China Builds First Basic Framework for Human Cell Map 80 After Zhejiang University Leads

Cells are the basic unit of life. After the completion of the Human Genome Project (HGP), a six-nation scientist, we have a preliminary genetic “codebook”, but to this day, humans have not been able to get a glimpse of their own cell maps. In recent years, the emergence of new technologies such as single-cell sequencing has allowed scientists to observe cells with unprecedented precision.

(Original title: China builds the first basic framework of human cell mapping, “after 80” Zhejiang University leader)

Journalist He Liping

In the early hours of March 26, Beijing time, Guo Guoxuan team of Zhejiang University Medical Center Stem Cell and Regenerative Medicine Center and Zhang Dan team of Zhejiang University Hospital, Wang Weilin Team, Chen Jianghua Team, Liang Tingbo Team and Yellow River Team jointly published their research results in the top academic journal Nature. Construction of a Human Cell Landscape at Single-Cell Level.”

They performed Microwell-seq high-throughput single-cell sequencing analysis of 60 human tissue samples and 7 cell culture samples, systematically mapping human cells across two periods, from embryo to adult age, to eight systems. The map’s ultimate mission is to radically improve understanding, diagnosis and treatment of diseases.

Notably, the results were launched in the form of the Accelerated Article Preview, which was received on March 12, local time. The first authors of the paper include Associate Professor Han Xiaoping of Zhejiang University School of Medicine, 17th-grade master’s student Zhou Zixuan, 19th-grade doctoral student Fei Lijiang, 17th-grade straight-bumno Sun Huiyu, 18th-grade doctoral student Wang Renying, 16th-grade straight-born Chen Wei, postdoctoral student Chen Haide and Wang Jingjing. The correspondents are Guo Guoxuan and Han Xiaoping.

“This work is a very important milestone in the human cell mapping program, which has constructed the basic framework of the human cell map and is of guiding significance for the further improvement of the future map,” Guo said in an interview with the journalists at www.thepaper.cn. He also mentioned that “the achievement was completed by Chinese first and reflects the strength of our country in related fields.” “

Human Cell Atlas is an international scientific program that has emerged in the life sciences field in recent years. “In the long run, the Human Cell Mapping Program aims to describe the detailed characteristics of each cell in the human body (approximately 37 trillion), presenting the 3D structure of different types of cells in human tissue, mapping the interlinkages of all human systems, and revealing the relationship between map changes and health and disease. The Human Cell Mapping Program will radically improve understanding, diagnosis and treatment of diseases. Guo Guoxuan said.

The big science project, also thought to be comparable to the Human Genome Project, was originally led by British and American scientists. In October 2017, Aviv Regev, a computational biologist at the MIT-Harvard University,research and computational biologist, and Wellcome Trust, head of cytogenetics at the Wellcome Trust’s Sanger Institute in the United Kingdom. Sarah A. Teichmann of the Sanger Institute published an article on bioRxiv, the preprint platform, entitled “The Human Cell Atlas”, which systematically discusses the meaning, objectives, tasks, and implementation paths of HCA. Nearly a year before the article was published publicly, Regev and others held a conference on the plan in London, England.

Guo Guoxuan, 37, is a professor and doctoral tutor at the Stem Cell and Regenerative Medicine Center of Zhejiang University School of Medicine, a double professor at Zhejiang University’s First Hospital, deputy director of the Stem Cell and Regenerative Medicine Center of Zhejiang University School of Medicine, and deputy director of the Institute of Hematology of Zhejiang University.

He graduated from Wuhan University with an undergraduate degree in 2005 and a Ph.D. in Science from the National University of Singapore in 2010. He then went to Harvard Medical School in the United States to do postdoctoral research, in 2014 joined Zhejiang University Medical School.

In 2017, he was awarded the National Fund for Excellence in Excellence, and in 2019 he was selected as a leader in scientific and technological innovation under the “Million People’s Program”, and was awarded the Shulan Medical Youth Award, the “Ho Yingdong Youth Teacher Award” and the “Cell Biology Society Young Scientist Award” in 2019.

China Builds First Basic Framework for Human Cell Map 80 After Zhejiang University Leads

Guo Guoxuan

Guo Guoxuan is a veteran in the field and a “black horse”. As early as the National University of Singapore, Guo Guoxuan has entered the field of single-cell histomics, which has been committed to the development and application of single-cell analysis technology. Just over three years after returning home, his team published an unexpected achievement in cell, one of the world’s leading academic journals, building the first mammalian cell map to grab the next shot in a highly competitive global environment. The results have moved China from almost blank to “world-first” in the field of high-throughput single-cell sequencing.

“Our team published the first mouse cell map and had a deeper understanding of the structure and cell type of mammals, which gave us the experience to complete the study,” Guo said. On the other hand, we used a self-built Microwell-seq single-cell analysis platform, rather than a commercialized 10XGenomics instrument, or a streaming sorting instrument, which reduced the cost of our single-cell analysis by an order of magnitude, leaving the resources to complete the study. “

Of course, he also said, “Our team is very hard-working, otherwise nothing would have happened.” “

China Builds First Basic Framework for Human Cell Map 80 After Zhejiang University Leads

Build the world’s first mammalian cell map 2 years ago

On February 23, 2018, Guo’s team published an academic paper in Cell, the world’s leading academic journal, to build the world’s first mammalian cell map. At that time, guo Guoxuan returned from Harvard Medical School to join Zhejiang University just three years later.

The team systematically analyzed more than 400,000 single-cell transcriptions of nearly 50 organ tissues in mice to build the first mammalian cell map.

The map covers the various major cell types in mammals and describes in detail the tissue cell subtypes, matrix cell subtypes, vascular endothelial cell subtypes, and immunocellular subtypes in each organ.

The achievement was a milestone in the field of cell mapping, which surprised European and American research institutions that had a pre-emptive advantage.

At the time, one of the key technologies in this work was the construction of a single-cell sequencing platform, and it was the maturity of single-cell sequencing technology that was considered increasingly feasible for human cell mapping. Prior to this technique, traditional sequencing techniques could only “look” into hordes of cells, and the specificity of individual cells could easily be ignored.

The advent of single-cell sequencing technology has revolutionized traditional cellular cognitive systems and enabled the non-differentiated analysis of high-abundance gene transcriptions in individual cells, thus establishing a universal cell classification system.

Guo Guoxuan’s team took more than a year to build a fully local microwell-seq high-throughput single-cell sequencing platform. Using microporous matrix, molecular marker and amplification technology, high-throughput and high-precision single-cell level analysis are used to solve the problem of small, easy to lose and high cost of analysis in traditional sequencing.

“In the past, it used to take 100 yuan to analyze a cell, but now we’ve developed a platform that only costs 1 yuan, ” Mr Guo said at the time. And the accuracy is even higher than the most advanced equipment in the United States today. “

However, their platforms are constantly being optimized, and there are still many technical barriers to human cell mapping. “The cost of single-cell sequencing is still too high, the flux is not enough, the accuracy is low, and the problem of batch effect sits still to be solved, ” Guo told reporters. For spatial transcription group analysis technology, the experimental operation is relatively complex, the resolution and field of view are difficult to balance, and the generality of different organizations needs to be improved. For single-cell multi-group analysis technology, the experimental flux is low, and the stability of data needs to be improved.

For the first time, a comprehensive analysis of the type of human cell in embryos and adulthood is completely analyzed from the single-cell level

Human cells carry the same basic genetic information, but they express very different genes, and the genes expressed by the cells define the cell’s function. The human body’s single-cell gene expression map is expected to help us understand the function of these cells and the factors that influence cell activity.

Global laboratories, including Guo Guoxuan’s team, have also previously mapped the cells of animals and individual tissue types of human bodies. It was on the basis of the above-mentioned mouse cell mapping work that the team continued microwell-seq high-throughput single-cell sequencing analysis of 60 human tissue samples and 7 cell culture samples, systematically mapping human cells spanning both embryonic and adult periods, covering eight systems.

China Builds First Basic Framework for Human Cell Map 80 After Zhejiang University Leads

They took full advantage of microwell-seq’s low cost, low double-cell contamination rate and wide cell universality, and established a database of more than 700,000 single-cell transcription slots, identifying more than 100 cell classes and more than 800 cell subspecies in the human body. Based on this database, the team developed a single-cell ratio system for the identification of human cell types by scHCL (single-cell human cell map) and built a human cell blueprint website http://bis.zju.edu.cn/HCL/(national gene bank mirror https://db.cngb.org/HCL/).

“We found that a variety of adult epithelial, endothelial and matrix cells appear to act as immune cells in tissues, ” Guo said. The positive epithelial cells of the chemokine, antigen-positive endothelial cells and leukocyl-positive fibroblasts are widely distributed in various tissue organs of the adult body and are classified independent of the traditional epithelial, endothelial, matrix and immune cells. “

“We believe that extensive immunoactivation of adult non-immune cells is an important regulatory mechanism for regional immunity in the human body. “

Through cross-period, cross-tissue and interspecies cell mapping analysis, the team also revealed a universal mammalian cell destiny-determining mechanism: the transcriptional state of stem cells and progenitor cells is mixed and random, the transcription allotent state of differentiated and mature cells is clear and stable, and the regulator in the genome predetermines the stable state of the differentiation terminal.

It is worth noting that this study for the first time from the single-cell level of a comprehensive analysis of the embryonic and adult human cell species, research data will be a treasure trove of exploration of cell destiny decision mechanism, research methods will have a profound impact on the human body’s normal and disease cell state identification.

The team also noted that the study has limitations, namely that the cell sample size of each tissue is small. “Our work has some limitations in the depth of sequencing, but we have a big advantage in the comparability of data across organizations and species, ” Guo said. The perfect version of the human cell map should also integrate spatial information, multi-group data, and population analysis, which requires the joint efforts of scientists around the world. “

Ambitious “Human Cell Map” Program

In the 1970s, John Sulston, a British developmental biologist who spent 18 months observing the development of nematodes with an optical microscope, mapped what he saw every five minutes, and eventually hundreds of maps explained the early development of the nematodes. Based on these and other information, Sulston et al. have painted one of the most complete cell lineages of multicellular biological species to date, concentrating the fate of nearly a thousand cells of nematodes.

Because of this work, Sulston won the Nobel Prize in Physiology or Medicine at the age of 60, in 2002.

Half a century after Sulston used a microscope to observe the development of nematodes, Aviv Regev, a computational biologist at the MIT-Harvard University,research- and research-based researcher Slater. Sarah A. Teichmann, head of cytogenetics at the Wellcome Trust Sanger Institute in London, UK, and others, held a conference in London, England, to recommend the implementation of a “human cell map” that is far larger than the study of nematode cell lineage. (Human Cell Atlas, HCA) International Cooperation Research Program.

The HCA program is considered comparable to the Human Genome Project. Ten months after the conference, in August 2017, Regev et al. published an article on bioRxiv, the preprint platform, entitled “The Human Cell Atlas”, which systematically discusses the meaning, objectives, tasks, and implementation path of HCA.

The basic goal of HCA is to use a specific molecular expression spectrum to determine all cell types in the body and to connect this information to a description of the classical cell space location and morphology. Their ultimate goal is to identify each cell in the human body, to determine the spatial location of each cell, to identify each cell that appears at every moment of a person’s life through cell lineages, and to annotate each individual’s cell map, depending on its health, genotype, lifestyle, and external environment.

However, the job is huge and complex. Wu Jiarui, a researcher at the Institute of Biochemistry and Cell Biology of the Shanghai Institute of Life Sciences of the Chinese Academy of Sciences and director of the Key Laboratory of Systems Biology of the Chinese Academy of Sciences, said in an article published in November 2018 that this ultimate goal means the end of life science.

It is worth noting that in the international Human Genome Project announced in 2003, China was the only developing country to participate in the so-called Life Sciences “Moon Landing Project” by actively seeking to eventually be allowed to join, and finally to complete 1% of the total sequence, or 30 million base pairs on chromosome 3.

Similarly, in the above article published on the bioRxiv platform, 62 authors are largely AMERICAN and British research institutions, but none from China are among them.

Guo Guoxuan told reporters that the human cell map initiative is an open initiative, Chinese scientists in this plan does not have a very clear division of labor, “but because of China’s strong field of single-cell grouping, the future work of Chinese scientists will certainly make a huge contribution to the final version of the human cell map.” “

Of the paper’s results, he said, “Our work systematically completes the first draft of the human cell map, which should be a very important achievement in the relevant fields.” “

It’s worth noting that in October 2017, Facebook founder Mark Zuckerberg and his wife, Priscilla Chan, announced on their personal Facebook page that the chan-zuckerberg foundation (CZI), the two of them, had decided to fund the first 38 projects of the Human Cell Mapping Program. This has also become a hot topic in the global biological field.

Original text: https://www.nature.com/articles/s41586-020-2157-4