Clinical OMICS

MAY-JUN 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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28 Clinical OMICs May/June 2018 www.clinicalomics.com allowed researchers to build lineage trees. Using single-cell analysis, the team could then determine the diversity of cell types and their lineage relationships. Collectively, this work provided a snapshot of how cells and cell types diverge in lineages as the brain develops. "Single-cell analysis is providing us with a lot of information about small differ- ences at cell type-specific levels, information that is missed when looking at the tissue-wide level," said Bushra Raj, Ph.D., a post- doctoral fellow in Alex Schier 's lab at Harvard University and first author on the paper. Raj's collaborators included University of Washington's Jay Shendure, Ph.D., and Harvard Medical School's Allon Klein, Ph.D., pioneers in the field of single-cell analysis. The team sequenced 60,000 cells from the entire zebrafish brain across multi- ple animals. The researchers identified more than 100 cell types in the juvenile brain, including several neuronal types and subtypes in distinct regions, and dozens of marker genes. "What was unknown was the genetic markers for many of these cell types," Raj explained. "This work is a stepping stone," she added. "It's easy to see how we might one day compare nor- mal gene–expression maps of the brain and other organs to help characterize changes that occur in congenital disease or cancer." Raj credits single-cell analysis with accelerating the field of developmental biology. "People have always wanted to work at the level of the cell, but the technology was lacking," she said. "Now that we have all of these sequenced genomes, and now that we have these tools that allow us to compartmentalize individ- ual cells, this seems like the best time to challenge ourselves as researchers to understand the nitty-gritty details we weren't able to assay before." Building an Atlas Human disease-relevant scRNA-seq is not just for verte- brates. For example, a team of researchers at the Wellcome Sanger Institute are working on developing a Malaria Cell Atlas. Their goal is to use single-cell technology to produce gene activity profiles of individ- ual malaria parasites throughout their complex lifecycle. "The sequencing data we get allows us to under- stand how the parasites are using their genomes," said Adam Reid, Ph.D., a senior staff scientist at the Sanger. In March 2018, the team published the first part of the atlas, detailing its results for the blood stage of the Plasmodium lifecycle in mammals. Reid con- tends these results will change the fight against malaria. "Malaria research is a well-funded and very active area of research. We've managed to get quite a bit of understanding of how the par- asite works. What single-cell analysis is doing is allowing us to better understand the parasite in populations. We thought they were all doing the same thing. But, now we can see they are behaving differently." The ability to amplify very small amounts of RNA was the key innovation for malaria researchers. "When I started doing transcriptome analysis 10 years ago, we needed to use about 5 micrograms of RNA. Now, we can use 5 pico grams, 1 million times less," Reid said. That innovation allows scientists like Reid to achieve unprecedented levels of resolution in their work. For Reid, increased resolution means there is hope that science will be able to reveal how malaria evades the immune system in humans and how the parasites develop resistance to drugs. Reid predicted the Atlas will serve as the underpinning for work by those developing malaria drugs and vaccines. "They will know where in the life cycle genes are used and where they are being expressed," he said. Drug developers can then target those genes. The Atlas should be complete in the next two years, Reid added. In the meantime, Reid and his colleagues are focused on moving their research from the lab to the field, particularly to Africa. "We want to look at these parasites in real peo- (continued from previous page) "Single-cell analysis is providing us with a lot of information about small differences at cell type-specific levels, information that is missed when looking at the tissue-wide level." —Bushra Raj, Ph.D., Harvard University A gold leaf paint and ink depiction of the Plas- modium falciparum lifecycle by Alex Cagan.

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