Mapping the Human Cell Atlas – charting the body’s cellular world

Advances in technology over the last five years mean it is possible to map our bodies in more detail than ever before. Our 37 trillion cells can be defined by the activity of each of their 20,000 genes, their precise location, and their interactions with neighbouring cells.

Researchers around the globe are creating these cellular maps of our body’s organs and tissues. Together, they are forming the Human Cell Atlas, a freely available resource that can be used to guide future research into human development, biology, health, and disease.

The Human Cell Atlas was showcased at the American Association for the Advancement of Science (AAAS) meeting in Seattle earlier this year. Aviv Regev, Kerstin Meyer and Shannon Hughes presented some of the latest findings from the Human Cell Atlas and other atlas initiatives.

Cells

Aviv Regev is a Chair of the Faculty and Core Member at the Broad Institute of MIT and Harvard in the USA. Together with Sarah Teichmann at the Wellcome Sanger Institute, she is a Co-Chair of the Human Cell Atlas Organising Committee.

Speaking to a packed room, with people in every chair, leaning up against walls and hovering in the doorway, Aviv opened the session.

“I’m going to talk about cells,” she stated.

Each of our 37 trillion cells has an identical copy of our genetic code, the genome, yet their forms and functions are hugely varied. “They are the basic units of life,” said Aviv. From muscle cells that contract, to immune cells that defend the body from pathogens, to nerve cells that transmit electrical signals – each has a specialised role.

“You might ask yourself, how come?” said Aviv. She described how each cell uses the genome in a different way. This is something that can, thanks to recent technological developments, be measured. Researchers can determine a cell’s ‘expression profile’ – which genes it is using, and how much of them.

“Why does it matter? Because this plays out very importantly in disease,” said Aviv. “When someone has a genetic variant that influences the risk of disease, all the cells of the body carry that variant. But it is only going to manifest in relevant cell types. For example, a neurodevelopmental disorder might be caused by a genetic variant that affects how nerve cells function. Knowing the cell types affected is essential for understanding disorders.”

“One problem. We don’t really know all the cells in our body,” she said.

“If you open a textbook, it says there are 300 types of cells in the whole body. But if you talk to a neuroscientist they will tell you there are 100 types of neurons just in your eye, each doing something different.”

20,000 dimensions

Our genome has 20,000 genes that each cell may use to varying extents. To visualise that information, scientists have created algorithms that can take the information from these 20,000 genes and map it into something that is 2D. Cells that have similar gene expression profiles – they are using those 20,000 genes in a similar way, often appear close to each other in 2D space.

Single-cell technologies

This analysis is only possible because of advances in single-cell genomics in recent years. Previously, scientists would take billions of cells together and measure an average of gene activity. Now, it is feasible to measure each cell’s individual gene expression profile.

Aviv rapidly described single-cell genomics and a technique called single-cell RNA-sequencing (scRNAseq). Researchers take samples of tissues from the body and put them through a process: “Dissociate, suspend, capture, isolate the RNA, and sequence.” This gives researchers information about which genes are being used in a cell.

Even more recently, scientists have developed spatial technologies. This enables single cells to be studied in the same way, but in their physical location within a tissue.

“We need to do this cheaply, quickly,” said Aviv. “These techniques are massively parallel, allowing us to process thousands or millions of cells in one day.”

The fruit smoothie analogy. Previously cells were analysed in a mixture, like a smoothie. Now, individual cells can be analysed - the fruit salad. Spatial technologies mean cells can be analysed in their physical location.

What can we learn?

“We can learn what we are made of, how we develop and about disease,” said Aviv.

Aviv shared short stories of discovery, each impacting on human health. The first was the identification of a new cell type in the lungs, relevant to cystic fibrosis.

The second story was the identification of types of immune T cells which can affect a person’s response to cancer immunotherapies. Clinical trials are now underway to test a drug that affects the T cells and potentially boosts the response to treatments that would otherwise fail.

Another example was the identification of a rare cell type in ulcerative colitis, a type of inflammatory bowel disease (IBD). The cell type was not found in people without IBD – suggesting it would make a good target for new treatments.

Cell maps can also be used to understand development. Humans start as just one cell, which divides to become all the different cell types of the body. Charting a cell’s development can show the process of differentiation and specialisation over time.

Aviv also mentioned the strain of coronavirus (COVID-19) currently spreading across the globe. “What is special about the cells in the airway that coronavirus is infecting? Researchers are using data from the lung cell atlas, alongside other resources, to answer this question.”

Latest findings

Kerstin Meyer, Principal Staff Scientist at the Sanger Institute spoke about some of the recent discoveries made by Human Cell Atlas scientists.

In June last year, teams from the Sanger Institute, University Medical Center Groningen, Open Targets, GSK and others revealed the identity of each cell type in the lung. They were also able to create a trajectory of lung cell development.

“Something very interesting happened when we compared healthy and asthma cells.”

“Towards the end of development – we see a particular cell type in asthma but not in people without asthma,” said Kerstin. The cells were in a state that had not been seen before, producing mucus in asthma patients. “We don’t really know yet if the cells went through development but got stuck – or maybe they developed and then went backwards. But just by knowing they are stuck in this developmental timeline will allow us to generate new therapeutic hypotheses.”

Kerstin also shared the newest research on the thymus, a gland located in the chest that produces T cells, key white blood cells that fight infection and disease.

“We’ve built a single-cell atlas of the human thymus across a lifetime. Starting early in development, all the way to adulthood,” she said.

“The thymus is a really interesting organ. It instructs the ‘police’ T cells in knowing which bits of the body are self, and which bits are invaders that need to be killed. So inside the thymus, the cellular universe is represented. T cells in the thymus learn what is self and what is non-self.”

The team undertook single-cell sequencing of 200,000 cells from the developing, child and adult thymus. Published last month in Science, the thymus atlas revealed new cell types and identified signals that tell immature immune cells how to develop into T cells. The atlas could help scientists understand diseases that affect T cell development such as severe combined immunodeficiency (SCID). In the future, it could be used as a reference map to engineer T cells outside the body with the properties to kill a specific cancer – creating tailored treatments for tumours.

From map to an atlas

Image credit: Alex Cagan @AJTCagan

Shannon Hughes is Program Director at the Division of Cancer Biology, National Cancer Institute in the USA.

She spoke first about making atlases, thinking about them in terms of collections of individual maps: “An atlas has layers of information. Geographical features, political boundaries as well as social and economic statistics. Another element is time,” she said. Shannon showed a map of Amsterdam in the Netherlands, where the colour of the buildings indicates the year they were built.

map from http://code.waag.org/buildings/#52.3689,4.8505,13

“To map disease, we also need information about time,” Shannon said. She described the NCI Human Tumor Atlas Network, where the goal is to create 3D atlases of the cellular, morphological and molecular features of human cancers over time. The layers of information collected include timings and dose of treatments as well as a person's symptoms. The atlases describe important transitions during cancer, such as the transition of pre-cancerous cells to malignant tumours, the progression to metastatic cancer, the response to cancer treatment, and the development of cancer’s resistance to treatments. Ultimately, the atlases can be used to help improve treatment selection for patients.

“Another element of modern atlases is their multimedia format. They are not only available as spiral-bound paper books, but online via your computer, or your phone,” Shannon said.

“There is a challenge of how to visually display information, depending on the user. An atlas may be used by a patient, clinicians, researchers, data scientists, computational biologists.” She showed how the NIH Kidney Precision Medicine Program is bringing together the entire community, with patients being equitable partners in the entire research effort.

These initiatives, and others, sit alongside the Human Cell Atlas, bringing a huge community of researchers together.

Figure modified from: Mol Syst Biol, Volume: 12, Issue:  DOI: (10.15252/msb.20155865)
HTAN, HuBMAP, BICCN, LungMAP, GUDMAP, KPMP and SPARC are all NIH atlas-building initiatives

Global and open

All of the speakers stressed the importance of collaboration and open data in the Human Cell Atlas project, and beyond.

Aviv said: “This is not something that one lab, or one institute, or one country can build alone. The Human Cell Atlas is an international initiative. It is open to anyone who adheres to the mission. We have 1,700 members in 71 countries and thousands of institutes are engaged as members.”

“All are committed not just to scientific rigour and making the best maps possible but also to open data. Sharing our code, our data, our protocols.”

“We are well on way to complete the first draft 100 million cells, from 14 organs and systems in the next five years.”