Second in a two-part series on mitochondria. See part 1.
Recent advances in single-cell genomics have made it possible to study individual cells and learn how they develop into specialized cells. However, we have only limited information on cells’ origins and how they’re related to the other cells around them.
Meanwhile, efforts to understand more about how cells differentiate and divide have looked at whole cell categories at a time, offering little knowledge of individual cells.
“It’s like looking at the statistics for a college — you can determine what the average student is like, but you have no idea what any one individual student is doing,” says Vijay Sankaran, MD, PhD, a hematologist at Boston Children’s Hospital. “Learning about cellular relationships is critical — it can help us understand how many stem cells give rise to any tissue in our body, what cell types cancers emerge from, or how some cells can be dysfunctional in particular diseases.”
In today’s Cell, Sankaran and his team, led by Leif Ludwig, PhD and graduate students Caleb Lareau and Jacob Ulirsch, in collaboration with Aviv Regev, PhD, of the Broad Institute of MIT and Harvard, describe a new approach. They applied single-cell gene sequencing to trace mutations in mitochondrial DNA, providing a more accurate picture of a cell’s developmental history and family tree.
This approach does not require any genetic manipulation of cells.
The mitochondrial approach not only works with cells grown in the lab, but also with any cell or tissue sample from a living person. It’s able to identify cell lineage correctly about 95 percent of the time and can do so at a scale 1,000 times greater than standard genome sequencing.
Mitochondrial DNA has many desirable characteristics for single-cell sequencing. The tiny organelles have fewer genes than other cell organelles, making their DNA less expensive to sequence. Hundreds to thousands of mitochondria can be found in every cell, and their DNA is more prone to acquiring new mutations that can be identified and tracked. And, conveniently, many existing methods already allow us to get information on the mitochondrial genome, says Sankaran.
The team uses mutations in the mitochondria to keep track of a cell over time or to assess how different cells in a tissue are related to one another. Each mutation makes the cell look unique and, as the mutations are passed from mother to daughter cells, they can also help researchers establish a cell family tree.
“Unlike other approaches for lineage tracing, using genetic labels as ‘barcodes,’ this approach does not require any genetic manipulation of cells,” says Sankaran. “The barcodes exist in all of our cells naturally.”
Filling in the gaps
Wayward cell division and differentiation play a large part in many illnesses, so understanding cell relationships has implications for a range of diseases, including cancer.
“Patients often have cancer cells that survive treatment,” says Sankaran. “If we could survey those cells, we could learn which ones survive and what’s different about them.”
Perhaps most importantly, mitochondrial DNA may help fill in the huge knowledge gaps we still have about how the human body works. “One of the problems in studying humans,” says Sankaran, “is we’re limited in our understanding of what happens in them. We can’t say where one cell comes from and what it is giving rise to.”
Ludwig, Lareau and Ulirsch were co-first authors on the paper. Regev and Sankaran were senior authors. Supporters of the study include the National Institutes of Health, the Broad Institute, the Allen Institute, the German Research Foundation, the New York Stem Cell Foundation, the Howard Hughes Medical Institute and the Klarman Cell Observatory.
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