the heart of the inherited respiratory disorder cystic fibrosis.
Another is the finding that although goblet cells in the bronchi are morphologically similar, only one specific cell subtype is involved in recruiting T cells and prompting an inflammatory response in asthma patients.
Mapping healthy colonic mucosa and that of patients with ulcerative colitis has shown some cells types are only found in diseased tissue, and that disease genes are only expressed in specific cells. In particular, four risk genes are found to be expressed only in microfold cells. The level of expression of the four genes goes up together during disease flares, presenting a potential drug target.
In pharmaceutical development, the Human Cell Atlas is on the way to becoming a comprehensive resource for checking where else in the body the target of a drug is active, making it possible to predict likely side effects, or for considering the most appropriate route for delivering a drug.
A further advance has come from tracking the differentiation of progenitor cells in the thymus, to build precise understanding of the genetic programs underlying the development of different types of T cells.
Most recently, in research published on Feb. 17, scientists at the Wellcome Sanger Institute in Cambridge, U.K., reported the first detailed atlas of immune cells and gut bacteria. That provides the raw data for building greater understanding of how the healthy immune system tolerates microbial cells and what goes wrong in disease. By sequencing the expression profiles of 41,000 immune cells from three different locations, the research shows different genes are switched on in different parts of the colon.
“If we understand the programs that govern these processes, we can mimic them,” said Kerstin Meyer, principle scientist leading Human Cell Atlas projects at the Sanger Institute in Cambridge, U.K. “That will have enormous application,” she told attendees of the AAAS meeting.
Tabulating the specific differences between gene expression in healthy and diseased cells is providing better understanding of the underlying mechanisms of disease. “There are examples where we know what the genetic defects are, but we might not necessarily know how they play out,” Meyer said.
Each tissue in the body has many different cell types that are intimately connected. The Human Cell Atlas will not only describe all the different cells but also how they interact with each other. The project involves 1,700 researchers around the world, who are working on profiling cells in different organs and also in developing tools to interrogate the mountains of data they are generating.
There is a commitment to publish all the data and make available all the software code for analyzing it. The complete Human Cell Atlas will provide a unique ID card for each cell type, a three-dimensional map of how cell types work together to form tissues, show how all body systems are connected, and deliver insights into how changes in the map underlie health and disease.
It will identify which genes associated with disease are active and where, and analyze the regulatory mechanisms that govern the production of different cell types.
Individual cell types are distinguished using transcriptomics to plot the gene expression profile, or “calling card” of each kind of cell. That is complemented by recently developed tools for tracking gene expression in the context of a specific tissue, giving a spatial view of what genes are expressed at what time.
Meyer is involved in a project that combines the two approaches to look at bronchial cells from healthy individuals and asthma patients. That “cellular census” has identified novel cell states in asthma.
“We now know all the 20,000 different genes and how they are expressed, so we can then dig in and ask what are the exact differences between these two different [tissue samples]. That gave us a list of genes that are highly expressed in asthma,” Meyer said. “Actually we find that a lot of these genes have to do with how cells talk to and recruit immune cells such as interleukins and cytokines. That is highly relevant to the disease,” she said.
The number of ciliated cells in the protective mucous layer of the airways increases in asthma. Current understanding is that this is a result of normal cells starting to express mucin.
Meyer said it is possible to study the mechanisms that underlie overproduction of mucous ciliated cells. “We can design functional experiments to really dig into that, and then hopefully design therapeutics that will allow them to return back to the normal cell state, or to eliminate them,” she said.
Further tracking the etiology, the research shows the genes that are known to be associated with asthma are not uniformly expressed everywhere in the lungs, but in very specific cell subtypes.
Looking at how those cell subtypes interact with the immune system shows they engage TH2 helper cells. Meyer and colleagues have found evidence the type 2 cytokines secreted by the TH2 cells maintain the altered epithelial cell states in asthma.
“This is important for therapy. You can design inhibitors or come in with antibodies that will prevent that interaction and prevent it from happening. And therefore, you change the disease response,” Meyer said.
Meyer also is part of a team working on the cell atlas of the thymus, using RNA sequencing to look at how common progenitor cells radiate out into different types of T cells. The research has led to the identification on new types of T cells.
“We now know what the actual signals are that lead to the differentiation of different sorts of T cells,” Meyer said. “We hope to be able to take the cells and differentiate them in vitro, to get exactly the functionality we want, and then infuse them back into the body.”
That approach to therapeutic development will not hold just for T cells. The data compiled in the Human Cell Atlas will eventually provide the gene expression programs for differentiating any type of cell from its progenitor, Meyer said.