How Does Life Unfold? A Landscape Metaphor Comes Into Its Own.

In this update to Waddington’s image, a ball (representing a cell lineage) multiplies and specializes into cell types (represented by color) as it traverses a dynamic landscape.

在沃丁顿图像的更新中，一个球（代表细胞谱系）在穿越动态景观时会繁殖并专门研究细胞类型（用颜色代表）。

This animation was generated from Waddington’s original drawing using an AI tool.

该动画是使用 AI 工具根据 Waddington 的原始绘图生成的。

B y the middle of the 20th century, it had begun to seem that biology was almost solved.

到了 20 世纪中叶，生物学似乎已经几乎被解决了。

Charles Darwin’s theory of evolution by natural selection explained how organisms change and adapt.

查尔斯·达尔文的自然选择进化论解释了生物体如何变化和适应。

The modern science of genetics showed how it works at the molecular scale.

现代遗传学展示了它如何在分子尺度上发挥作用。

Genes governing the traits of organisms get passed down from parent to offspring, and random mutations create the variations from which natural selection picks the “fittest.” Natural selection and genetics fitted together in what the biologist Julian Huxley christened “the modern synthesis” in his 1942 book .

控制生物体特征的基因从亲本遗传给后代，随机突变产生变异，自然选择从中选择“最适者”。自然选择和遗传学结合在一起，被生物学家朱利安·赫胥黎 (Julian Huxley) 在他 1942 年的书中称为“现代综合”。

Once it was shown in 1953 that the genes are encoded by DNA, the rest of biology looked like little more than piecing together details.

1953 年，当人们发现基因是由 DNA 编码时，生物学的其余部分看起来只不过是拼凑细节而已。

But not everyone was satisfied.

但并非所有人都满意。

The British biologist Conrad Hal Waddington , known to his friends and colleagues as Wad, thought this focus on genes was all very well.

英国生物学家康拉德·哈尔·沃丁顿（Conrad Hal Waddington）（他的朋友和同事们称其为“Wad”）认为对基因的关注非常好。

But it wasn’t clear to him, or anyone else, exactly how genes shape the forms and features of organisms — how they reliably generate all the different tissues of the body, in all the right places, during embryonic development.

但他或其他任何人都不清楚基因究竟如何塑造生物体的形式和特征——它们如何在胚胎发育过程中在所有正确的位置可靠地产生身体的所有不同组织。

Around the same time that Huxley unveiled the modern synthesis, Waddington presented a novel picture of how this might unfold.

大约在赫胥黎揭开现代综合体的同时，沃丁顿提出了一幅关于它如何展开的新颖图景。

He visualized the developmental process as a landscape with hills and valleys that split every so often like those in a river network .

他将发展过程想象成一幅山峦和山谷的景观，这些山丘和山谷时不时地分裂，就像河流网络中的山峦和山谷一样。

At the very top of the highest hill he imagined a ball, which represented a population of cells in their earliest embryonic form — what we now call stem or pluripotent cells, which have the potential to become any cell type.

在最高的山顶上，他想象了一个球，它代表了处于最早胚胎形式的细胞群——我们现在所说的干细胞或多能细胞，它们有可能成为任何细胞类型。

The progression of the cells towards their fates — to become, say, skin cells, muscle cells, or nerve cells — is like the ball rolling downhill through the landscape.

细胞朝着它们的命运发展——比如成为皮肤细胞、肌肉细胞或神经细胞——就像球在风景中滚下山一样。

When the ball reaches a branching point (bifurcation), the model’s “gravity” pulls it to one track or the other: In scientific terms, it must differentiate.

当球到达分支点（分叉）时，模型的“重力”将其拉向一条轨道或另一条轨道：用科学术语来说，它必须区分。

Through a particular sequence of such branching decisions, Waddington argued, cells specialize into their mature types, or fates, each expressing a particular set of genes.

沃丁顿认为，通过这种分支决定的特定序列，细胞专门化为它们的成熟类型或命运，每个细胞表达一组特定的基因。

The cells are restricted to a small number of well-defined states because they are “canalized,” in Waddington’s lexicon: trapped and channeled by the sides of the valley.

这些细胞被限制在少数明确的状态，因为用沃丁顿的术语来说，它们是“运河化的”：被山谷两侧困住和引导。

In this way, a limited number of cell types reliably arise from the activity of an army of genes.

通过这种方式，有限数量的细胞类型可靠地由基因大军的活动产生。

The biologist Conrad H.

生物学家康拉德 H.

Waddington’s prescient ideas shaped the modern understanding of gene regulation, epigenetics, and evolutionary developmental biology.

沃丁顿的先见之明塑造了对基因调控、表观遗传学和进化发育生物学的现代理解。

He died in 1975.

他于 1975 年去世。

Walter Stoneman, National Portrait Gallery London

沃尔特·斯通曼，伦敦国家肖像画廊

Waddington’s landscape has been “remarkably useful as a conceptual scaffold,” said James Briscoe , a developmental biologist at the Francis Crick Institute in London.

伦敦弗朗西斯·克里克研究所的发育生物学家詹姆斯·布里斯科说，沃丁顿的景观“作为概念支架非常有用”。

“The core ideas — that development is progressive, that cell states are distinct, that bifurcations represent [cell] fate decisions, that canalization implies robustness — all survive.”

“核心思想——发育是渐进的、细胞状态是独特的、分叉代表[细胞]命运决定、运河化意味着稳健性——所有这些都得以生存。”

“There’s so much richness to some of the concepts Waddington was trying to share,” said Susanne Rafelski , a biochemist at the Institute for Stem Cell and Regenerative Medicine in Seattle.

“沃丁顿试图分享的一些概念非常丰富，”西雅图干细胞和再生医学研究所的生物化学家 Susanne Rafelski 说。

But the concept was more of a visual metaphor than a representation of an actual biological process.

但这个概念更多的是一种视觉隐喻，而不是实际生物过程的表示。

Or so it seemed.

或者看起来是这样。

In the past several years, researchers have mapped out the real topography of cell-state spaces — in effect, Waddington’s landscapes — from experimental data collected from many thousands of cells over the course of embryonic development.

在过去的几年里，研究人员根据胚胎发育过程中从数千个细胞收集的实验数据，绘制出了细胞状态空间的真实地形——实际上是沃丁顿的景观。

Those analyses are revealing that development is not a mere readout of a genetic program, but rather a dynamic process in which communities of cells build themselves, and the very landscape they navigate, by mutual negotiation and interaction, into an organism.

这些分析表明，发育不仅仅是遗传程序的读出，而是细胞群自我构建的动态过程，以及它们通过相互协商和相互作用形成有机体的景观。

This cartography of development is now helping researchers understand how identical cells in the early embryo develop into the distinct tissues and cell types of a complex organism.

这种发育制图现在正在帮助研究人员了解早期胚胎中的相同细胞如何发育成复杂生物体的不同组织和细胞类型。

This matters enormously for regenerative medicine and stem-cell engineering, Briscoe said: “If you understand the landscape topology and know where the bifurcations lie, you can in principle design methods that steer cell populations to desired states with precision, rather than by trial and error.”

这对于再生医学和干细胞工程来说非常重要，布里斯科说：“如果你了解景观拓扑结构并知道分叉在哪里，原则上你就可以设计方法，精确地将细胞群引导到所需的状态，而不是通过反复试验。”

Waddington’s metaphor, then, could be the key to understanding and reshaping possibilities for what cells, tissues, and embryos can be.

那么，沃丁顿的比喻可能是理解和重塑细胞、组织和胚胎可能性的关键。

In the 1940s, genetics and embryology were separate sciences; not everyone even believed that genes played a significant role in development.

在 20 世纪 40 年代，遗传学和胚胎学是独立的科学。甚至不是每个人都相信基因在发育中发挥着重要作用。

Yet Waddington’s own experiments in embryology, and those of others, convinced him that the formation and patterning of tissues in an embryo were indeed controlled by genes.

然而沃丁顿自己和其他人的胚胎学实验使他相信胚胎中组织的形成和模式确实是由基因控制的。

The cells of different tissues had different groups of genes activated in their chromosomes, he thought.

他认为，不同组织的细胞在其染色体中激活了不同的基因组。

A process of differentiation gradually specialized cells into skin cells, nerve cells, and so on.

细胞逐渐特化为皮肤细胞、神经细胞等的分化过程。

Waddington figured that the developmental pathways — for example, the formation of the neural tube from a layer of embryonic tissue called ectoderm, which ultimately develops into the central nervous system — are inevitable once the process has begun, just as water flowing down a river valley is constrained by its surroundings.

沃丁顿认为，一旦这个过程开始，发育途径——例如，从一层称为外胚层的胚胎组织形成神经管，最终发育成中枢神经系统——是不可避免的，就像流下河谷的水受到周围环境的限制一样。

The path might meander a little, but the valley keeps the river on course.

这条路可能有点蜿蜒，但山谷使河流保持在正确的方向。

Differentiation corresponds to the branching of a valley, and the final destinations are the mature cell types of the body.

分化相当于山谷的分支，最终的目的地是身体的成熟细胞类型。

Waddington’s classic drawing of the epigenetic landscape.

沃丁顿对表观遗传景观的经典描绘。

A ball, representing a pluripotent cell or population, is poised to roll downhill into valleys, each of which represent a specialized cell type, such as a blood cell, liver cell, or brain cell.

代表多能细胞或群体的球准备滚下山进入山谷，每个山谷代表一种特殊的细胞类型，例如血细胞、肝细胞或脑细胞。

From The Strategy of the Genes by C.H.

摘自《基因的策略》，作者：C.H.

Waddington

沃丁顿

Waddington visualized this as a landscape in drawings, but they had “no grounding in physical reality,” wrote Scott Gilbert, a developmental biologist at Swarthmore College in Pennsylvania, in a 1991 essay in Biology & Philosophy .

宾夕法尼亚州斯沃斯莫尔学院的发育生物学家斯科特·吉尔伯特 (Scott Gilbert) 在 1991 年《生物学与哲学》杂志上的一篇文章中写道，沃丁顿将其形象化为图画中的风景，但它们“没有物理现实的基础”。

They were useful schematics for thinking about the problem of development, and nothing more.

它们只是思考发展问题的有用图表，仅此而已。

“Without mathematical content,” Briscoe said, the metaphor “could not distinguish between alternative mechanisms, make quantitative predictions, or be falsified.” As a result, he said, Waddington’s landscape “has sometimes become a cliché rather than a meaningful explanation.”

“如果没有数学内容，”布里斯科说，这个比喻“无法区分替代机制，无法做出定量预测，也无法被证伪。”他说，因此，沃丁顿的景观“有时变成了陈词滥调，而不是有意义的解释。”

What, for example, determines the topography of the hills and valleys?

例如，是什么决定了丘陵和山谷的地形？

In his 1957 book The Strategy of the Genes , Waddington depicted the landscape as he figured it might look from underneath: as a sheet that is tugged into shape by a network of ropes attached to pegs.

沃丁顿在 1957 年出版的《基因的策略》一书中描绘了他认为从下面看起来的景观：一张被附在钉子上的绳索网络拉动成形的床单。

The pegs represented individual genes, and the ropes their effects on development.

钉子代表个体基因，绳子代表个体基因对发育的影响。

Expressing a particular gene — turning it into its corresponding protein — is like pulling on its ropes to change the shape of the sheet.

表达特定的基因——将其转化为相应的蛋白质——就像拉动绳索来改变薄片的形状。

What determines the landscape’s shape?

景观的形状由什么决定？

Waddington sketched a network of pegs and ropes beneath the rolling hills; the pegs are genes, and the ropes are their interconnections.

沃丁顿在连绵起伏的山丘下绘制了一个由钉子和绳索组成的网络；钉子是基因，绳子是它们的相互联系。

Together they shape the landscape above and represent what we now call gene regulatory networks.

它们共同塑造了上面的景观，并代表了我们现在所说的基因调控网络。

From The Strategy of the Genes by C.H.

摘自《基因的策略》，作者：C.H.

Waddington

沃丁顿

It’s rather more complex than that, Waddington realized, because the ropes are connected in a network.

沃丁顿意识到，事情比这要复杂得多，因为绳索是连接在网络中的。

Any one of them might influence the landscape at several points, and any given point on the landscape might be attached to several ropes.

它们中的任何一个都可能在多个点影响景观，并且景观上的任何给定点都可能连接到几根绳子。

These hidden connections correspond to what researchers now call gene regulatory networks: interactions among genes whereby an increase in the expression of one might change, or regulate, the activity of others.

这些隐藏的联系对应于研究人员现在所说的基因调控网络：基因之间的相互作用，其中一个基因表达的增加可能会改变或调节其他基因的活动。

Herein lies the cryptic complexity of development.

这就是发展的神秘复杂性。

A given process, such as formation of the neural tube, might be influenced by many interacting genes; there’s no simple relationship between genes (genotype) and the developmental landscape that determines form (phenotype).

一个给定的过程，例如神经管的形成，可能会受到许多相互作用的基因的影响。基因（基因型）和决定形式（表型）的发育景观之间不存在简单的关系。

Gene regulatory networks mediate between them.

基因调控网络在它们之间发挥中介作用。

It makes no sense, then, to look for genes dedicated to creating specific tissues, organs, or structures in a whole organism, which is one reason Waddington’s metaphor proved useful.

那么，在整个有机体中寻找专门用于创造特定组织、器官或结构的基因是没有意义的，这也是沃丁顿的比喻被证明有用的原因之一。

The landscape image was “valuable in providing an alternative to a purely gene-centric view of development,” Briscoe said.

布里斯科说，景观图像“对于提供纯粹以基因为中心的发展观点的替代方案很有价值”。

By emphasizing the landscape’s shape, it pointed “toward system-level properties that cannot be read off from any single gene.”

通过强调景观的形状，它指出了“无法从任何单个基因读取的系统级属性”。

Given that the channels and spheres had no physical reality, what was an embryologist supposed to do with them?

鉴于通道和球体没有物理现实，胚胎学家应该用它们做什么呢？

Scott Gilbert, Swarthmore College

斯科特·吉尔伯特，斯沃斯莫尔学院

Gene regulation wasn’t understood when Waddington first devised his landscape and rope network.

当沃丁顿第一次设计他的景观和绳索网络时，基因调控还没有被理解。

A few years later, in the early 1960s, it became clear that one gene could turn another on or off .

几年后，即 20 世纪 60 年代初，人们发现一个基因可以开启或关闭另一个基因。

Researchers, such as the complexity theorist Stuart Kauffman, began to construct simple mathematical models of the networks of gene interactions.

复杂性理论家斯图尔特·考夫曼等研究人员开始构建基因相互作用网络的简单数学模型。

But too little was then known about real gene networks to connect abstract theory to experiment.

但当时对真实基因网络知之甚少，无法将抽象理论与实验联系起来。

“Given that the channels and spheres had no physical reality,” Gilbert wrote, “what was an embryologist supposed to do with them?”

“鉴于通道和球体没有物理现实，”吉尔伯特写道，“胚胎学家应该用它们做什么呢？”

Answers have begun to emerge over the past two decades thanks to new experimental tools for characterizing cell states.

由于表征细胞状态的新实验工具的出现，答案在过去二十年中已经开始出现。

Biologists are now finally becoming able to map experimental data to a real mathematical landscape for differentiation and show just how prescient Waddington was.

生物学家现在终于能够将实验数据映射到真实的数学景观中以进行区分，并展示沃丁顿的先见之明。

One way to define the state of a given cell in an embryo is by the expression levels of its genes.

定义胚胎中给定细胞状态的一种方法是通过其基因的表达水平。

These levels can now be measured simultaneously in many cells using a technique called single-cell RNA sequencing, which supplies a snapshot of all the different RNA molecules each cell contains.

现在可以使用一种称为单细胞 RNA 测序的技术在许多细胞中同时测量这些水平，该技术提供每个细胞包含的所有不同 RNA 分子的快照。

An RNA molecule (or transcript) is a kind of copy of a gene used to translate it into a functional protein, and generally, more RNA transcripts means higher expression of that gene.

RNA 分子（或转录本）是基因的一种副本，用于将其翻译成功能性蛋白质，一般来说，RNA 转录本越多意味着该基因的表达越高。

Each cell type is characterized by particular gene-expression settings, which are inherited when a cell divides.

每种细胞类型都有特定的基因表达设置，这些设置在细胞分裂时遗传。

This ensures that a liver cell will stay a liver cell as it progresses through an organism’s development process.

这确保了肝细胞在生物体的发育过程中始终是肝细胞。

In principle, RNA-sequencing data can be modeled as a high-dimensional mathematical space in which each axis denotes the number of RNA transcripts of a single gene.

原则上，RNA 测序数据可以建模为高维数学空间，其中每个轴表示单个基因的 RNA 转录本的数量。

Such a plot, with maybe thousands of dimensions to represent thousands of genes, is impossible to visualize, but it can be mathematically projected onto a space with fewer dimensions, usually just two, to produce something like the shadow of a complex 3D object.

这样的图可能有数千个维度来代表数千个基因，无法可视化，但可以通过数学方式将其投影到维度较少（通常只有两个）的空间上，以产生类似于复杂 3D 对象的阴影的效果。

On such a plot, called a UMAP (uniform manifold approximation and projection) , different cell types appear as clusters of points — blood cells cluster together, say, as do cells of the muscle or forebrain — as they share a gene expression profile.

在这样一个称为 UMAP（均匀流形近似和投影）的图上，不同的细胞类型显示为点簇（例如，血细胞聚集在一起，就像肌肉或前脑细胞一样），因为它们共享基因表达谱。

Cell lineages follow paths through this map as development proceeds.

随着发育的进行，细胞谱系遵循这张图谱的路径。

When the data is mapped through time — in what’s known as a network flow model — it looks very much like a population of cells rolling through a Waddington-like landscape, being channeled along valleys that lead to basins that correspond to distinct cell types.

当数据随时间映射时——在所谓的网络流模型中——它看起来非常像一群细胞在沃丁顿式的景观中滚动，沿着山谷引导，通向与不同细胞类型相对应的盆地。

Mark Belan /Quanta Magazine; Modified from Cell 184, 2825-2842 (2021) with permission of the authors

马克·贝兰/Quanta 杂志；经作者许可，修改自 Cell 184, 2825-2842 (2021)

We should be wary of supposing, though, that this gene-expression map is literally Waddington’s landscape.

不过，我们应该警惕，不要假设这张基因表达图谱实际上就是沃丁顿的风景。

Julie Theriot , a biophysicist at the University of Washington, cautioned that single-cell RNA sequencing is not the only or even the best way to characterize cell states.

华盛顿大学生物物理学家 Julie Theriot 警告说，单细胞 RNA 测序并不是表征细胞状态的唯一方法，甚至不是最好的方法。

The technique was “mind-blowing” at first, she said, but RNA transcripts don’t map perfectly to gene expression.

她说，这项技术一开始“令人兴奋”，但 RNA 转录本并不能完美地映射到基因表达。

Plus, when researchers collapse the data into low-dimensional maps, they often do so in ways that reflect prior assumptions about how cells cluster into different types.

另外，当研究人员将数据折叠成低维图时，他们通常会以反映细胞如何聚集成不同类型的先前假设的方式进行。

Still, it’s clear that, as Waddington supposed, cells undergo changes in state, defined by which genes are active or which proteins are made, as they mature and develop, and that these changes have a trajectory through time that carries them toward a limited number of final states.

尽管如此，很明显，正如沃丁顿所认为的，细胞在成熟和发育过程中会经历状态变化，这些变化是由哪些基因活跃或哪些蛋白质产生来定义的，并且这些变化随着时间的推移有一条轨迹，将它们带向有限数量的最终状态。

So how is that landscape of possibilities shaped?

那么，这种可能性的格局是如何形成的呢？

What governs the paths it offers?

它提供的路径由什么决定？

We think this reflects something real about how gene regulatory networks are organized.

我们认为这反映了基因调控网络如何组织的真实情况。

James Briscoe, Francis Crick Institute

詹姆斯·布里斯科，弗朗西斯·克里克研究所

In 2007, the biologist Sui Huang , now at the Institute for Systems Biology in Seattle, described a bifurcation in cell state of the sort proposed by Waddington.

2007 年，现供职于西雅图系统生物学研究所的生物学家黄隋描述了沃丁顿提出的细胞状态分叉。

He found that blood-forming cells called myeloid progenitor cells differentiate into two specialized types, setting them on course to become red or white blood cells, in a process dominated by two proteins, GATA1 and PU.1.

他发现，称为骨髓祖细胞的造血细胞分化为两种特殊类型，使它们逐渐成为红细胞或白细胞，这一过程由两种蛋白质 GATA1 和 PU.1 主导。

This landscape of cell differentiation can thus be represented with just two values: the concentrations of these two proteins.

因此，细胞分化的这种情况可以只用两个值来表示：这两种蛋白质的浓度。

More GATA1 promotes the formation of red blood cells, while more PU.1 sends the cell toward a white-blood-cell fate.

更多的 GATA1 会促进红细胞的形成，而更多的 PU.1 会使细胞走向白细胞的命运。

Huang and his colleagues mapped out the landscape using data from RNA-sequencing experiments and theoretical calculations.

黄和他的同事利用 RNA 测序实验和理论计算的数据绘制了景观图。

At first there is just a single basin, corresponding to the pool of myeloid progenitor cells.

起初只有一个盆地，对应于骨髓祖细胞池。

But as differentiation proceeds, this basin becomes less stable — less deep — relative to two new adjacent basins, which correspond to the red (high GATA1) and white (high PU.1) blood-cell states.

但随着分化的进行，相对于两个新的相邻盆地（对应于红色（高 GATA1）和白色（高 PU.1）血细胞状态），该盆地变得不太稳定，深度也更浅。

Think of it like a sheet suspended horizontally from its corners, with water pooled in the middle.

可以把它想象成一张从四角水平悬挂的床单，中间积着水。

If you push up on the pool from below, the water flows out sideways toward new, lower pools on either side.

如果你从下面向上推水池，水就会从侧面流向两侧新的、较低的水池。

These basins are what mathematicians call attractors: states toward which the cells are inevitably drawn, like water following gravity across a landscape.

这些盆地就是数学家所说的吸引子：细胞不可避免地被吸引到的状态，就像水随着重力穿过景观一样。

The biologist Sui Huang has found that blood cell differentiation can be mapped like a real epigenetic landscape, with changes in gene activity altering the shape of the landscape, resulting in an output: red or white blood cell.

生物学家黄隋发现，血细胞分化可以像真实的表观遗传景观一样绘制出来，基因活动的变化会改变景观的形状，从而产生输出：红细胞或白细胞。

Researchers have now documented many cell-fate decisions that can be described in this way: as changes in gene activity that alter the shape of a landscape.

研究人员现在已经记录了许多细胞命运决定，这些决定可以这样描述：基因活动的变化改变了景观的形状。

The changes produce new attractors that correspond to stable cell types in the low-lying valleys; unstable gene-activity configurations constitute the high ground.

这些变化产生了与低洼山谷中稳定细胞类型相对应的新吸引子；不稳定的基因活性结构构成了制高点。

Briscoe is part of a research group that has pursued the landscape idea using the language of dynamical systems theory, which explores how systems described by sets of interacting variables evolve.

布里斯科是一个研究小组的成员，该小组一直使用动力系统理论的语言来追求景观理念，该理论探索由一组相互作用的变量描述的系统如何演化。

“Our work starts from Waddington’s metaphor,” said David Rand , a mathematician at the University of Warwick in the United Kingdom, who collaborates with Briscoe.

“我们的工作从沃丁顿的隐喻开始，”与布里斯科合作的英国华威大学数学家戴维·兰德 (David Rand) 说。

It’s more than a convenient image, he said: It “reveals something [fundamental] about the structure of developmental systems.”

他说，这不仅仅是一个方便的图像：它“揭示了有关发展系统结构的一些[基本]内容。”

Combining experiments and theory, they too have found that a small number of key genes drive cell-fate decisions.

结合实验和理论，他们也发现少数关键基因驱动细胞命运的决定。

The rest of the network enacts the decision, as other genes are activated or suppressed farther downstream, but isn’t active in it.

网络的其余部分制定了决定，因为下游的其他基因被激活或抑制，但在其中并不活跃。

“We think this reflects something real about how gene regulatory networks are organized,” Briscoe said.

“我们认为这反映了基因调控网络如何组织的真实情况，”布里斯科说。

This makes sense from an evolutionary perspective.

从进化的角度来看，这是有道理的。

For any multicellular organism, the various cell types must be reliably generated and stable.

对于任何多细胞生物体，各种细胞类型必须可靠且稳定地生成。

Gene regulatory networks that have deep, well-separated attractors will be selected for, Briscoe said.

布里斯科说，将选择具有深度且分离良好的吸引子的基因调控网络。

These deep wells represent canalization of cell-fate decisions in the way Waddington supposed.

这些深井代表了沃丁顿假设的细胞命运决定的渠道。

The molecular world is noisy, filled with random fluctuations.

分子世界充满噪音，充满随机波动。

Two cells of the same type will inevitably have slightly different levels of gene expression at any moment.

同一类型的两个细胞在任何时刻都不可避免地会出现略微不同的基因表达水平。

In the landscape picture, they don’t have to occupy the exact same spot.

在风景图片中，它们不必占据完全相同的位置。

But so long as a group of cells is in the same basin, they will all follow the same basic trajectory.

但只要一组细胞位于同一个盆地中，它们就会遵循相同的基本轨迹。

“If fate decisions were highly sensitive to any molecular fluctuation,” Briscoe said, “development would not be robust.”

布里斯科说：“如果命运决定对任何分子波动都高度敏感，那么发展就不会强劲。”

Waddington’s alluringly intuitive view left some open questions.

沃丁顿迷人的直觉观点留下了一些悬而未决的问题。

What does the height of the landscape actually represent?

景观的高度实际上代表什么？

And what’s the developmental equivalent of time passing as his balls roll down the slopes?

当他的球滚下斜坡时，时间的流逝相当于什么？

Briscoe and Rand’s dynamical-systems view provides some answers.

布里斯科和兰德的动力系统观点提供了一些答案。

It suggests that the landscape’s height reflects the stability of the cells’ states, with the least stable states on the highest peaks and the most stable in the lowest valleys.

这表明景观的高度反映了细胞状态的稳定性，最不稳定的状态在最高峰，最稳定的状态在最低的山谷。

Time, meanwhile, is not literal time, but a kind of “pseudo-time” that reflects how the gene-expression profiles of all the cells change.

与此同时，时间并不是字面上的时间，而是一种“伪时间”，反映了所有细胞的基因表达谱如何变化。

In theory, all the cells can be ordered along a single pseudo-time axis so that the greater the change in a given cell’s state, the farther along the axis it is.

理论上，所有细胞都可以沿着单个伪时间轴排序，这样给定细胞状态的变化越大，它沿着轴的距离就越远。

But these changes won’t all be in sync, so there’s no ticking clock that applies to them all at any instant — hence, pseudo-time.

但这些变化不会全部同步，因此不存在任何时刻都适用的滴答作响的时钟——因此，出现了伪时间。

The biologist James Briscoe has found that a small number of key genes determine whether a cell specializes into a certain cell type, such as a brain or liver cell.

生物学家詹姆斯·布里斯科发现，少数关键基因决定细胞是否专门分化为某种细胞类型，例如脑细胞或肝细胞。

Those genes then activate or suppress other genes farther downstream in the network.

然后这些基因激活或抑制网络中更下游的其他基因。

The trouble is that this notion of time doesn’t always work, Rand said.

兰德说，问题在于这种时间概念并不总是有效。

It fits when cells are crossing over high, unstable points in the landscape.

当细胞穿越景观中高而不稳定的点时，它就适合了。

But when they are in a low-lying attractor basin, their expression profiles don’t settle into a single, stable pattern but rather seem to evolve more randomly than systematically, as if “time” meanders.

但当它们处于低洼吸引盆地时，它们的表达谱不会形成单一、稳定的模式，而是似乎更加随机而不是系统地进化，就好像“时间”蜿蜒而行。

And what plays the role of gravity in this picture?

重力在这张照片中扮演什么角色？

What is the force that moves cells along their development pathway?

推动细胞沿着其发育路径移动的力量是什么？

“In developmental biology, gravity is [equivalent to] the inevitable progression of differentiation in multi-celled organisms, starting from a small number of cell types,” Rafelski said.

“在发育生物学中，重力[相当于]多细胞生物体中从少数细胞类型开始的不可避免的分化过程，”拉菲尔斯基说。

This process seems to have an inexorable direction and impetus.

这个过程似乎有一个必然的方向和推动力。

“Most of the time, cells follow a predictable order in which they differentiate,” Theriot said.

“大多数时候，细胞遵循可预测的分化顺序，”Theriot 说。

But that order is not programmed into the genome ; after all, the cells in an organism all have the same genome.

但这个顺序并没有被编入基因组；毕竟，生物体中的细胞都具有相同的基因组。

Rather, the cell-fate decisions are made collectively, as cells interact with and communicate with one another through chemical signals that are read at the cell surface, and through the tugging and squeezing on cell membranes that takes place as tissues grow and fold.

相反，细胞命运的决定是集体做出的，因为细胞通过在细胞表面读取的化学信号，以及通过组织生长和折叠时发生的细胞膜的拉扯和挤压来相互作用和交流。

“In development, there’s always feedback,” Theriot said, “and things [in the cell] can adjust depending on inputs from the outside.”

“在开发过程中，总会有反馈，”Theriot 说，“并且（细胞中的）事物可以根据外部输入进行调整。”

It is as though the landscape is constantly being reshaped by underlying tectonic forces.

就好像地貌不断被潜在的构造力重塑。

So while Waddington’s landscape looked like a static territory waiting to be traversed, the real landscape changes as cells develop.

因此，虽然沃丁顿的景观看起来像是一个等待被穿越的静态领域，但真正的景观随着细胞的发育而变化。

“In our framework, the landscape is a feature of each cell and is not fixed,” Rand said.

“在我们的框架中，景观是每个细胞的一个特征，并且不是固定的，”兰德说。

“Attractors appear and disappear through bifurcations, and the routes connecting them change.” It is as though the landscape is constantly being reshaped by underlying tectonic forces.

“吸引子通过分叉出现和消失，连接它们的路线也发生变化。”就好像地貌不断被潜在的构造力重塑。

Waddington’s rope network, you might say, is itself in constant motion, pulling the sheet this way and that.

你可能会说，沃丁顿的绳网本身就在不断运动，把床单拉来拉去。

In this respect, Rand said, Waddington’s picture was incomplete.

兰德说，在这方面，沃丁顿的描述并不完整。

It was never really a kind of universal gravity that made the ball roll; rather, cell lineages all move through a constantly shifting landscape in the process of life’s unfolding.

使球滚动的从来都不是真正的万有引力；而是一种万有引力。相反，在生命展开的过程中，细胞谱系都经历着不断变化的景观。

In such ways, modern data has both confirmed and complicated Waddington’s powerful metaphor.

通过这种方式，现代数据既证实了沃丁顿强有力的隐喻，又使其变得复杂化。

Combined theoretical and experimental approaches have helped to elucidate the complex but vital process through which the cells of multicellular organisms like us navigate a path from all-purpose, pluripotent stem cells to well-defined and specific tissues.

理论和实验相结合的方法有助于阐明像我们这样的多细胞生物的细胞从通用的多能干细胞到明确的特定组织的复杂但重要的过程。

Briscoe, for instance, has found that in neural-tube patterning there are two ways of reaching the same place in the landscape — a finding that reconciled previously contradictory observations.

例如，布里斯科发现，在神经管图案中，有两种方法可以到达景观中的同一位置——这一发现调和了之前相互矛盾的观察结果。

His team could not have made sense of their results without the landscape framework, he said.

他说，如果没有景观框架，他的团队就无法理解他们的结果。

Huang is now applying the landscape picture to the development of cancers.

黄现在正在将风景画应用于癌症的发展。

The traditional perspective is that cancer cells are malfunctioning, generally because gene mutations have damaged cell division so that it proceeds unchecked.

传统观点认为，癌细胞出现故障，通常是因为基因突变破坏了细胞分裂，使其不受控制地进行。

It’s a picture that sees cancer as an aberrant state.

这张照片将癌症视为一种异常状态。

But Huang regards it as just another attractor in the landscape — albeit a potentially catastrophic one — that can be all too easily accessed by many different routes.

但黄认为它只是景观中的另一个吸引物——尽管可能是灾难性的——可以通过许多不同的路线轻松到达。

In this view, becoming cancerous is just one of the possible things that our cells do: an inevitable consequence, you might say, of being a multi-tissue organism.

按照这种观点，癌变只是我们的细胞可能发生的事情之一：你可能会说，这是作为多组织有机体的不可避免的结果。

This doesn’t mean, however, that there’s nothing we can do about it.

然而，这并不意味着我们对此无能为力。

Once we view cancer as an attractor state, a new option becomes possible: to guide those cells back out of the cancer basin and into another that is more benign — one where the cells do nothing, undergo spontaneous cell death, or even regain a healthy state.

一旦我们将癌症视为一种吸引子状态，一种新的选择就成为可能：引导这些细胞从癌症盆地返回到另一个更良性的状态——细胞什么都不做，经历自发的细胞死亡，甚至恢复健康状态。

“Rather than just saying we need to kill them all,” Theriot said, “the idea is: Can we drive them to differentiate?”

“我们不只是说我们需要把他们全部杀死，”塞里奥特说，“我们的想法是：我们能否促使他们产生差异化？”

Such control of landscape trajectories might also be used for tissue regeneration, or for transforming one cell type into another — for example, to regrow damaged nerves.

这种对景观轨迹的控制也可用于组织再生，或将一种细胞类型转化为另一种细胞类型——例如，再生受损的神经。

There could be uses in agriculture as well, for selectively enhancing edible parts of plants, Theriot said.

塞里奥特说，它也可以用于农业，选择性地增强植物的可食用部分。

Briscoe said that “the landscape framework provides a rational basis” for this kind of developmental design, opening up the promise of a “generative” biology in which tissues and possibly organisms can be sculpted to order.

布里斯科说，“景观框架为这种开发设计提供了合理的基础”，开启了“生成”生物学的希望，在这种生物学中，组织和可能的生物体可以按顺序进行雕刻。

In that case, Waddington’s landscape model is far more than metaphor — it could be an atlas of a hitherto uncharted terrain.

在这种情况下，沃丁顿的景观模型不仅仅是隐喻——它可能是迄今为止未知地形的地图集。

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辱骂、亵渎、自我推销、误导、语无伦次或偏离主题的评论将被拒绝。

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版主在正常工作时间（纽约时间）有工作人员，并且只能接受英文评论。