Scientists at Wellcome Trust Sanger Institute to create Human Cell Atlas

PUBLISHED: 15:24 27 November 2016 | UPDATED: 15:24 27 November 2016

Dr Sarah Teichmann FMedSci, Cellular Genetics Programme Head, WTSI,  in front of the computer cluster at Sanger. Picture: Pari Naderi

Dr Sarah Teichmann FMedSci, Cellular Genetics Programme Head, WTSI, in front of the computer cluster at Sanger. Picture: Pari Naderi

ILIFFE

Hinxton scientists are preparing to explore humanity at a once-unimaginable level of intimacy.

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They are about to embark on the Human Cell Atlas. Think of it as literally a corpus of knowledge, a three-dimensional topography that places every distinctive cell type and cell state according to its position in the human body.

And, with ever-increasing robotics and enough funding, they and their international partners hope to finish the atlas in a decade. It could revolutionise the understanding of disease.

One of the begetters of the idea is Sarah Teichmann, who heads one group at the Wellcome Trust Sanger Institute at Hinxton, and another at the European Bioinformatics Institute on the same Wellcome Genome Campus.

“The idea does sound kind of unachievable and crazy, but the idea has been bubbling,” she says. She and her partners have yet to decide precisely where to start. “That is being negotiated at the moment. We have decided to have pilot projects around the core set of tissues. The one I have gone furthest with is the lung, the skin,” she says.

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“I do have a fondness for lung and skin – those epithelial tissues are exposed to the outside world, and interact with it by breathing. The immune system is actually my super super-favourite and that is a funny one because it is distributed all over the body.”

But first, the story so far: to a chorus of cries that it could not be done, a worldwide consortium of biologists 30 years ago announced an ambition to sequence all of the three billion bits of DNA in the human cell. They did it within the half-century of the identification of the double helix in 1953. Separate teams then started compiling lists of the tiny genetic variations that made one human different from another, or marked descent from this or that lineage.

But a puzzle remained: the cell itself. Every human being starts as one single embryo cell, and in the course of 40 weeks develops into tens of trillions of cells of at least 300 different kinds – nerve, bone, skin, fat, muscle, sinew, heart, liver, lungs and so on – all doing utterly different things, according to 
where they are, but all with identical DNA.

And that 300 is just a conventional figure. There could be vastly more cell types, or cell states. And everything that happens to a human starts with the cell.

3d render DNA strands close-up (depth of field)3d render DNA strands close-up (depth of field)

So the Human Cell Atlas is an international initiative to work out, in fine detail, why and how humans become what they are. But until a few years ago it was enormously difficult to sequence just one cell. The pioneers grew cell cultures, and tried to read the DNA from a little dish of them.

“Basically what we were doing was taking 100,000 cells and what I realised was that we were averaging across them and losing the information about let us say, three different substates those cells were in, because of the averaging process,” Dr Teichmann says.

Even within a single cancer tumour sample, seemingly identical cells were doing different things: that is, behaving like different cell types.

So just to understand the machinery of cancer, scientists needed information at the level of a single cell, but many times.

She, and Aviv Regev of the Broad Institute at MIT at the other Cambridge, in Massachusetts, took the initiative.

“We were already thinking about it a long time back and I know that Aviv was too,” Dr Teichmann says. “And then more than a year ago we thought now the time is right. We won’t be viewed as utter lunatics if we call a meeting and float this idea. There has been lots of support from scientists and funders and it is really moving.”

She was born to a German father and an American mother, in Karlsruhe in Germany, but graduated from Trinity College, Cambridge, and pursued her doctoral research at the Laboratory for Molecular Biology. She is married, with two daughters, aged four and eight.

She is now locked in to the logistics of science at an international level, involving a two-year pilot study, three years 
on a first draft of the human cell atlas, based on samples of every cell state present at a frequency of at least one per cent of the tissue, and then perhaps five years finishing a high precision guide to what constitutes a human. It means manipulating phenomenal quantities of information: just the thing for someone who came into genomics from computational biology.

“I just think the activity is fun, on a daily basis. That is important because even if you are intellectually engaged but you don’t actually like what you are doing, it is tough: whereas with programming, it is fun.”

“I really like the global view that genomics gives you,” she says. “With genomics you are trying to get a handle on the whole of biology: the big picture.”

Sanger: ‘Just a chap who messed about in a lab’

Cambridge has always been the stage on which some of the great drama of DNA research played out.

The first act was in 1953, when Francis Crick and James Watson used imagination and x-ray diffraction imagery to work out the double helix structure of the molecule that seemed to be the agency that contained the information of inheritance: it gained them a Nobel award in 1962.

It was a Cambridge scientist, Frederick Sanger who described himself as “just a chap who messed about in a lab”, who won his first Nobel chemistry prize in 1958 for the structure of insulin, and then a second laureate in 1980 for working out how to “read” a sequence of DNA. This delivered, for the first time, hope that humans might be able to study their own inheritance, and explore their own ancestry.

But before the human genome, scientists started on the simpler forms of life. John Sulston joined Sydney Brenner at the Laboratory of Molecular Biology in Cambridge to understand one tiny nematode worm. In 1992 Sulston founded the Sanger Centre and fought to make the data from the Human Genome Project freely available to everyone. Sulston shared a Nobel Prize with Brenner and a third researcher in 2002.

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