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DNA Barcodes Make for Better Single-Cell Analysis

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Variations within neurons

Caption: Single-cell analysis helps to reveal subtle, but important, differences among human cells, including many types of brain cells.
Credit: Shutterstock, modified by Ryan M. Mulqueen

Imagine how long it would take to analyze the 37 trillion or so cells that make up the human body if you had to do it by hand, one by one! Still, single-cell analysis is crucial to gaining a comprehensive understanding of our biology. The cell is the unit of life for all organisms, and all cells are certainly not the same. Think about it: even though each cell contains the same DNA, some make up your skin while others build your bones; some of your cells might be super healthy while others could be headed down the road to cancer or Alzheimer’s disease.

So, it’s no surprise that many NIH-funded researchers are hard at work in the rapidly emerging field known as single-cell analysis. In fact, one team recently reported impressive progress in improving the speed and efficiency of a method to analyze certain epigenetic features of individual cells [1]. Epigenetics refers to a multitude of chemical and protein “marks” on a cell’s DNA—patterns that vary among cells and help to determine which genes are switched on or off. That plays a major role in defining cellular identity as a skin cell, liver cell, or pancreatic cancer cell.

The team’s rather simple but ingenious approach relies on attaching a unique combination of two DNA barcodes to each cell prior to analyzing epigenetic marks all across the genome, making it possible for researchers to pool hundreds of cells without losing track of each of them individually. Using this approach, the researchers could profile thousands of individual cells simultaneously for less than 50 cents per cell, a 50- to 100-fold drop in price. The new approach promises to yield important insights into the role of epigenetic factors in our health, from the way neurons in our brains function to whether or not a cancer responds to treatment.

Creative Minds: Programming Cells to Write Their Own Memoirs

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MEMOIR cells

Caption: MEMOIR cells variably activate (cyan). The recorded information is then read out to visualize certain RNA transcripts (red).
Credit: Elowitz and Cai Labs, Caltech, Pasadena, CA

One of the most fascinating challenges in biology is understanding how a single cell divides and differentiates to form a complex, multicellular organism. Scientists can learn a lot about this process by tracking time-lapse images through a microscope. But gazing through a lens has its limitations, especially in the brain and other opaque and inaccessible tissues and organs.

With support from a 2017 NIH Director’s Transformative Research Program, a California Institute of Technology (Caltech) team now has a way around this problem. Rather than watching or digging information out of cells, the team has learned how to program cells to write their own molecular memoirs. These cells store the information right in their own genomic hard drives. Even better, that information is barcoded, allowing researchers to read it out of the cells without dissecting tissue. The programming can be performed in many different cell types, including stem or adult cells in tissues throughout the body.

DNA Barcodes Interrogate Cancer Cells

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Blue and green blobs with one purple and red blob with a yellow and red striped box

Caption: A mix of cells collected from an abdominal cancer. The cancer cells (green) are positive for a cell surface cancer marker called EpCAM. The red cell is a normal mesothelial cell. The nuclei of all the cells are stained blue. Each of the five rows in the red, orange, and yellow “heat map” in the corner represents one cell, and the intensity of the color in each of the ~30 narrow columns reflects the abundance of a particular protein. It is apparent that there is a lot of heterogeneity in this collection of cancer cells.
Credit: Ralph Weissleder, Center for Systems Biology, Massachusetts General Hospital, Boston

The proteins speckling the surface of a cancer cell reveal critical clues—the type of cancer cell and a menu of possible mutations that may have triggered the malignancy.  Since these proteins are exposed on the outside of the cell, they are also ideal targets for so-called precision cancer therapies (especially monoclonal antibodies), optimized for the particular individual. But in the past, to analyze and identify these different proteins, large samples of tissue have been needed. Typically, these are derived from surgical biopsies. But biopsies are expensive and invasive. Furthermore, they aren’t a practical option if you want to monitor the effects of a drug in a patient closely over time.

Using a minimally invasive method of cell sampling called fine needle aspiration, physicians can collect miniscule cell samples frequently, cheaply, and safely. But, until now, these tiny samples only provided enough material to analyze a handful of cell surface proteins. So, it comes as particularly good news that NIH-funded researchers at Massachusetts General Hospital in Boston have developed a new technology that quickly identifies hundreds of these proteins simultaneously, using just a few of the patient’s cells [1]. The key to this new method is a clever adaptation of the familiar barcode.