The new technology visualizes the expression of all genes in the tissue.
The approximately 30,000 genes that make up the human genome contain instructions that are vital to life. However, each of our cells expresses only a part of these genes in their daily functions. For example, the difference between heart cells and liver cells depends on the genes expressed—correct expression of genes can mean the difference between health and disease.
Until recently, researchers who studied underlying disease genes have been limited because traditional imaging techniques can only study a few genes at a time.
New technology developed by Dr. Jun Hee Lee. And his team at the University of Michigan School of Medicine (part of the Michigan School of Medicine) used high-throughput sequencing instead of microscopes to obtain ultra-high-resolution images of gene expression from tissue slides. The technology they called Seq-Scope allows researchers to observe each expressed gene, as well as the individual cells and structures within these cells, with incredible high resolution: 0.6 microns or 66 smaller than a human hair Times-defeat the current method in many ways by an order of magnitude.
"Whenever pathologists obtain a tissue sample, they will stain it and observe it under a microscope-this is how they diagnose disease," explains Lee, an associate professor in the Department of Molecular and Integrative Physiology. "We did not do this, but used our new method to make a miniature device that you can overlap with the tissue sample and use a barcode with spatial coordinates to sort everything in it."
Every so-called barcode is composed of a sequence of nucleotides—the patterns of A, T, G, and C found in DNA. Using these barcodes, the computer can locate each gene in the tissue sample, creating a Google-like database containing all the mRNAs transcribed from the genome.
"People have been trying to do this with other methods, such as microprinting, microbeads or microfluidic devices, but due to technical limitations, their resolution has always been between 20-100 microns. At that resolution, you Can't really see the level of detail needed to diagnose the disease," Lee said.
Lee added that the technology has the potential to create an unbiased systematic method to analyze genes.
"Whenever we are engaged in scientific research, we have to make assumptions about the role of two or three genes, but now we have micro-scale genome-wide data and more knowledge about what is happening inside the tissues of patients or model animals. "
Lee said that this knowledge can be used to gain insight into why some patients respond to certain drugs while others do not.
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The team used normal and diseased liver cells to prove the effectiveness of the technology, successfully identifying dying liver cells, surrounding inflamed immune cells, and liver cells with altered gene expression.
"This technology actually shows many known pathological features that people have previously discovered, but it also shows many previously undiscovered genes that have been regulated in new ways," Lee said. "Seq-Scope technology combined with other single-cell RNA sequencing technologies can accelerate scientific discovery and may lead to a new paradigm in molecular diagnostics."
The latest issue of "Cell" magazine describes this work.
Other authors include: Chun-Seok Cho, Jingyue Xi, Yichen Si, Sung-Rye Park, Jer-En Hsu, Myungjin Kim, Goo Jun, and Hyun Min Kang.
This work was carried out by the National Institutes of Health (T32AG000114 to CSC, K01AG061236 to MK, U01HL137182 to HMK, JX and YS, R01DK118631 and R03HD098552 to GJ, R01DK114131 and R01DK102850 to JHL, P30AG024503824, P30DK034933, P30AG024503824, P30DK034933, P30DK046592 ), Chan Zuckerberg Initiative (to HMK), Frankel Cardiovascular Center inaugural funding (to JHL and MK), American Association for the Study of Liver Diseases (to JHL and HMK), Mcubed (to MK, HMK and JHL), Glenn Foundation ( (For JHL)), Taiwan Government Scholarship (for JEH) and ADVANCE and MTRAC Award (for JHL), funded by the Michigan Economic Development Corporation.
Disclaimer: Jun Hee Lee is the inventor of Seq-Scope related patent applications.
Paper cited: "Using Seq-Scope to microscopically examine the spatial transcriptome", Cell. DOI: 0.1016/j.cell.2021.05.010
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