The complete, day 14 synthetic models may open new avenues of research into infertility, drug testing and growth of tissues for transplant – as well as help scientists peer into the dramatic first weeks of embryonic development
完整、第14天的合成模型，除了有助於科學家們仔細觀察胚胎發育，戲劇性的第一周之外，也可能為不孕症、藥物測試及移植之組織成長的研究開闢新途徑。
A research team headed by Prof. Jacob Hanna at the Weizmann Institute of Science has created complete models of human embryos from stem cells cultured in the lab – and managed to grow them outside the womb up to day 14.
一支由以色列魏茨曼科學研究所，Jacob Hanna教授領導的研究團隊，從於實驗室中培養的幹細胞，已經創造了完整的人類胚胎模型，且設法於子宮外培養它們達第14天。
As reported today in Nature, these synthetic embryo models had all the structures and compartments characteristic of this stage, including the placenta, yolk sac, chorionic sac and other external tissues that ensure the models’ dynamic and adequate growth.
如同今天(2023年8月31日)《自然》雜誌報道的那樣，此些合成的胚胎模型，具有該階段之所有結構物及部分的特徵，包括確保該模型動態、充分成長的胎盤、卵黃囊、絨毛膜囊及其他外部組織。
圖1. 一顆衍生自人類胚胎模型，於發育階段相當於第14天胚胎的幹細胞。 該模型具有定義此階段的所有部分：卵黃囊(黃色)及將成為胚胎本身的部分，頂部是羊膜(藍色)——所有由會成為胎盤(粉紅色)的細胞所包裹。
A stem cell–derived human embryo model at a developmental stage equivalent to that of a day 14 embryo. The model has all the compartments that define this stage: the yolk sac (yellow) and the part that will become the embryo itself, topped by the amnion (blue) – all enveloped by cells that will become the placenta (pink)
Cellular aggregates derived from human stem cells in previous studies could not be considered genuinely accurate human embryo models, because they lacked nearly all the defining hallmarks of a post-implantation embryo. In particular, they failed to contain several cell types that are essential to the embryo’s development, such as those that form the placenta and the chorionic sac.
於先前諸多研究中，源自人類幹細胞的細胞聚集體，不能真正被認為，是精確的人類胚胎模型。因為，它們幾乎缺乏植入後胚胎之所有定義的特徵。特別是，它們不具有對胚胎發育不可或缺之諸如，那些形成胎盤及絨毛膜囊的若干細胞類型。
In addition, they did not have the structural organization characteristic of the embryo and revealed no dynamic ability to progress to the next developmental stage.
此外，它們不具有胚胎的結構組織特徵，且沒有展現出進展到下一發育階段的動態能力。
Given their authentic complexity, the human embryo models obtained by Hanna’s group may provide an unprecedented opportunity to shed new light on the embryo’s mysterious beginnings.
鑒於其真實的複雜性，由Hanna團隊獲得的人類胚胎模型，可能為胚胎之神秘起源，提供前所未有的新闡明機會。
Little is known about the early embryo because it is so difficult to study, for both ethical and technical reasons, yet its initial stages are crucial to its future development. During these stages, the clump of cells that implants itself in the womb on the seventh day of its existence becomes, within three to four weeks, a well-structured embryo that already contains all the body organs.
有關初期胚胎，鮮為人知。因為，倫理及技術的原因，很難進行研究。不過，其諸多初期階段，對其未來的發育至關重要。在此些階段中，於其存在之第七天，自行植入子宮的細胞團，在三到四週內，變成一個已經具所有身體器官之結構良好的胚胎。
“The drama is in the first month, the remaining eight months of pregnancy are mainly lots of growth,” Hanna says. “But that first month is still largely a black box. Our stem cell–derived human embryo model offers an ethical and accessible way of peering into this box. It closely mimics the development of a real human embryo, particularly the emergence of its exquisitely fine architecture.”
Hanna宣稱：「此腳本在第一個月，其餘懷孕的八個月主要是大量成長。不過，第一個月絕大部分仍然是個黑盒子。我們幹細胞衍生的人類胚胎模型提供了一種，合乎道德且可以獲得的方法，來探究這個盒子。它密切模仿真實人類胚胎的發育，特別是其完美結構的出現。」
Hanna’s team built on their previous experience in creating synthetic stem cell–based models of mouse embryos. As in that research, the scientists made no use of fertilized eggs or a womb.
Hanna的團隊以其先前，在創造以幹細胞為基礎之小鼠胚胎模型的經驗為基礎。如同於那研究中那樣，此些科學家們沒有使用受精卵或子宮。
Rather, they started out with human cells known as pluripotent stem cells, which have the potential to differentiate into many, though not all, cell types. Some were derived from adult skin cells that had been reverted to “stemness.” Others were the progeny of human stem cell lines that had been cultured for years in the lab.
恰恰相反，他們使用具有分化成諸多，雖然並非全部之細胞類型的潛力，被通稱為多能幹細胞的人類細胞開始。有些衍生自，已經被恢復“幹性”的成人皮膚細胞。其他是，於實驗室中，已經被培養多年之人類幹細胞系的後代。
The researchers then used Hanna’s recently developed method to reprogram pluripotent stem cells so as to turn the clock further back: to revert these cells to an even earlier state – known as the naïve state – in which they are capable of becoming anything, that is, specializing into any type of cell.
之後，此些研究人員使用了，Hanna最近開發的方法，來重新編碼多能幹細胞的指令序列，以便進一步倒轉此時鐘：將此些細胞恢復到一種，被通稱為原始狀態之甚至更早的狀態。在此狀態中，它們能夠成為任何東西。也就是，特化成任何類型細胞。
This stage corresponds to day 7 of the natural human embryo, around the time it implants itself in the womb. Hanna’s team had in fact been the first to start describing methods to generate human naïve stem cells, back in 2013; they continued to improve these methods, which stand at the heart of the current project, over the years.
此階段相當於自然之人類胚胎的第7天，大約是其自行胚胎植入子宮的時候。事實上，早在2013年，Hanna的團隊已經是，最早描述產生人類原始幹細胞之方法的團隊；多年來，他們不斷改進此些，是當前計劃核心的方法。
Video of a stem cell–derived human embryo model at a developmental stage equivalent to that of a human embryo at day 14. It shows the hormone used in pregnancy tests (green) and the outer layer that will become the placenta (pink), including characteristic cavities, called lacunae. During normal pregnancy, the lacunae allow the exchange of nutrients and waste products between the maternal blood and the fetus.
衍生自人類胚胎模型，在相當於人類胚胎第14天之發育階段的短片網址：https://youtu.be/m1OwekXUwig。它顯示了，於妊娠測試中，使用的荷爾蒙(綠色)及將成為胎盤的外層(粉紅色)，包括被稱為腔隙的獨特空腔。在正常懷孕期間，腔隙使母體血液與胎兒之間，得以交換營養物質及廢物。
The scientists divided the cells into three groups. The cells intended to develop into the embryo were left as is. The cells in each of the other groups were treated only with chemicals, without any need for genetic modification, so as to turn on certain genes, which was intended to cause these cells to differentiate toward one of three tissue types needed to sustain the embryo: placenta, yolk sac or the extraembryonic mesoderm membrane that ultimately creates the chorionic sac.
此些科學家將這些細胞分成三群。打算發育成胚胎的細胞保持原樣。在其他每群中的細胞，僅用化學物質處理，沒有任何基因改造，以便打開某些目的是促使這些細胞分化朝，維持此胚胎所需之胎盤、卵黃囊或最終形成絨毛膜囊的胚外中胚層膜，三種組織類型之一的基因。
Soon after being mixed together under optimized, specifically developed conditions, the cells formed clumps, about 1 percent of which self-organized into complete embryo-like structures.
在最佳化、特別開發的條件下，被混合在一起後不久。此些細胞形成團塊，其中約1%自行組織成，完整的類胚胎結構物。
“An embryo is self-driven by definition; we don’t need to tell it what to do – we must only unleash its internally encoded potential,” Hanna says. “It’s critical to mix in the right kinds of cells at the beginning, which can only be derived from naïve stem cells that have no developmental restrictions. Once you do that, the embryo-like model itself says, ‘Go!’”
Hanna宣稱：「根據定義，胚胎是自行驅動的。我們無需告知它做什麼，我們僅需解開，其內部編碼指令序列的潛力。在僅能衍生自，沒有發育限制的原始幹細胞開始時，以正確類型的細胞進行混合，這是至關重要的。一旦這樣做，類胚胎的模型本身發出，“運作吧！”。」
The stem cell–based embryo-like structures (termed SEMs) developed normally outside the womb for 8 days, reaching a developmental stage equivalent to day 14 in human embryonic development. That’s the point at which natural embryos acquire the internal structures that enable them to proceed to the next stage: developing the progenitors of body organs.
以此幹細胞為基礎之類胚胎的結構物(被稱為SEMs)，正常在子宮外發育達8天，這達到相當於，在人類胚胎發育中，第14天的發育階段。那是自然胚胎獲得，使它們能持續進展到，發育成身體器官前身物之內部結構物的時刻。
When the researchers compared the inner organization of their stem cell–derived embryo models with illustrations and microscopic anatomy sections in classical embryology atlases from the 1960s, they found an uncanny structural resemblance between the models and the natural human embryos at the corresponding stage.
當此些研究人員進行，衍生自其幹細胞之胚胎模型的內部組織，與來自1960年代，於古典胚胎學圖集中之插圖及顯微解剖切片的比較時。他們發現了一種，在此些模型與於對應階段的自然人類胚胎之間，不可思議的結構相似性。
Every compartment and supporting structure was not only there, but in the right place, size and shape. Even the cells that make the hormone used in pregnancy testing were there and active: When the scientists applied secretions from these cells to a commercial pregnancy test, it came out positive.
每一部分及次要結構物不僅在那裡，而且處於正確之位置、尺寸及形狀的狀態中。甚至產生妊娠測試中，被使用之激素的細胞，也在那裡且活躍：當此些科學家將來自這些細胞的分泌物，使用於商業妊娠測試時，其呈現陽性反應
This implied that their models faithfully emulated the process by which an early embryo gains all the structures it needs for beginning its transformation into a fetus.
這意味著，他們的模型忠實模擬了，初期胚胎獲得開始其轉變成胎兒所需之所有結構物的過程。
“Many failures of pregnancy occur in the first few weeks, often before the woman even knows she’s pregnant,” Hanna says. “That’s also when many birth defects originate, even though they tend to be discovered much later. Our models can be used to reveal the biochemical and mechanical signals that ensure proper development at this early stage, and the ways in which that development can go wrong.”
Hanna宣稱：「諸多懷孕失敗發生於最初幾週，甚至經常在女性知曉自己懷孕之前。那也是諸多出生缺陷的起源，即使它們傾向較晚得多，才被發現。我們的模型能被用來揭露，確保於此初期階段，適確發育的生化及物理訊號，及發育會出錯的方式。」
A video presenting the characteristic structure of the yolk sac (yellow) in a stem cell–derived human embryo model at a developmental stage equivalent to that of a human embryo at day 12. It shows the sac’s upper and lower parts, which have different shapes and functions, and a cavity between the two.
呈現於衍生自幹細胞的人類胚胎模型中，在發育階段，卵黃囊(黃色)相當於，人類胚胎第12天之特有結構物的短片網址：https://youtu.be/LRyE9_veSag。它顯示了，卵黃囊具有不同形狀與功能的上層及下層部分，及在兩者之間的空腔。
In fact, the study has already produced a finding that may open a new direction of research into early pregnancy failure. The researchers discovered that if the embryo is not enveloped by placenta-forming cells in the right manner at day 3 of the protocol (corresponding to day 10 in natural embryonic development), its internal structures, such as the yolk sac, fail to properly develop.
事實上，該項研究已經獲得了一項，可能開啟探索初期懷孕失敗之新方向的發現。此些研究人員發現，倘若此胚胎不是，在此方案的第3天(相當於自然胚胎發育的第10天)，以正確方式，形成胎盤之細胞所包裹。則其內部結構物，諸如卵黃囊，無法正適切發育。
“An embryo is not static. It must have the right cells in the right organization, and it must be able to progress – it’s about being and becoming,” Hanna says. “Our complete embryo models will help researchers address the most basic questions about what determines its proper growth.”
Hanna宣稱：「胚胎不是靜態的。它必須在正確的組織中，擁有正確的細胞，並且必須能夠進展。這關乎存在及變化過程。我們完整的胚胎模型，將有助於研究人員們面對，有關什麼決定其適切成長的最基本問題。」
This ethical approach to unlocking the mysteries of the very first stages of embryonic development could open numerous research paths. It might help reveal the causes of many birth defects and types of infertility. It could also lead to new technologies for growing transplant tissues and organs.
此解開胚胎發育極初期諸階段之謎團的倫理方法，可能開啟諸多研究途徑。這能有助於揭露，許多出生缺陷及不孕類型的原因。也可能引領出，培養移植之組織及器官的新技術。
And it could offer a way around experiments that cannot be performed on live embryos – for example, determining the effects of exposure to drugs or other substances on fetal development.
因此，這可能提供一種，繞過無法於活體胚胎上，進行之實驗的方法。譬如，確認曝露於藥物或其他物質，對胎兒發育的影響。
網址：https://wis-wander.weizmann.ac.il/life-sciences/human-embryo-models-grown-stem-cells
翻譯：許東榮
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