The A To Z Of You
OUR BODIES CONTAIN SOME 30 TRILLION CELLS, AND A NEW PROJECT AIMS TO MAP THE MOLECULAR SIGNATURE OF EVERY SINGLE ONE
A new project aims to map the molecular signature of every single one of our bodies’ 30 trillion cells
Mapping the human body is one of biology’s oldest endeavours. By studying the battered bodies of Roman gladiators, the 2nd-Century philosopher-surgeon Galen of Pergamon wrote medical texts that stood as the pinnacle of anatomical knowledge for more than 1,000 years, until the Flemish doctor Andreas Vesalius came up with more accurate works. But it wasn’t until the invention of the first practical microscope in the mid-1600s, a century after Vesalius’s death, that curious scientists could finally begin to study cells – the building blocks that make up our tissues and organs.
Just as studying the tiniest subatomic particles has helped physicists to unravel the workings of the cosmos, so biologists have found that zooming in on our individual cells can reveal new insights into the human body. For a long time, this has been the domain of pathologists, studying the physical appearance of cells and tissues, along with a relatively limited number of molecular markers. But, backed by the exciting new science of single-cell genomics, a project called the Human Cell Atlas is aiming to create the ultimate inventory of the human body, mapping every single one of our cells in intricate detail. And the resulting guidebook could revolutionise our understanding of health and disease.
It’s long been clear that cells in different organs look and behave in their own distinctive ways. For example, spherical immune cells are primed to recognise infections, while spidery nerve cells crackle with hundreds of connections. Nevertheless, each cell still has the same basic set of instructions in the form of the human genome, encoded within our DNA. The thing that makes each cell type different is the particular set of genes active within it, producing molecular messages called RNA. And because a particular pattern of gene activity will be unique to a specific cell type, the RNA made within it will be unique too, acting as a kind of molecular ‘fingerprint’.
For several decades, researchers have been able to measure the activity of genes in different cell types (known as gene expression) by mashing up millions of cells and analysing the different RNAs, getting a read-out of which genes are switched on and which are off.
Yet this is only an average, and this method can’t pick up differences between individual cells. It’s like looking at a crowd from a distance and only seeing a colourful blur, rather than the exact hue of each person’s shirt. But thanks to recent advances in technology, we can now zoom right in to look at gene activity in a single cell (see diagram, below).
A typical human body contains around 30 trillion cells, but while it is often said that there are around 200 different types, more detailed molecular analysis has revealed that this is a massive underestimate. Is every cell in the liver exactly the same, or have we only been measuring averages? What about the billions of neurons in the brain, or the multitude of distinct immune cells? These questions provided the spark for the Human Cell Atlas, which aims to map gene expression patterns in billions of individual cells.
THE JOURNEY BEGINS
The idea flickered into life in 2012 when geneticist Dr Sarah Teichmann came to the Wellcome Trust Sanger Institute near Cambridge to set up a research group studying gene activity in single cells in the mouse immune system. Over coffee and conversation with her new colleagues, she realised that her techniques might solve a much bigger challenge.
“Despite centuries of microscopy, we don’t actually fully understand the different cell types in the body,” she says. “When I came to the Sanger Institute we started bouncing ideas around. It was a bit utopian because the technology just wasn’t there yet, but we thought what if someday it would be possible to atomise a human body – take a human and look at all their cells. Of course, you’re not vaporising a whole person, but we thought we could take tiny samples from many different people and stitch it all together into a kind of universal atlas.”
With trillions of cells to analyse, this isn’t the kind of task that a single laboratory, or even a single institute, can handle alone. Teichmann and her colleagues soon realised that a number of other researchers were starting to have the same thoughts as them – notably Dr Aviv Regev at the Broad Institute in Massachusetts – and began to build an international consortium of single-cell enthusiasts ranging from geneticists and molecular biologists to surgeons and machine learning specialists. So far, the team has committed to studying four types of tissue: the brain, the immune system, epithelial tissue (which lines the surfaces of organs and blood vessels), and foetal and placental cells. As well as cataloguing the cells of healthy people, a key part of the project will be to understand
how cells change their activity when we get sick, so cancer cells are on the initial list, too.
The scale of the Human Cell Atlas and the accuracy required means that this is no longer the kind of work that can be done by hand. To find out more about the technology involved, I visited Dr Stephan Lorenz. He heads up the single-cell genomics facility at the Sanger Institute, where a significant proportion of the work for the Human Cell Atlas will be carried out.
He shows me around several large rooms full of huge cabinets containing an army of high-tech, liquid-handling robots for preparing and processing single-cell samples, supervised by just two human staff. One impressive machine isn’t so much a sonic screwdriver as a sonic sampler, using sound pulses to whack precisely-measured microscopic drops of liquid from one plastic plate to another. Another can process more than 1,200 samples in 90 minutes.
“Over the last couple of years there’s been an explosion of methods that allow us to measure these tiny quantities of RNA that are present in a single cell,” he says. “We can now understand how
“WE CAN NOW UNDERSTAND HOW CELLS ‘THINK AND FEEL’ AND SEE INSIDE THE ‘MIND’ OF A CELL”
cells ‘think and feel’ and see inside the ‘mind’ of a single cell. By looking at the messages in cells we can infer their function and even their identity.” What’s more, he explains, he can even see how individual cells in the immune system change when they are activated to fight infection, or watch the genes that are switched on and off as one cell splits into two.
Yet RNA messages aren’t the only thing that gives a cell its identity. RNA carries instructions to make proteins, which build physical structures inside cells and carry out biological functions in the body (for example, digestive enzymes in the stomach or sturdy keratin proteins that make up our skin and hair). Lorenz and his colleagues are now developing methods to analyse all the proteins inside a single cell.
It currently takes about three weeks to analyse all the RNA in an individual cell, though the process is speeding up all the time. Perhaps an even bigger challenge than analysing all of the cells is coping with the quantity of data generated. Around 850,000 messages are sequenced per cell. Multiply that by millions of cells, and it quickly adds up.
To help with this, the Human Cell Atlas consortium secured funding from the Chan Zuckerberg Initiative (set up by Facebook founder Mark Zuckerberg and his wife Priscilla Chan) to develop ways to process and present the torrent of information coming from the sequencing labs.
Making the Atlas searchable and usable is vital if it is to become a meaningful resource for scientists. Although Teichmann doesn’t yet know how the data will be presented, she does have one fun idea. “The really futuristic vision is that we will all be wearing virtual reality headsets and be able to look at a virtual body to point out parts that we want to see,” she says.
MAPPING THE FUTURE
It’s still early days for this incredibly ambitious project, which officially kicked off in October 2016, but Teichmann thinks it’s feasible. “I would say for a draft Atlas we need to analyse between approximately 30 million and 1 billion cells,” she explains. “Over the last eight years, there has been an exponential decrease in cost per cell and an exponential increase in the number of cells per experiment. If that trend continues then we are in good shape.”
As well as satisfying our scientific curiosity about what we’re all made of, Teichmann sees the Atlas as a source of huge potential benefits for biomedical research, revealing leads for new drugs or finding molecules that act as biomarkers for diagnosing and monitoring disease. At a deeper level, she hopes it will answer fundamental questions about the links between genes and health. As an example, she mentions the harmful change (mutation) in a gene called CFTR that causes cystic fibrosis, which affects the lungs and other organs.
“We know that CFTR is active in the lungs, but in fact is expressed in other parts of the body, too. So you could interrogate the Human Cell Atlas and find those cells, to understand why things are going wrong when it’s mutated,” she explains. “Or say you want to know the side effects of a drug that targets the product of a particular gene. You could search the Atlas to see where that gene is expressed – which organs, tissues and cells – and then predict what the anticipated side effects might be.”
Understanding exactly what has gone wrong in a wide range of diseases, quickly identifying which cells and which molecules are misbehaving, will help doctors to diagnose conditions faster and select the most appropriate treatment with less of the guesswork that goes on at the moment.
Ultimately, Teichmann and her team see the Human Cell Atlas as a fundamental resource that will one day have an impact on almost every aspect of biology and medicine. Perhaps we could even call it Human Genome 2.0.
“I like that!” she laughs. “The Human Genome Project was all about deciphering the DNA sequence, but the Human Cell Atlas is asking what does that sequence actually stand for? How is the genetic code read out to make a human body? It really is mind-blowing!”
Airborne Event is a piece of art created by Fred Tomaselli in 2003
A laboratory at the Sanger Institute, where a lot of the Human Cell Atlas research will be carried out