Cartographers of the human body

Almost every cell in a person’s body contains the same genetic blueprint, written in DNA. The reason that a heart cell is a heart cell and a brain cell is a brain cell, however, is because not every gene is active in each cell. By looking another molecule – RNA, which ‘translates’ DNA into the proteins that make our bodies work – scientists can determine exactly which genes are active and in which cells. This picture can be finessed even further by looking at epigenetic modifications to the genetic code – that is, small molecules that sit on the DNA and turn the ‘volume’ of the genes up and down – and by measuring protein levels within the cells.

“Having this data at such a high resolution of the individual cell has been a real game changer,” says Teichmann. “It’s what's really opened up all of the new insights.”

Being able to make these measurements at single cell resolution allows researchers not only to describe the difference between a heart cell and a muscle cell, for example, or even a cell in the wall of the heart’s atrium and a cell in its ventricle – they can even tell the difference between different subsets of cardiomyocytes (the cells that make up cardiac muscle and are responsible for the heart's contraction).

“At a very coarse, grand level, if you look up cell types on Wikipedia, it says there are about 200 cell types, whereas with these new technologies, the Human Cell Atlas has been able to distinguish thousands of nerve cell subtypes alone!”

"It's incredibly exciting from a discovery science point of view. That's what gets a lot of people up in the morning. But it's also got massive meaning from a diagnostics and drug discovery point of view."

^{Sarah Teichmann}

Much of drug discovery work involves the use of animal models, particularly mice – a significant proportion of mouse genes have human analogues and their physiology shares some of the same characteristics as ours. But while useful for studying our human biology and disease, there are also fundamental differences. The discovery of the GLP1 receptor on human pacemaker cells, for example, surprised scientists because it has not been found in mouse pacemaker cells.

“Having a healthy human map for large cohorts of people helps us understand what the cells are like in their normal ground state or reference state and then provide that framework for comparison to disease samples. It allows us to study the mechanisms of disease and to understand progressions of disease better for drug discovery.”

Today sees a landmark moment for the project, with the publication of 13 new papers in the prestigious Nature journals. Together with a number of papers published recently and a handful more to come, these are being released as a collection of 43 HCA papers.

Asked what are some of the key discoveries enabled by the HCA, Teichmann says it’s difficult to know where to even begin.

“I can bore you to death on exciting cell discoveries!” she says. “It's changed how we understand our brain. It’s changed how we understand the immune system. It's changed how we understand the hormonal signalling across the human body. It's changed how we understand vasculature – the blood vessels. It's really changed everything.”

The Human Cell Atlas has even helped change public health policy. Just over three years after it launched at its inaugural meeting at the Wellcome Trust, London, in 2016, the world was struck down by the appearance of a new virus, SARS-CoV-2, causing the Covid-19 pandemic.

“Within a couple of weeks of the beginning of the pandemic, the whole Human Cell Atlas community pulled together and everybody shared data that was published and unpublished, and mapped where the SARS-CoV-2 virus was docking,” says Teichmann. “It showed that the virus could enter through cells in the eyes, nose and mouth.”

This information was reported to the government’s Scientific Advisory Group for Emergencies (SAGE) committee, helping inform how it responded to the virus, such as implementing policies around mask-wearing.

Although it has become something of a cliché for scientists to describe their project as a ‘Google Map for X’, in this case it seems wholly suitable.

“You can use the Human Cell Atlas as a sort of Google Maps of the molecules and cells in the human body, because you can find out how a virus could enter the body and how it can move around inside from tissue to tissue. It was an exciting learning curve during the pandemic, and a really proud moment for the Human Cell Atlas community. It illustrates the reason why we need a map of the healthy human body.”

The willingness to share data both within the HCA community and more widely is fundamental to the entire project. Any research group can join the community, says Teichmann. “It’s completely open – any researcher from any country is welcome to join.” The only requirement is that they sign up to the project’s ethical principles and commitment to open data sharing.

The international consortium is crucial to delivering on the promise of the HCA. As Teichmann points out, “It’s a huge project and requires a lot of people to work together”. But there is another reason by she encourages scientists from every corner of the globe to participate.

“[The HCA] is an underpinning resource for science and humanity, and so we felt it was appropriate to have it be a global project that's open for everyone to join and that's inclusive of the whole international scientific community. That also means the samples that we study will come from patients and donors from all over the world, so it will be more representative of humankind.”

The studies published today are not, of course, the first to emerge from the project – and nor will they be the last. There is still a lot of work to be done, for example to map some missing tissues across head, thoracic, abdominal and peripheral structures of the body, and then to assemble all the data sets together into a spatially-resolved complete atlas.

“I'm incredibly proud of what we've achieved by working together,” says Teichmann. “It's been eight years and over that time, a number of young researchers have risen up and developed their careers. The community and the culture that we've all built together has been very special and different. It’s been supportive and collaborative and inclusive.

"I'm super proud of how much we've achieved. It’s been mind-blowing, such an exciting journey."

^{Sarah Teichmann}