A number of rare muscle diseases, such as Duchenne muscular dystrophy, begin with an atypical version of a single gene.
But every cell in the body of a person with the disorder contains this variant. So the question is: How does this gene cause disease in skeletal muscle and not in the heart or gut? After all, these organs contain their own types of muscles.
According to a study by a team of cell biologists and geneticists this week, many muscle disorders are caused by genes expressed not in muscle cells but in all the supporting cells around them. That finding was included in one of four studies published together this week in the diary science from the Atlas of Human Cells, an international collaboration aimed at cataloging every cell in the body. He hints at the power of the cellular atlas to shed light on how the raw information in our genes is used to assemble a living, breathing person.
“People often think of the genome as a drawing of the body, but that’s not really right,” said Stephen Quake, a bioengineer at Stanford University and Chan-Zuckerberg Biohub, at a press briefing on the Human Cell Atlas on Tuesday. “The genome is more like a list of parts.” Each cell uses only a certain set of parts of its DNA to build the necessary proteins, whether its role is to transmit electrical impulses or to pump blood.
Muscle is also full of fat cells, nerves and connective tissue and they all specialize in working together as an organ. The work of the consortium led to a key insight: a muscle fiber with a broken instrument can cause muscular dystrophy, but a malfunctioning fat cell or nerve cell can also do so.
With an almost omniscient look, researchers at the Atlas of Human Cells can begin to see how cells in the body use their genetic blueprint to create our life-sustaining organs. They can also begin to determine how a gene leads to a malfunctioning cell and then disease throughout the body. Together, their research documents several technological advances and experiments – from operations to extracting information from frozen tissue to computational tools – that have allowed researchers to peek inside half a million human cells from more than 30 organs at once.
Aviv Regev, co-chair of the cell atlas and co-author of the study of muscle disorders, compares the work with Google Maps, which can dramatically increase a particular molecule in a particular cell. “And you can reduce the scale and say, ‘This is how cells are organized next to each other, and that’s where it’s inside the organ,'” she says.
Over the last decade, researchers have become adept at understanding how individual cells work – like a muscle fiber. But a map-like perspective will allow biologists to ask questions about how cells connect with their neighbors and what makes nerve cells look different in different parts of the body.
“If you think about it in terms of therapy,” says Regev, “there’s no point in fixing muscle cells if the new cell in the tissue is actually broken.”
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With an atlas, the mysterious characteristics of the disease can suddenly make sense. Patients with Duchenne muscular dystrophy who have a deformed protein that is commonly used to help heal muscle tissue after use sometimes experience painful gastrointestinal disorders. “It’s hard to explain,” Regev said. “Why? What is the connection between the problems with your musculoskeletal system and the gut? As it turns out, the gene that causes Duchenne muscular dystrophy is expressed not only in muscle tissue but also in the lining of the esophagus and the nervous system that controls the gut. The effects of the gene scattered throughout the body illustrate how it can lead to both symptoms.
Although the team has identified thousands of possible links between gene expression, specific cells and disease, Gokcen Eraslan, a postdoctoral fellow at the Broad Institute, and lead author of the article, warns that they are all hypotheses. “It’s not muscle paper,” he says, “instead it’s a way to look at muscle to generate entirely new research questions.”
Among the questions raised is how we study muscle disorders. Mice, a classic laboratory model for Duchenne muscular dystrophy, experience the disease very differently from humans at the cellular level. Among other things, humans use many of the characteristic genes in fat cells in muscle fibers – mice do not.
“This is a truly striking example of how man and mouse are not the same,” Regev said. “When we develop drugs and so on, we often work a lot with mice – we have to – but it’s really important to know what’s the same and what’s different.”
Tracking a single gene from variant to cell to disorder was the simplest approach of the disease tracking project. Researchers are also looking at diseases that are linked to clusters of genes, such as type 2 diabetes or heart disease. In these cases, geneticists have previously identified risk factors, but there is no clear path from gene to disorder. However, the atlas offers clues.
Risk genes for type 2 diabetes are used in certain muscle cells that are associated with insulin resistance. But genes are also used in the lining of blood vessels and the heart, says Ayelet Segre, a geneticist at Harvard University and co-author of the study. Although Segre notes that this is still a working theory, the observation suggests “the genes that act in these [blood vessels] may affect the increased risk of vascular disease ”- which suggests that both diseases have a major cell root.
Another analysis suggests that sperm and some lung cells use the same sets of genes. “At first we were really puzzled,” says Eraslan. But when they entered the medical literature, they saw a well-documented real world relationship between bronchitis and sperm function. It turns out that both cells rely on the same set of genes to build cilia, fluttering “tails” that feed sperm and clean the surfaces of the lungs.
“There are certain patterns that get really obvious when you zoom in,” says Eraslan. “And that has been the case for the last decade – research is taking up one tissue and increasing it as much as possible. But certain patterns only become visible when you zoom out. ”Hidden genetic connections between cell types probably cross our bodies – we just can’t see them without a map.