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报告标题:Development of macroporous hydrogel sponges for soft tissue
organoid culture and applications报 告 人:余严军 教师主 持 人:王 均
教师告诉时间:2018年四月10日10:00报告地方:大学城校区B2-101会议场所接待广大师生加入!生物文学科学与工程高校2018年十一月15日ABSTRACTSoft
tissue organoids have found various applications in disease modelling
and drug testing. Forming organoids is relatively straightforward but
maintaining them in culture can be tricky. We had previously developed a
class of soft macroporous cellulose sponges for forming and maintenance
of liver cell spheroids. We also demonstrated its ability to preserve
the heterogeneity and complexity of patient-derived xenograft of liver
cancer. To retrieve the spheroids/organoids for applications and
characterization, we have developed a variant that is readily dissolved
with reducing agents. A liver progenitor cell differentiate rapidly in
the 3D organoid configuration. To enable high-content and higher
throughput applications in drug screening, we further developed a
transparent variant that form soft macroporous hydrogel sponge directly
in multi-well cell culture plates. These developments enable the studies
and drug testing applications at different scales.报告人简单介绍:Professor
Hanry Yu researches the interface between Mechanobiology, biomaterials
and tissue engineering, biomedical optics and image data analytics. He
published >180 journal articles, >250 conference papers, >50
patent applications; spun off 6 companies, and trained many PhD students
and postdocs with successful careers in academia and industry. He led
multiple education and research programs; and advise various agencies,
organizations and institutions. He is a handling editor of Biomaterials.

报告标题:Microphysiological Systems for Emulating Human Tissues and
Diseases报 告 人:张宇先生(Y. Shrike Zhang)博士,加州洛杉矶分校(science and technology卡塔尔(قطر‎大文化水平史高校(Harvard
Medical School)报告时间:二〇一八年六月二日清晨9:00报告地方:制浆造纸工程国家关键实验室306会议厅款待广大师生前往!轻工科学与工程高校二〇一八年五月22晚报告剧情:Microphysiological
systems are microfluidic three-dimensional miniature human tissue and
organ models that recapitulate the important biological and
physiological parameters of their in vivo counterparts. They have
recently emerged as a viable platform for personalized medicine and drug
screening. These biomimetic organoids are anticipated to replace the
conventional planar, static cell cultures, and to bridge the gaps
between the current pre-clinical animal models and the human body. In
addition, multiple organoids may be channeled together through the
microfluidics in a similar manner they arrange in vivo, providing the
capacity to analyze interactions among these models. In this talk, I
will discuss our recent efforts on developing integrated
multi-organ-on-a-chip platforms formed by sophisticated microfluidics
and bioengineered organoids, which can operate in a continual and
automated manner over extended periods. I will also discuss a series of
bioprinting strategies including sacrificial bioprinting, microfluidic
bioprinting, and multi-material bioprinting, along with various
cytocompatible bioink formulations, for the fabrication of biomimetic
organoids. These platform technologies will likely provide new
opportunities in constructing functional tissue and disease models with
a potential extension into clinical therapeutics and precision
therapy.报告人简单介绍:Dr. Zhang received a B.Eng. in Biomedical
Engineering from Southeast University, China in 二〇〇八, after which he
then obtained a M.S. in Biomedical Engineering from WashingtonUniversity in St. Louis and a Ph.D. in Biomedical Engineering at Georgia
Institute of Technology and Emory University School of Medicine . Dr.
Zhang then pursued postdoctoral training at Brigham and Women’s
Hospital, Harvard Medical School, Harvard-MIT Division of Health
Sciences and Technologies, and Wyss Institute for Biologically Inspired
Engineering. (www.shrikezhang.comState of QatarDr. Zhang is currently a Research
Faculty at Harvard Medical School and Associate Bioengineer at the
Brigham and Women’s Hospital. His research is focused on innovating
medical engineering technologies, including 3D bioprinting,
organs-on-chips, microfluidics, biomedical imaging, and biosensing, to
recreate functional tissues and their biomimetic models. In
collaboration with a multidisciplinary team encompassing biomedical,
mechanical, electrical, and computer engineers as well as biologists and
clinicians, his laboratory seeks to ultimately translate these
cutting-edge technologies into the clinics. He is an author of >120
publications and his scientific contributions have been recognized by
>40 international, national, and regional awards. More information
can be found on his website.

图1 荧光显微镜下的类器官(图片源自网络)

类器官研讨的现状和发展趋向——诺Bell生历史学或文学奖获得者专访

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类器官(Organoids)是生机勃勃种在体外碰着下培育而成的装有三维构造的微器官(图1),具有相通真实器官的复杂布局,并能部分模拟来源组织或器官的生理作用。依附类器官,商讨人口可深远观察身体组织的改造,更加好地知道发育进度,并可用来再生文学以致药品的医疗效果筛选。由此,类器官商量有着广阔的发展前程。

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图2 “Organoid Modeling of the Tumor Immune Microenvironment”散文封面

图1 荧光显微镜下的类器官

海洋生物宗旨针对二零一八年12月美利坚同盟国印度孟买理管理大学Calvin J.
Kuo教师团队公布在列国特级杂志Cell的散文“Organoid Modeling of the Tumor
Immune Microenvironment”(图2),邀约诺Bell历史学和生历史学奖获得者Thomas C.
Südhof教师、有名情形毒医学及神经类器官行家EllenFritsche讲师就类器官研讨的现状、瓶颈、应用价值甚至以往的升高趋势实行演说。上边将为读者呈现访谈内容。

类器官(Organoids)是生机勃勃种在体外情形下培育而成的有所三个维度布局的微器官,具备近似真实器官的眼花缭乱布局,并能部分模拟来源协会或器官的生理作用。依据类器官,钻探人口可深远调查肉体组织的调换,更加好地通晓发育进程,并可用来再生教育学以致药品的医疗效果筛选。因而,类器官钻探具有遍布的发展前途。

  1. 问:什么是类器官?类器官的首要品种和她俩分其他重要脾气是怎么着?
    Question:What is organoid? What are the main organoid types and their
    key characteristics?
    Thomas C.
    Südhof答:近期有大多该领域的总结和专著可供参谋,以下是自己推荐的有的总结。(编者按:综述列表见土耳其共和国语回答卡塔尔(قطر‎
    Thomas C. Südhof’s answer:There are innumerable review articles and
    textbooks on organoids that I would suggest you consult.
    Here are some reviews:
    [1] Little MH, Hale LJ, Howden SE, Kumar SV. Generating Kidney from
    Stem Cells. Annu Rev Physiol. 2019 Feb 10;81:335-357
    [2] Rowe RG, Daley GQ. Induced pluripotent stem cells in disease
    modeling and drug discovery. Nat Rev Genet. 2019 Feb 8.
    [3] Sontheimer-Phelps A, Hassell BA, Ingber DE. Modeling cancer in
    microfluidic human organs-on-chips. Nat Rev Cancer. 2019
    Feb;19(2):65-81.
    [4] Mittal R, Woo FW, Castro CS, Cohen MA, Karanxha J, Mittal J,
    Chhibber T, Jhaveri VM. Organ-on-chip models: Implications in drug
    discovery and clinical applications. J Cell Physiol. 2019
    Jun;234(6):8352-8380.
    [5] Amin ND, Paşca SP. Building Models of Brain Disorders with
    Three-Dimensional Organoids. Neuron. 2018 Oct 24;100(2):389-405.
    EllenFritsche答:类器官是后生可畏种在体外培育而成的全体来源器官显微解剖特征的多细胞三个维度布局。于今截至,不一致团体、病魔模型及模拟发育的类器官已出版。类器官的工具细胞首要为集体特异性多能干细胞。类器官的注重特征包涵基于细胞类其他自己组织及空间约束的定向分歧,与体内发育进程日常。他们(类器官)含有四种器官特异性细胞,这个细胞的空间组织、排列与来自器官相符。其它,他们(类器官)具备部分源点器官特有的遵从。至今,来源于各个器官的类器官业已应际而生,富含脑、肠道、胃、舌、甲状腺、胸腺、睾丸、肝脏、胰腺、身体发肤、肺、肾、心脏及网膜。除了来自健康协会的类器官,多量病症模型(富含癌症模型)的类器官也不断涌现。最终,类器官为科学商量人士举行生长生物学研商提供了绝佳模型。
    Ellen Fritsche’s answer:An organoid is a three-dimensional (3D),
    multicellular structure with microanatomical features of the organ of
    origin produced in vitro. So far, organoids of different tissues,
    disease models, as well as organoids resembling development have been
    created. Cellular basis for organoids are mainly pluripotent or
    tissue-specific stem cells. Key features of organoids include their
    self-organization through cell sorting and spatially restricted lineage
    commitment in a manner similar to in vivo. They contain multiple,
    organ-specific cell types which are spatially organized in a manner
    similar to the organ. In addition, they recapitulate some specific organ
    functions. Organoids from multiple organs have so far been created.
    These include brain, intestine, stomach, tongue, thyroid, thymus,
    testis, liver, pancreas, skin, lung, kidney, heart and retina. In
    addition to the healthy organoids, a plethora of disease models
    including tumor models, have been developed. Last, organoids offer
    researchers an exceptional model to study developmental biology.
  2. 问:可否谈谈类器官在生物理学领域的首要性采取?
    Question:What are the main applications of the organoids in the field
    of biomedicine?
    Thomas C.
    Südhof答:类器官的市场股票总值在于其具有在体外培养境况下营造人类器官病痛模型的潜在的能量。那十分适用于像心脏那样的集体,在人类开始时代脑发育的钻研上也逐年变得平价。但类器官在复兴艺术学上的使用依然前路漫漫。
    Thomas C. Südhof’s answer:The attraction of organoids is that they
    potentially allow disease modeling of human organs in a dish. This works
    best for tissues such as heart, and is becoming feasible for early human
    brain development. The use of organoids in regenerative medicine is
    still far in the future.
    EllenFritsche答:作为意气风发项首要的技术突破,类器官如今已被公众承认为生物研究的最主要工具,并具有举足轻重的治病应用价值。类器官允许在二个模拟内源性细胞组织和器官协会的条件中张开组织生物学、发育、再生、病魔建模(包含骨良性肉瘤钻探卡塔尔、器官移植工夫改善、药物开掘/医疗效果评估以至毒农学的讨论。
    Ellen Fritsche’s answer:Starting as a major technological breakthrough,
    organoids are now well-established as an essential tool in biological
    research and also have important implications for clinical use.
    Organoids allow research on tissue biology, development, regeneration,
    disease modeling (including cancer research), improvements in organ
    transplantation, drug discovery/response as well as toxicological
    studies in an environment that mimics endogenous cell organization and
    organ structures.
    3.
    问:在癌症生物学及新药开荒世界,类器官相对于细胞系、动物模型的重大优势在哪个地方?
    Question:What are the main advantages of using organoids instead of
    cell lines, or animal models in the field of tumor biology and new drug
    development?
    Thomas C.
    Südhof答:绝对于细胞系来讲,类器官创设了一个有所三个维度构造的器官样组织,固然并不完全(模拟人类器官)。相较于动物模型,类器官的优势体今后其促成了选取人源性协博览会开尝试研商。
    有关进行Singapore国立高校余严军教师学术报告的照看。Thomas C. Südhof’s answer:The advantage over cell lines is that
    organoids model a three dimensional organ, although not completely. The
    advantage over animal models is that organoids enable studies of human
    material.
    Ellen Fritsche答:守旧的二维 (2D卡塔尔国肿瘤细胞系培育和动物人源性癌症异种移植物 (PDTXsState of Qatar长久以来一贯被用作肉瘤模型, 并为肉瘤研究做出了赫赫进献。然则,
    各个弱点阻碍了那几个模型的看病使用,这首倘使出于与肉瘤临床相关的药品开辟是成功率最低的。二维细胞作育类别不持有免疫性细胞、微境遇、间质成分和五藏六府特异性的作用。其余节制富含癌症细胞系经数13遍传世后缺少来源癌症的遗传异质性,
    原因是细胞在职培训育皿二维持生活长的条件下会产生优势克隆选用,但那并不合乎生理。此外,
    PDTX 模型还经历了小鼠特异性的肉瘤演化。在能源方面,
    这几个模型也是十二万分的费钱费时。类器官能够克制在那之中的风流倜傥部分限量。类器官的基因修饰可实今后相似生理条件的情状下打开病痛建立模型。比如,
    将癌症性突变导入健康干细胞可以发生遗传决定的肿瘤类器官。别的,
    类器官能够从伤者来自的不奇怪协会和肿瘤组织中火速培养,进而使伤者特异性药物检查评定和特性化学医学治方案的付出成为可能。在此种伤者特异性的肉瘤类器官中,可观望到集体稳态(histostasis卡塔尔国,如3D营造保留了与来自病者癌症相平等的团体病历史学特征,为前程性格化肉瘤临床的发展提供了盼望。与
    PDTX 分化,类器官维护方便,具备整合免疫性细胞的恐怕,易举办基因改造(遗传性肿瘤建立模型卡塔尔,协理合作对照的钻研,并可用以MTK量药物筛选和生物库的建设。
    除去肉瘤学,
    类器官也为新药开辟提供了绝佳模型。新药开辟的失利率异常高,那在必然水平上是由于动物药代引力学和药效学的分歧或动物病魔模型并无法完全模拟人体病理过程。具备人体极其生理和病理特点的类器官有利于击溃那个标题。基于特定病痛,以致一定个人,以色列德国州仪器量格局培育的类器官揣度将向上成为标准医疗的强有力工具。以往可依靠生物库举行筛选,不止是为了判断新药,还可宣布哪些病者能够从有个别(现成)药物的治病中收益。别的,对地下药物的重点检查测试可为制药业提供新的指导。其它,类器官现在可能用于毒艺术学检查评定,
    以作为动物试验的无敌补充(假设不是有的代表的话卡塔尔国。
    Ellen Fritsche’s answer:Traditional two-dimensional (2D) tumor cell
    line cultures and patient-derived tumor xenografts (PDTXs) in animals
    have long been employed as tumor models and have made tremendous
    contribution to cancer research. However, a variety of drawbacks hamper
    these models for clinical use as success rates for tumor therapeutics
    are lowest in the field of drug development. 2D cell line cultures do
    not contain immune cells, microenvironment, stromal compartments, and
    organ-specific functions. Other limitations include the lack of genetic
    heterogeneity of original tumors after many passages for cancer cell
    lines because clonal selection in the dish happens for superiority in 2D
    growth, which is not physiologic. Moreover, PDTX models experience
    mouse-specific tumor evolution. On the resource side, such models are
    highly money- and time-consuming. Organoids can overcome some of these
    constraints. Genetic modification of organoids allows disease modeling
    in a setting that approaches the physiological environment. Here,
    insertions of tumor mutations into healthy stem cells allow generation
    of genetically-controlled tumoroids. Additionally, organoids can be
    grown with high efficiency from patient-derived healthy and tumour
    tissues, potentially enabling patient-specific drug testing and the
    development of individualized treatment regimens. In such
    patient-specific tumoroids, histostasis is observed, i.e. conservation
    of histopathological traits between 3D cultures and the matched patient
    tumor, promising advances in personalized tumor therapies in the future.
    In contrast to PDTX, organoids are of easier maintenance, bear the
    possibility to integrate immune cells, are amenable to genetic
    modification (genetic cancer modeling), allow study of matched controls,
    can be used for high throughput drug screening and biobanking.
    Besides oncology, organoids are promising models for drug development.
    Attrition rates in new drug development are high. This is partly
    reasoned indifferences between animal pharmacokinetics and –dynamics or
    in animal disease models that do not correctly resemble human pathology.
    Organoids with human-relevant physiology and pathology are thought to
    help overcoming these issues. Organoid cultures based on a specific
    disease and even on a specific individual used in a high-throughput
    manner are expected to develop into powerful tools for precision
    therapy. Future screens may be performed using biobanks with the aim of
    not only identifying new drugs but also revealing which patients may
    benefit from treatment with certain (existing) drugs. In addition,
    focused tests of potential drugs should identify new leads for the
    pharmaceutical industry. Furthermore, organoids may be used in the
    future for toxicology testing to complement, if not in part replace,
    animal testing.
    有关进行Singapore国立高校余严军教师学术报告的照看。4.
    问:当前类器官的局限是何许?为了知足癌症生物学、干细胞生物学、移植、新药开辟领域的钻探须要,类器官必要在哪些方面进一层修改?
    有关进行Singapore国立高校余严军教师学术报告的照看。Question:What are the limitations of organoids and what aspects of
    organoids can be further improved to meet the demand for research in
    tumor biology, stem cell biology, transplantation and drug
    development?
    Thomas C. Südhof答:
    类器官领域的钻研仍在运维阶段。即便对于如心脏和肝脏那样的组织,类器官也十分不成熟,仅能某个模拟人体器官。对于脑协会则更甚。许多为主的(脑协会)生理效能,如细胞生理、生物化学作用依然有待突破。那将花费数年的年华。
    有关进行Singapore国立高校余严军教师学术报告的照看。Thomas C. Südhof’s answer:The field of organoid research is still in
    the beginning. Even for tissues like heart and liver, organoids are very
    immature and only partly model the human organ. This is worse for brain.
    Much fundamental biology, such as cell biology and biochemistry, is
    needed to advance the field. This will take many years.
    EllenFritsche答:类器官是融入了各个器官特异性细胞类型、协会形态和效能的公司模型。但类器官仅为有限度的模仿,干扰那项本领应用的叁个根本限定是它的体量。当类器官体量增添时,缺氧症和缺点和失误可溶性因子所致的集体坏死是必要解决的难题。消弭这么些主题素材的叁个只怕方案是激明目管生成路子,
    进而使类器官血管化。那早就在hiPSC衍生的肝脏类器官上得逞促成。类器官领域的另一个挑衅在于贰个完璧归赵的生命个体中所自然存在的五藏六府“对话”。类器官钻探可满意生物工程的须要,
    通过培养操练包含区别类型hiPSC衍生类器官(显示多少个器官系统的结商谈魔法)的五藏六府微芯片设备,用以在更临近于体内的情状中筛选药物。别的,通过在类器官中增多免疫性细胞,
    还可模拟具备免疫性系统的组织间“对话”。其它,在药理和毒教育学商量中,物质的肝脏代谢至关心注重要,那可透过以器官微电路的样式富含肝脏代谢来达成。
    Ellen Fritsche’s answer:Organoids are organ models recapitulating an
    assortment of organ-specific cell types, tissue morphogenesis and
    functions. Yet, there are limitations in their mimicry. One important
    limitation plaguing the application of this technology is their size.
    When the organoids’ volume increases, the issue of tissue necrosis
    caused by the lack of diffusion of oxygen and soluble factors needs to
    be addressed. One solution for this problem might be the activation of
    angiogenic pathways that will lead to vascularised organoids. This was
    already succeeded with hiPSC-derived liver organoids. One more challenge
    of the organoid field lies in organ crosstalk, which is naturally
    present in an intact organism. Here, organoid research meets
    bioengineering by producing organ-on-a-chip devices containing different
    types of hiPSC-derived organoids representing the structure and function
    of multiple organ systems for screening the effects of drugs in more in
    vivo-like settings. The crosstalk of tissues with the immune system can
    be modelled by adding immune cells to the organoids. For pharmacological
    and toxicological applications, liver metabolism of compounds is
    crucial. Including such metabolism via an organ-on-a-chip approach can
    solve this issue.
  3. 问:当前类器官研讨的升高大方向如何?
    Question:What are the current trends for organoids research?
    Thomas C.
    Südhof答:(当前的现状是)全数人都在盲目追求应用,却忽视了一个稳固的不错底蕴。笔者感至今会有巨额的商铺在这贩售希望,但他俩半数以上将以诉讼失败告终。因为有关生文学斟酌成果并不足以支撑这么些使用类型。类器官最有前途的应用领域应是用于肝脏、心脏和肉瘤的药品筛选。
    Thomas C. Südhof’s answer:Everybody rushes towards applications,
    without a solid scientific basis. I think hundreds of companies will be
    founded that will sell hope, but will mostly fail because the biology
    isn’t there to support applications. Most promising are drug screens in
    tissue organoids such as liver or heart and in cancer.
    EllenFritsche答:近些日子类器官商讨的大方向包含创设用于MTK量筛选的类器官库和平台,
    创立别的病症模型,
    以至创立用于全体生物体建立模型的器官微电路和微流体集成电路。在那特意要重申的是培育基的范围亟待消除。对微流体微芯片来说,要求朝气蓬勃种集成电路上全数类器官均适用的通用作育基。其余,依据器官系统的两样,
    需求支出与生理进度有关的来源于类器官的MTK量数据输出装置。在治疗方面,为了支付最好个体化学医学疗方案,使用源自病人特异性hiPSC类器官的个体化诊疗商讨要求开展。在毒历史学领域,类器官近期已被用来代表动物实行毒性测验。
    Ellen Fritsche’s answer:Current trends for organoid research include
    generation of organoid banks and platforms for high-throughput screening
    approaches, generation of additional disease models, and set up of
    organ-on-a-chip and microfluidics devices for whole organism modeling.
    Here, especially medium constrictions have to be solved. For
    microfluidics a common medium for all organoids on the chip is needed.
    Moreover, depending on the organ system, physiologically relevant
    high-throughput readouts from organoids need to be developed. On the
    clinical side, research on personalized medicine using organoids derived
    from patient-specific hiPSC is warranted for optimal individual
    treatment regimes. In the toxicology field, organoids as substrates for
    toxicity testing replacing animals is currently exploited.
  4. 问:可以还是不可以预测一下接下去5年内类器官研商领域的前进?
    Question:How the organoids research field will be look like in 5
    years?
    Thomas C. Südhof答:
    笔者的预后是在接下去的5年内好的实验室将学会怎么推动类器官的成熟,并分明该措施的局限。小编感到,即使类器官为干细胞钻探提供了庞大的空子,如推动新意识和疗法的面世;但那将消耗10年或更加长的时间来提升。到那时,也独有到那个时候,走向应用能力真的变为大概。在这里此前,大批量初创公司将会烧掉数以亿计的基金,他们中的少部分将会走向成功,并找到扩充营业收入的新路线。
    Thomas C. Südhof’s answer:My prediction is that in 5 years, good
    science labs will have learned how to mature organoids and the
    limitations of the approach will have been defined. I think organoids
    are a tremendous opportunity in stem cell approaches that will enable
    novel discoveries and therapies, but that this will take at least 10
    years to develop. Then and only then will it be possible to rationally
    move towards applications. Until then, lots of start-ups will have spent
    hundreds of millions of dollars, and a few of them will have been
    successful in generating some future avenue of revenue.
    有关进行Singapore国立高校余严军教师学术报告的照看。埃伦Fritsche答:在5年内,类器官的遗传操作与类器官库相结合将给生物医研带给倾覆的更改。购买来源于具备不一样遗传背景病人的病魔特异性类器官将改成或者。器官微芯片平台将有着特定标准,由公约商讨组织(CRO)以与眼下动物试验相同的方式提供。类器官将大幅地推进药品医疗效果试验和安全性测量试验的展开,因而也将步向药物开垦和化学安全性评估探讨的禁锢领域。
    Ellen Fritsche’s answer:In 5 years, genetic manipulation of organoids
    in combination with organoid banking will have revolutionized biomedical
    research. It will be possible to purchase disease-specific organoids
    from broad ranges of patients with distinct genetic backgrounds.
    Organ-on-a-chip platforms will be standard and offered by CROs in a
    similar manner than currently animal testing. Organoids will have
    tremendously facilitated drug efficacy and safety testing and thus will
    have entered also into the regulatory areas of research for drug
    development as well as chemical safety assessment.

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附:

图2“Organoid Modeling of the Tumor Immune Microenvironment”文章封面

  1. Thomas C. Südhof教授简单介绍

神州生物才能发展中央本着二零一八年1十一月U.S.A.帝国矿业学院Calvin J.
Kuo教师团队公布在列国特级杂志Cell的文章“Organoid Modeling of the Tumor
Immune Microenvironment”,约请诺Bell生教育学或法学奖拿到者Thomas C.
Südhof教授、盛名意况毒管理学及神经类器官行家EllenFritsche教授就类器官钻探的现状、瓶颈、应用价值乃现今后的进步大势举办演说。上面将为读者展现访问内容。

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  1. 问:什么是类器官?类器官的显要品种和他们分别的主要本性是何等?

有关进行Singapore国立高校余严军教师学术报告的照看。加州洛杉矶分校大学管理大学教师、Howard-Hughes医研所 (HHMI卡塔尔(قطر‎钻探员、美利哥科高校院士、美利坚合资国医科院院士、United Kingdom皇家学会外国国籍院士、二零一二年诺Bell艺术学和生教育学奖获得者。1954年生于德意志联邦共和国哥廷根,1983年赢得哥廷根大学军事学大学生学位。Südhof教师的研究重视聚集于突触前神经递质释放的成员机制,为该领域的一流化学家。他意识了囊泡内神经递质释放进程中的两种注重蛋白,并申明了神经递质释放的实际分子机制。鉴于在囊泡转运领域的开创性专门的学业,他前后相继荣立Russ克根基艺术学奖及诺Bell生教育学和艺术学奖等重大历史学奖项。

Question:What is organoid?What are the main organoid types and their
key characteristics?

  1. 埃伦 Fritsche教授简单介绍

有关进行Singapore国立高校余严军教师学术报告的照看。Thomas C.
Südhof答:最近有许多该领域的回顾和专著可供参谋,以下是自己推荐的风度翩翩对归纳。(编者按:综述列表见乌Crane语回答State of Qatar

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Thomas C. Südhof’s answer:There are innumerable review articles and
textbooks on organoids that I would suggest you consult.

德国IUF-莱布尼茨情形医研所(IUF-Leibniz Research Institute for
Environmental
Medicine)遭遇毒法学助教,球模型轻风险评估行家组经理。1996年获雷根斯堡大学和休斯敦高校历史学硕士学位,曾前后相继在美利哥国立环卫探讨所(NIEHS卡塔尔(قطر‎和IUF-莱布尼茨情形医研所成功大学子后研讨职业,二零一零-二〇一一年任亚琛药中国科学技术大学学身体发肤毒医学教授。如今为Neurotoxicology杂志副主要编辑、欧洲化学理事委员会(cefic)智囊团、欧洲联盟地平线2020布置行家组成员、亚洲替代动物试验商量中央(CEPRADOST-NENCOREW)项目起头人、代替法信托大会(ACT)成员和OECD发育神经毒性行家组织委员会委员员。历任澳洲代替动物试验社团(EUSAAT)副主席、主席。

Here are some reviews:

[1] Little MH, Hale LJ, Howden SE, Kumar SV. Generating Kidney from
Stem Cells. Annu Rev Physiol. 2019 Feb 10;81:335-357

[2] Rowe RG, Daley GQ. Induced pluripotent stem cells in disease
modeling and drug discovery. Nat Rev Genet. 2019 Feb 8.

[3] Sontheimer-Phelps A, Hassell BA, Ingber DE. Modeling cancer in
microfluidic human organs-on-chips. Nat Rev Cancer. 2019 Feb;19:65-81.

[4] Mittal R, Woo FW, Castro CS, Cohen MA, Karanxha J, Mittal J,
Chhibber T, Jhaveri VM. Organ-on-chip models: Implications in drug
discovery and clinical applications. J Cell Physiol. 2019
Jun;234:8352-8380.

[5] Amin ND, Paşca SP. Building Models of Brain Disorders with
Three-Dimensional Organoids. Neuron. 2018 Oct 24;100:389-405.

埃伦Fritsche答:类器官是生龙活虎种在体外培育而成的享有来源器官显微解剖特征的多细胞三个维度布局。到现在甘休,分歧团体、病痛模型及模拟发育的类器官已出版。类器官的工具细胞主要为团队特异性多能干细胞。类器官的首要特色富含基于细胞类别的自身组织及空间范围的定向差异,与体内发育进度相像。他们带有种种器官特异性细胞,那一个细胞的空间组织、排列与来自器官相同。其余,他们具有局地来源器官特有的效果。于今,来源于各样器官的类器官业已现身,包涵脑、肠道、胃、舌、甲状腺、胸腺、睾丸、肝脏、胰腺、四肢、肺、肾、心脏及网膜。除了来自健康组织的类器官,大量毛病模型的类器官也不断涌现。最终,类器官为调研人士举行生长生物学切磋提供了绝佳模型。

Ellen Fritsche’s answer:An organoid is a three-dimensional ,
multicellular structure with microanatomical features of the organ of
origin produced in vitro. So far, organoids of different tissues,
disease models, as well as organoids resembling development have been
created. Cellular basis for organoids are mainly pluripotent or
tissue-specific stem cells. Key features of organoids include their
self-organization through cell sorting and spatially restricted lineage
commitment in a manner similar to in vivo. They contain multiple,
organ-specific cell types which are spatially organized in a manner
similar to the organ. In addition, they recapitulate some specific organ
functions. Organoids from multiple organs have so far been created.
These include brain, intestine, stomach, tongue, thyroid, thymus,
testis, liver, pancreas, skin, lung, kidney, heart and retina. In
addition to the healthy organoids, a plethora of disease models
including tumor models, have been developed. Last, organoids offer
researchers an exceptional model to study developmental biology.

  1. 问:可不可以谈谈类器官在生物军事学领域的要害运用?

Question:What are the main applications of the organoids in the field
of biomedicine?

Thomas C.
Südhof答:类器官的价值在于其全数在体外培育情形下创设人类器官病魔模型的潜质。那十一分适用于像心脏那样的团队,在人类早期脑发育的商量上也逐步变得实惠。但类器官在恢复教育学上的应用仍旧前路漫漫。

Thomas C. Südhof’s answer:The attraction of organoids is that they
potentially allow disease modeling of human organs in a dish. This works
best for tissues such as heart, and is becoming feasible for early human
brain development. The use of organoids in regenerative medicine is
still far in the future.

埃伦Fritsche答:作为意气风发项重大的手艺突破,类器官近日已被公众以为为生物钻探的重大工具,并富有主要性的医疗应用价值。类器官允许在一个模仿内源性细胞组织和器官组织的遭受中开展组织生物学、发育、再生、病魔建立模型、器官移植本领精雕细刻、药物发掘/医疗效果评估以致毒军事学的商讨。

Ellen Fritsche’sanswer:Starting as a major technological
breakthrough,organoids are now well-established as an essential tool in
biological research and also have important implications for clinical
use. Organoids allow research on tissue biology, development,
regeneration, disease modeling (including cancer research), improvements
in organ transplantation, drug discovery/response as well as
toxicological studies in an environment that mimics endogenous cell
organization and organ structures.

3.
问:在癌症生物学及新药开垦世界,类器官相对于细胞系、动物模型的主要优势在哪个地方?

Question:What are the main advantages of using organoids instead of
cell lines, or animal models in the field of tumor biology and new drug
development?

Thomas C.
Südhof答:相对于细胞系来讲,类器官塑造了叁个有着三个维度构造的器官样组织,就算并不完全。相较于动物模型,类器官的优势体未来其促成了动用人源性组织举行试验商讨。

Thomas C. Südhof’s answer:The advantage over cell lines is that
organoids model a three dimensional organ, although not completely. The
advantage over animal models is that organoids enable studies of human
material.

Ellen Fritsche答:古板的二维 癌症细胞系培育和动物人源性肉瘤异种移植物
一直以来一直被用作肉瘤模型,
并为骨良性肉瘤钻探做出了高大进献。然则,各个劣点阻碍了那一个模型的看病使用,那关键是出于与癌症临床相关的药物开拓是成功率最低的。二维细胞作育系列不辜负有免疫性细胞、微境况、间质元素和五藏六府特异性的成效。别的约束包含肉瘤细胞系经一再传世后紧缺来源癌症的遗传异质性,原因是细胞在培育皿二维持生活长的景况下会时有爆发优势克隆接受,但那并不符合生理。其他,PDTX
模型还资历了小鼠特异性的癌症衍变。在财富方面,那么些模型也是最最的费钱费时。类器官能够制伏个中的后生可畏都部队分限量。类器官的基因修饰可实今后看似生理条件的动静下开展病魔建立模型。比如,将癌症性突变导入健康干细胞能够发生遗传决定的癌症类器官。此外,类器官能够从病者来自的正常组织和肉瘤组织中神速培养,进而使病人特异性药检评定和性情化诊疗方案的付出成为也许。在这里种伤者特异性的肿瘤类器官中,可观看见集体稳态(histostasis卡塔尔国,如3D作育保留了与来自伤者肿瘤相平等的集团病医学特征,为前景天性化癌症医治的前进提供了希望。与
PDTX 分裂,类器官维护方便,具备整合免疫性细胞的或许性,易实行基因改换,帮助协作对照的商讨,并可用来德州仪器量药物筛选和生物库的建设。

而外癌症学,类器官也为新药开采提供了绝佳模型。新药开垦的失利率相当的高,那在早晚水准上是由于动物药代引力学和药效学的歧异或动物病魔模型并无法完全模仿人体病理过程。具备人体特别生理和病理特点的类器官有协助克制那几个难点。基于特定病魔,以至一定个人,以MediaTek量情势作育的类器官算计将升高成为规范医治的强硬工具。今后可凭仗生物库进行挑选,不唯有是为了决断新药,还可公布哪些病人能够从一些
药物的临床中收益。别的,对秘密药物的首要检查测验可为制药业提供新的指点。此外,类器官今后大概用来毒文学检测,以作为动物试验的不战而屈人之兵补充(假使不是一些代替的话卡塔尔。

Ellen Fritsche’s answer:Traditional two-dimensional tumor cell line
cultures and patient-derived tumorxenografts in animals have long been
employed as tumor models and have made tremendous contribution to cancer
research. However, a varietyof drawbacks hamper these models for
clinical useas success rates for tumor therapeutics are lowest in the
field of drug development. 2D cell line cultures do not contain immune
cells, microenvironment, stromal compartments, and organ-specific
functions. Other limitations include the lack of genetic heterogeneity
of original tumors after many passages for cancer cell lines because
clonal selection in the dish happens for superiority in 2D growth, which
is not physiologic. Moreover, PDTX models experience mouse-specific
tumor evolution. On the resource side, such models arehighly money- and
time-consuming.Organoids can overcome some of these constraints. Genetic
modification of organoids allows disease modeling in a setting that
approaches the physiological environment. Here, insertions of tumor
mutations into healthy stem cells allow generation of
genetically-controlledtumoroids. Additionally, organoids can be grown
with high efficiency from patient-derived healthy and tumour tissues,
potentially enabling patient-specific drug testing and the development
of individualized treatment regimens. In such patient-specific
tumoroids, histostasis is observed, i.e. conservation of
histopathological traits between 3D cultures and the matched patient
tumor, promising advances in personalized tumor therapies in the future.
In contrast to PDTX, organoids are of easier maintenance, bear the
possibility to integrate immune cells, are amenable to genetic
modification (genetic cancer modeling), allow study of matched controls,
can be used for high throughput drug screening and biobanking.

Besides oncology, organoids are promising models for drug development.
Attrition rates in new drug development are high. This is partly
reasoned indifferences between animal pharmacokinetics and –dynamics or
in animal disease models that do not correctly resemble human pathology.
Organoids with human-relevant physiology and pathology are thought to
help overcoming these issues. Organoid cultures based on a specific
disease and even on a specific individual used in a high-throughput
manner are expected to develop into powerful tools for precision
therapy. Future screens may be performed using biobanks with the aim of
not only identifying new drugs but also revealing which patients may
benefit from treatment with certain drugs. In addition, focused tests of
potential drugs should identify new leads for the pharmaceutical
industry.Furthermore, organoidsmay be used in the future for toxicology
testing to complement, if not in part replace, animal testing.

4.
问:当前类器官的受制是哪些?为了满足癌症生物学、干细胞生物学、移植、新药开采世界的商量须要,类器官供给在哪些方面进一层改正?

Question:What are the limitations of organoids and what aspects of
organoids can be further improved to meet the demand for research in
tumor biology, stem cell biology, transplantation and drug development?

Thomas C.
Südhof答:类器官领域的钻研仍在起步阶段。就算对于如心脏和肝脏那样的团伙,类器官也特不成熟,仅能有个别仿照人体器官。对于脑组织则更甚。大多主干的生理功效,如细胞生理、生物化学效率依然有待突破。那将开销数年的时日。

Thomas C. Südhof’s answer:The field of organoid research is still in
the beginning. Even for tissues like heart and liver, organoids are very
immature and only partly model the human organ. This is worse for brain.
Much fundamental biology, such as cell biology and biochemistry, is
needed to advance the field. This will take many years.

埃伦Fritsche答:类器官是融入了各样器官特异性细胞类型、组织形态和功效的团体模型。但类器官仅为有限度的模仿,苦闷那项手艺应用的壹个人命关天约束是它的体量。当类器官体积扩展时,缺氧症和非常不够可溶性因子所致的团伙坏死是内需解除的题目。清除那个标题标一个也许方案是激利尿管生成门路,
从而使类器官血管化。那早已在hiPSC衍生的肝脏类器官上成功贯彻。类器官领域的另贰个挑衅在于二个完璧归赵的机体中所自然存在的器官“对话”。类器官研商可满意生物工程的渴求,通过培养演练包蕴分化门类hiPSC衍生类器官(显示两个器官系统的结商谈职能)的器官集成电路设备,用以在更接近于体内的条件中筛选药物。其它,通过在类器官中增添免疫细胞,还可模拟具备免疫性系统的集体间“对话”。此外,在药理和毒军事学商量中,物质的肝脏代谢至关心重视要,那可经过以器官微芯片的款式包蕴肝脏代谢来促成。

Ellen Fritsche’s answer:Organoids are organ models recapitulating an
assortment of organ-specific cell types, tissue morphogenesis and
functions. Yet, there are limitations in their mimicry. One important
limitation plaguing the application of this technologyis their size.
When the organoids’ volume increases, the issue of tissue necrosis
caused by the lack of diffusion of oxygen and soluble factors needs to
be addressed. One solution for this problemmight be the activation
ofangiogenic pathways that will lead to vascularisedorganoids.This was
already succeeded with hiPSC-derived liver organoids. One more challenge
of the organoid field lies in organ crosstalk, which is naturally
present in an intact organism. Here, organoid research meets
bioengineering by producing organ-on-a-chip devices containing different
types of hiPSC-derived organoids representing the structure and function
of multiple organ systems for screening the effects of drugs in more in
vivo-like settings. The crosstalk of tissues with the immune system can
be modelled by adding immune cells to the organoids. For pharmacological
and toxicological applications, liver metabolism of compounds is
crucial. Including such metabolism via an organ-on-a-chip approach can
solve this issue.

  1. 问:当前类器官研究的进步大方向如何?

Question:What are the current trends for organoidsresearch?

Thomas C.
Südhof答:全数人都在盲目追求应用,却不经意了四个牢固的正确性功底。笔者以为现在会有千千万万的集团在此贩售希望,但他俩大多将以诉讼失败告终。因为有关生医学研商成果并不足以支撑那些使用类型。类器官最有前途的应用领域应是用来肝脏、心脏和肉瘤的药品挑选。

Thomas C. Südhof’s answer:Everybody rushes towards applications,
without a solid scientific basis. I think hundreds of companies will be
founded that will sell hope, but will mostly fail because the biology
isn’t there to support applications. Most promising are drug screens in
tissue organoids such as liver or heart and in cancer.

EllenFritsche答:近期类器官钻探的样子富含成立用于MediaTek量筛选的类器官库和平台,组建其余病痛模型,以至创建用于全体生物体建立模型的五藏六府集成电路和微流体集成电路。在这里特意要重申的是作育基的限制亟待消除。对微流体微芯片来说,须要风华正茂种晶片上享有类器官均适用的通用作育基。其它,依照器官系统的例外,须要耗费与生理进程有关的源于类器官的MediaTek量数据输出装置。在治病方面,为了支付最好个体化治疗方案,使用源自病者特异性hiPSC类器官的个体化医疗研商供给开展。在毒法学领域,类器官近期已被用来取代动物进行毒性测验。

Ellen Fritsche’s answer:Current trends for organoid research include
generation of organoid banks and platforms for high-throughput screening
approaches, generation of additional disease models, and set up of
organ-on-a-chip and microfluidics devices for whole organism modeling.
Here, especially medium constrictions have to be solved. For
microfluidics a common medium for all organoids on the chip is needed.
Moreover, depending on the organ system, physiologically relevant
high-throughput readouts from organoids need to be developed. On the
clinical side, research on personalized medicine using organoids derived
from patient-specific hiPSC is warranted for optimal individual
treatment regimes. In the toxicology field, organoids as substrates for
toxicity testing replacing animals is currently exploited.

  1. 问:可不可以预测一下接下去5年内类器官钻探领域的前行?

Question:How the organoids research field will be look like in 5 years?

Thomas C.
Südhof答:笔者的瞭望是在接下去的5年内好的实验室将学会怎么推动类器官的老到,并了解该办法的受制。小编以为,固然类器官为干细胞切磋提供了宏伟的火候,如力促新意识和疗法的产出;但那将花费10年或越来越长的年月来升高。到那时候,也唯有到那个时候,走向应用本事真正产生可能。在那早先,大量初创集团将会烧掉数以亿计的资本,他们中的少部分将会走向成功,并找到扩张营业收入的新路径。

Thomas C. Südhof’s answer:My prediction is that in 5 years, good
science labs will have learned how to mature organoids and the
limitations of the approach will have been defined. I think organoids
are a tremendous opportunity in stem cell approaches that will enable
novel discoveries and therapies, but that this will take at least 10
years to develop. Then and only then will it be possible to rationally
move towards applications. Until then, lots of start-ups will have spent
hundreds of millions of dollars, and a few of them will have been
successful in generating some future avenue of revenue.

EllenFritsche答:在5年内,类器官的遗传操作与类器官库相结合将给生物医研带给倾覆的扭转。购买来源于具有分歧遗传背景病人的病痛特异性类器官将改成恐怕。器官微电路平台将富有特定标准,由公约研商社团以与当下动物试验近似的秘技提供。类器官将庞大地推进药品疗效试验和安全性测验的开展,由此也将跻身药物开辟和化学安全性评估商量的禁锢领域。

Ellen Fritsche’s answer:In 5 years, genetic manipulation of organoids
in combination with organoid banking will have revolutionized biomedical
research. It will be possible to purchase disease-specific organoids
from broad ranges of patients with distinct genetic backgrounds.
Organ-on-a-chip platforms will be standard and offered by CROs in a
similar manner than currently animal testing. Organoids will have
tremendously facilitated drug efficacy and safety testing and thus will
have entered also into the regulatory areas of research for drug
development as well as chemical safety assessment.

附:

1、Thomas C. Südhof助教简单介绍

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Sverige皇家理经济高校教院教授、Howard-休斯医研所
研商员、美利坚联邦合众国中国科学技术大学学院士、米利坚医科院院士、大不列颠及英格兰联合王国皇家学会外国国籍院士、二〇一二年诺Bell生法学或工学奖得到者。1952年生于德国哥廷根,1984年收获哥廷根大学法学大学子学位。Südhof教师的钻研重大聚焦于突触前神经递质释放的积极分子机制,为该领域的五星级物教育学家。他发现了囊泡内神经递质释放进度中的三种第风华正茂蛋白,并表达了神经递质释放的维妙维肖分子机制。鉴于在囊泡转运领域的开创性职业,他前后相继荣获Russ克基本功历史学奖及诺Bell生教育学或艺术学奖等关键历史学奖项。

  1. Ellen Fritsche教师简要介绍

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德意志IUF-莱布尼茨意况医研所(IUF-Leibniz Research Institute for
Environmental
Medicine)意况毒工学教师,球模型轻风险评估行家组首席营业官。1997年获雷根斯堡大学和秘Luli马大学经济学大学子学位,曾前后相继在花旗国国立环卫切磋所和IUF-莱布尼茨情状医研所完毕博士后钻探专门的学问,二零零六-二零一三年任亚琛工业余大学学皮肤毒军事学讲师。最近为Neurotoxicology杂志副小编、欧洲化学理事委员会参照他事他说加以考察、欧盟地平线2020布置行家组成员、澳洲取代动物试验商量主旨(CEHavalST-NWranglerW)项目带头人、代替法信托大会成员和OECD发育神经毒性行家组织委员会委员员。历任南美洲代表动物试验组织副主席、主席。

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