In January 24, 2020, the essence of Science magazine, Chinese scientists published three Science papers in the same period.

January 30, 2020 / BIOON / - -- a new issue of Science Journal (January 24, 2020) is published this week What are the highlights of its research? Let Xiaobian come together The picture is from science journal 1 Science: great progress! RNA vaccine makes claudin car-t cells more effective against solid tumor doi: 10.1126/science.aay5967 Adoptive T cell therapy using T cells expressing car after gene transformation has achieved clinical success in B-cell malignant tumors However, in patients with solid tumors, car-t cell therapy has encountered challenges and is not so effective A key obstacle is the limited number of cell surface targets that allow high cancer specific expression and low risk of off-tumor / on-target toxicity of tumor eradication Recently, scientists have reported the cancer-related expression of CLDN6 CLDN6 is a quadruple membrane protein involved in tight junction In a new study, to assess whether CLDN6 can be used as a target for car-t cell therapy, researchers from biopharmaceutical New Technologies Corporation (bintech) in Germany analyzed its expression in a complete set of human and mouse tissues The results showed that the level of CLDN6 transcripts was higher in human fetal stomach, lung and kidney tissues, but could not be detected in normal adult tissue samples In addition, as before, CLDN6 transcript levels are generally higher in a variety of human cancers, such as testicular, ovarian, cervical, and lung adenocarcinoma In mice, CLDN6 is widely expressed in fetal organs, but it is down regulated before delivery, which results in its lack of expression in most organs of adult mice This shows that CLDN6 is a kind of carcinoembryonic cell surface antigen in a strict sense, and has an ideal expression profile suitable for car-t cell targeting The related research results were recently published in the Journal of science The title of the paper is "an RNA vaccine drives expansion and efficiency of claudin car T cells against solid tumors" When cldn6-car-t cells were co cultured with CLDN6 positive human tumor cell lines, they observed the up regulation of IFN γ secretion and T cell activation markers, but this did not happen when co cultured with CLDN6 negative tumor cells Cldn6-car-t cells were also able to effectively remove the globules of CLDN6 positive PA-1 ovarian cancer The results showed that cldn6-car-t cells could be eliminated completely by knocking out CLDN6 with CRISPR / cas9, which confirmed the high efficacy and target specificity of cldn6-car-t cells In recent years, these researchers stimulated tumor related T cells in cancer patients' natural cell bank by intravenous injection of liposomal antigen encoding RNA (RNA LPX) The nanoparticles deliver antigens to APCs in the spleen, lymph nodes and bone marrow, and initiate a toll like receptor (TLR) - dependent type I IFN driven immune activation program to promote antigen-specific T cell activation and strong proliferation In order to verify whether the improved method can play a role as car-t cell amplifying RNA vaccine (carvac), these researchers carried out a series of experiments First, they tested whether CLDN6 was shown on the surface of dendritic cells to stimulate cldn6-car-t cells in vitro They detected the dose-dependent expression of CLDN6 on the surface of dendritic cells treated with different doses of rna-lpx encoding CLDN6 The resulting expression of CLDN6 on the surface of dendritic cells induces the activation, cytokine secretion and proliferation of cldn6-car-t cells co cultured with dendritic cells in a dose-dependent manner After intravenous injection of cldn6-lpx to BALB / c mice, CLDN6 expression was detected on the surface of spleen dendritic cells and macrophages, but not on the surface of lymphocytes, which confirmed that CLDN6 was only delivered to antigen-presenting cells (such as dendritic cells and megaphagocytes) in vivo NK cells, B cells and T cells were strongly activated in spleen and lymph nodes of mice injected cldn6-lpx Since the most prominent serious adverse event of car-t cell therapy is cytokine release syndrome (CRS), these researchers explored the possibility of increased systemic cytokine release when cldn6-car-t cells are used in combination with carvac strategy They analyzed the levels of IFN γ, IL6 and NF α in the serum of cldn6-car-t cells transplanted mice after cldn6-lpx inoculation In addition to the slight transient increase of IFN γ in the early stage, no significant increase of proinflammatory cytokines was observed In addition, the spleen of mice inoculated with cldn6-lpx single time or repeatedly did not show any obvious pathological changes in structure; at different time points after receiving cldn6-lpx repeated inoculation, the cell composition of their spleen decreased slightly in CD11c + dendritic cells and F4 / 80 + macrophage population, while in T cells, B cells and NK cell population, there was no significant pathological change There was no change in quantity These findings suggest that carvac can be used to improve the antitumor effect of car-t cells This provides a new strategy for the use of car-t cells in the treatment of solid tumors that are difficult to treat However, these results are achieved in preclinical models, and whether they are the same in human body remains to be verified by further research 2 Science: it is the first time to construct a three-dimensional organ like body of human forebrain doi: 10.1126/science.aay1645 In a new study, researchers from Stanford University in the United States have constructed the organ like body of human forebrain for the first time The relevant research results were published in the Science Journal on January 24, 2020, and the title of the paper is "single cell transcription diversity is a hallmark of development potential" In this paper, they describe the cultivation and application of this kind of organ In most of the history of biological science, people have to use experimental animals to study the functional living brain - for ethical reasons, it is impossible to study the human brain in this way But in recent years, scientists have found a way to grow cells into clusters as substitutes for human organs, thus providing a better choice They are called organoids, and they are made from pluripotent stem cells that can differentiate into any type of human cell People use drugs and growth factors to guide them to grow into the types of organs they want to study In other studies, the brain or other nerve tissue has been cultivated - in this new study, the researchers have made further progress: inducing stem cells to grow into forebrain organs, and they live longer, which allows them to learn more about brain development As a spherical structure, human forebrain organs can self assemble into different parts of forebrain The forebrain includes the organs of the upper thalamus, thalamus, subthalamus and the hypothalamus These real organs play a key role in cognition, sensory processing and motor function As part of the study, the researchers also found a way to significantly prolong the life span of human forebrain organs (up to 300 days), enough to see them develop into more complex structures They hope that such a long period of growth will allow the study of brain diseases to develop and may find ways to prevent them 3 Science: new technology helps to find the most dangerous cancer cells doi: 10.1126/science.aax0249 in a new study, researchers from Stanford University, China West Lake University and Leiden University Medical Center in the Netherlands found that finding a number can help them develop the most dangerous cancer cells They also found that the number of genes cells use to make RNA is a reliable indicator of cell development, a finding that may make targeting oncogenes easier The relevant research results were published in the Science Journal on January 24, 2020, and the title of the paper is "single cell transcription diversity is a hallmark of development potential" These researchers found that as stem cells become more differentiated, they become more and more like adult cells, and they express fewer and fewer genes Before that, others had noticed the correlation and thought it might be an interesting coincidence But Newman and his colleagues are the first to classify thousands of single-cell genetic tests in a public database, and to confirm that the pattern is consistent and reliable Newman and the co-author gunsagar Gulati combine the measurement results of the number of genes expressed in cells with the measurement results of the number of RNA copies produced by each gene, as the basis for the development of computer algorithm cytotrace This algorithm aims to determine the degree of cell development In this paper, the researchers described using cytotrace to query single cell RNA data from triple negative breast cancer Triple negative breast cancer is rare but more dangerous because the growth of the tumor does not depend on the biochemical pathway doctors usually target when treating breast cancer Cytotrace can not only identify the known markers of cancer stem cells, but also find the previously considered unimportant markers 4 Science: to reveal the mechanism of phase separation to reduce the noise of protein concentration in cells doi: 10.1126/science.aav6691; doi: 10.1126/science.aba0446 because of the randomness of gene expression and the change of cell microenvironment, the protein concentration in cells fluctuates greatly When precision is important, how cells respond to protein concentration fluctuations is unclear Klosin et al Used the combination of theoretical and experimental work to confirm that the separated compartment can effectively reduce the protein concentration noise in cells These results indicate that phase separation provides a mechanism for enhancing the robustness of biological systems 5 Science: it is revealed that there is an atypical rotational enantiomerism in the small bicyclic molecule tryptorubin a DOI: 10.1126/science.aay9981 Some molecules are easy to draw on paper, while others contain rings and distortions that require people to think in three-dimensional perspective Reisberg et al Started to synthesize the small bicyclic molecule tryptorubin a, and found that their initial attempt to produce molecules with the right bond but the wrong molecular shape was a non classical phenomenon of rotational isomerism Then, the authors designed a synthesis method, in which they were locked on the right isomer before forming the second ring, thus forming a product that could not be distinguished from the real natural product When complex small molecules are used with limited rotation, such structural isomers may be latent 6 Science: to reveal the mechanism of amniotic membrane embryo during the formation of projejunum embryo by contraction ring doi: 10.1126/science.aaw1965 projejunum embryo formation is an essential step in the development of tissue separation in human body In birds and mammals, a series of similar molecular events have been known to determine the region of embryos, but how they are physically reshaped is still unknown Saadaoui et al Studied avian embryos