On a delicate tablet dating to between the late eighth to sixth centuries BC is inscribed a disc, surrounded by a ring of water called the ‘Bitter River’. Acquired by the British Museum in 1882, it is the oldest known map of the ancient world and marks a pioneering example of attempts to create atlases so that people can make sense of their surroundings with symbols, in this case marked on a piece of clay around the size of a child’s hand.
To make sense of the human body, scientists are now creating cell atlases – maps of organs and tissue down to the level of cells, the fundamental building blocks of tissues and organs – from post mortem samples, biopsies, developmental tissues and more, subject to consent and ethical guidelines – that they hope will mark new era in biology and medicine. Today, an international consortium reports major progress towards its goal of mapping all human cells.
The resulting freely available ‘Google maps’ of the body will allow scientists to zoom from organ to tissue to cell, from conception to old age, and when the body is in good health, as a framework to understand what changes during infection and disease. The atlas will help explore human development and the healthy human body, as a foundation to unravel the details of disease, diagnose illness, and spur the development of novel treatments.
Just as the latest maps depend on satellites, planes, computers and more, so it has taken a plethora of technologies to chart key differences in the more than 37 trillion cells – yes, that is 37,000,000,000,000 cells, give or take – in the human body (the human gut contains roughly the same number again of microbes, mostly bacteria).
Today, in the wake of earlier work on the uterus, placenta, lung, liver and so on, more than 40 papers, published in Nature and associated journals outline two remarkable feats of cellular cartography: one is a molecular map of the human digestive tract, including the cellular changes that underpin gut inflammatory diseases (IBD) such as Crohn’s disease and ulcerative colitis, which is already informing drugs under development by a startup company called Ensocell; and the second is the first complete map of a whole human organ, in space and time, known as the thymus, where disease–fighting white blood cells, notably T cells, develop.
These are the latest achievements of the Human Cell Atlas, a consortium co-founded in 2016 by Dr Sarah Teichmann, at the University of Cambridge and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard, near Boston. Today the consortium is an international collaboration with more than 3,600 members from over 100 countries who have worked together to profile more than 100 million cells from over 10,000 people.
HOW TO MAP THE BODY
These maps chart the fundamental molecular reality of cells. Although the DNA in each of our cells carries the same 20,000 or so genes, a muscle cell uses a quite different repertoire of genes to those harnessed by a brain or a gut cell.
Each gene carries the instructions to make a protein, the basic building block of cells, and to turn them into flesh and blood it transcribes the gene’s DNA into another kind of genetic material, RNA, which ferries the instructions to the ribosome, the cell’s protein factory.
By using cutting-edge single cell genomics, microscopy and computational techniques, HCA researchers use RNAs to reveal which of the 20,000 genes in an individual cell are switched on and where they are located in the organ. This creates a unique “ID card” or fingerprint for each cell type, technically called the transcriptome. As a bonus, this can also reveal ‘whether a cell is small or large or rounded or star-shaped,’ said Teichmann.
These tools have matured over the past few years so that they can quickly and efficiently look at tens of thousands or even millions of human cells in a single experiment, revealing their position and characteristics, such as the molecular machinery that allows one cell to ‘talk’ to its neighbours (known as receptors and ligands).
A 3D-rendered video of developing skeleton showing cartilage and bone. Source: A.Chédotal and R. Blain, Institut de la Vision, Paris, and MeLiS UCBL, HCL, Lyon.
The consortium also studies material called chromatin – a blend of RNA, protein, and DNA in each cell – that enables two metres of DNA to be tightly-packed into its heart, where it is accessible to the molecular machinery that reads the DNA instructions. By studying chromatin, they can reveal the regulatory ‘grammar’ of that particular kind of cell.
GUT ATLAS
When it comes to the gastrointestinal system, the tube that stretches from mouth to anus, the team compared the 1.6 million cells they studied from health and disease to understand key cell types in IBD and cancer. In particular, they focused on crypts, glands that contain stem cells (cells that can develop into many other different cells) and other cells that renew the lining of the intestine.
The body’s immune system is active in IBD and these inflamed crypts turn into ‘Frankensteinian disorganised glands’ and encourage further damage to intestinal tissue by the immune system during IBD and coeliac disease (a severe gluten intolerance). ‘This is something that really fascinates me,’ said Teichmann.
THYMUS ATLAS
The thymus, a small gland located in front of the heart, is vital for the establishment of the body’s protective immune system and the new atlas reveals how its structure develops.
The atlas shows how various kinds of white blood cells are fashioned by passing through the outer shell and inner core of the organ. To ensure white blood cells don’t turn against your own body, as occurs in diseases such as multiple sclerosis or rheumatoid arthritis, the inner core of the thymus uses a clever mechanism: it mimics all the tissues and organs of the body to trigger a self-destruct mechanism in any white cells that recognise cells in the body.
The atlas also pinpoints the exact embryonic stage where the thymus becomes fully functional, which happens surprisingly early by the beginning of the second trimester. This early establishment helps explain why humans are born with a very rich immunological white blood cell repertoire.
‘What is of huge interest to pharma companies is how to rejuvenate the thymus and immune response,’ she said. Another approach is to grow an artificial thymus, or organoid, to test treatments or make immunotherapies, notably to target tumours.
WE’RE COMPLICATED
This landmark project has taken us a long way from the outdated idea that there are only a couple of hundred different human cell types, which led to the oft cited two hundred kinds of cancer, which begins when a cell multiplies with its own survival agenda, not that of the entire body.
The Human Cell Atlas has revealed that the reality is much more complex, with thousands of different cells and, moreover, cells that change their state over time, or are even programmed to die, by a process called apoptosis. The overall repertoire of cells in the body changes as we develop from a single fertilised egg into a highly cooperative community of trillions of cells.
Although, explains Teichmann, the cells lie on a continuum they can be classified into distinct groups – in the case of the brain, for example, there are around five thousand distinct kinds of cell, which exist in hundreds of different states.
After the brain and nervous system, perhaps the next most complex features of the body include the immune system and the heart, which is fashioned from roughly thirty different tissues – by studying just eight of these, the consortium found they can exist in seventy-five different cell states. ‘That gives you a feel for the numbers we are talking about.’
For example, there are six subtypes of cardiomyocytes, muscle cells, in the two lower chambers, or ventricles of the heart, which handle the most pressure during a heartbeat, and eight types in the two upper chambers, or atria, which receive blood and, she said, are ‘mechanically very different.’
‘Working cardiac muscle cells are quite distinct from the ‘pacemaker’ cells in heart fibres that transmit electrical signals in the heart to make it beat, with the help of cell membrane channel proteins that allow charged ions to whizz back and forth across their membranes’, she added.
She said the rich and detailed information from the Human Cell Atlas will be used to help simulate the next generation of digital heart twins, one of which is beating in the Science Museum’s Engineers gallery, part of a global effort to develop virtual organs to make medicine personalised and predictive.
Commenting on today’s papers, Aviv Regev, founding co-Chair of the HCA, who is now at Genentech, said: ‘This is a pivotal moment for the HCA community, as we move towards achieving the first draft of the Human Cell Atlas.’