内容来源：https://www.quantamagazine.org/the-biophysical-world-inside-a-jam-packed-cell-20260218/

内容总结：

长期以来，生物学教科书将细胞描绘成一个井然有序、空间宽敞的“微型工厂”，各种细胞器各司其职。然而，最新科学研究彻底颠覆了这一经典认知：活细胞内部实际上拥挤不堪、动态激烈，更像一个午夜时分人潮涌动的夜店。

过去几年，借助先进的成像与基因工程技术，科学家首次直接观测到活体细胞内惊人的拥挤程度。研究表明，这种拥挤并非偶然，而是细胞进化出的关键调控策略，旨在利用物理原理促使分子高效碰撞，以维持每秒约十亿次的生化反应。纽约大学朗格尼健康中心的细胞生物学家利亚姆·霍尔特形象地比喻：“在空旷的酒吧里，人们很少互动；但当场所拥挤时，你更易与身旁的人交谈或共舞。”

细胞如何在如此拥挤的环境中确保分子精准找到反应伴侣？这成了科学界的新谜题。早期研究曾提示细胞质拥挤存在“金发姑娘原则”——既不能太稀疏也不能太密集，否则生命活动将停滞。霍尔特团队通过基因工程创造出直径约40纳米、与核糖体大小相仿的荧光标记纳米颗粒（GEMs），作为“示踪剂”深入细胞。2018年，他们发现细胞能通过营养感应枢纽mTORC1调控核糖体浓度，从而像“旋钮”一样动态调节细胞质的物理拥挤度，这为理解细胞如何主动管理内部环境提供了突破。

然而，在活体多细胞生物中情况更为复杂。加州大学戴维斯分校的卢克斯顿与斯塔尔团队将GEMs植入透明线虫体内，意外发现其上皮细胞的拥挤程度高达培养细胞的50倍，细胞质稠密如“草莓酱”。更令人惊奇的是，当破坏细胞内支架蛋白ANC-1的功能后，原本停滞的GEMs开始移动。这表明细胞还通过空间组织、区室化等结构机制应对拥挤，拓宽了仅靠培养细胞得出的认知。

后续研究进一步揭示，不同细胞类型拥有适应其功能的独特拥挤度：肌肉细胞与脂肪细胞的物理特性截然不同，而癌细胞因异常增殖可能导致内部拥挤状态改变，这为疾病诊断提供了新思路。目前，科学家正构建不同组织与疾病模型的“细胞拥挤图谱”，并利用类器官开展三维研究。

“每观察一种新组织，我们都会发现意想不到的现象。”卢克斯顿表示。这场跨生物物理、显微成像与基因工程的探索，正开启细胞生物学一个充满惊喜的新领域。

中文翻译：

拥挤细胞内的生物物理世界

引言

这是一幅熟悉的画面，无数次出现在生物学教科书中：一个典型细胞的示意图，像葡萄柚般被剖开，露出内部结构。内质网丝带环绕着漂浮在中央的细胞核，如同一个筏子。RNA分子在核糖体旁耐心等待，准备传递制造蛋白质的指令。几个液泡和高尔基体轻轻晃动。几乎空无一物的细胞质提供了一个空白的背景。这些场景呈现出一种宁静、稀薄的秩序感，仿佛细胞是一个整洁的工厂，工人们各自专注于自己的任务。

现在，请立刻将这幅画面从脑海中抹去：细胞绝非宁静或稀薄。如果你被困在一个细胞里，你会感觉自己像一个在拥挤夜店里的舞者，不断被周围的邻居推挤。

过去几年，得益于成像和基因工程技术的惊人进步，科学家们首次得以观察和测量活体生物细胞内部的拥挤程度。这些实验揭示了一个比任何人预想的都更动态、更拥挤的场所，并且是最新证据，表明细胞主动调节其内部拥挤度，以优化生命所需的化学反应。

分子被塞进微小空间，这远非生物物理学的偶然，而是细胞进化出的一种基本方式，利用物理学将分子聚集在一起，以完成我们身体每个细胞每秒估计发生的10亿次生化反应。

"如果你在一个不太拥挤的酒吧或夜店，你可能不会和任何人交谈或跳舞，"纽约大学朗格尼健康中心的细胞生物学家利亚姆·霍尔特说。"但在午夜时分，当酒吧人满为患时，你更有可能与旁边的人交谈或跳舞。但如果你想看到房间另一头的人，就很难走到他们身边。"

这些新发现正在挑战科学家们的预期，提出了关于分子如何在熙熙攘攘、拥挤不堪的空间中精确找到其反应伙伴的问题——进而，细胞究竟如何能够正常运作。

生物物理学的刀刃边缘

细胞可能是生物实体，但它们同样受物理定律支配。量子物理学家埃尔温·薛定谔在他1944年的著作《生命是什么？活细胞的物理观》中提出，生物体与非生物体一样，必须服从物理定律的支配。他的远见卓识自此激励着具有生物学思维的物理学家和具有物理学思维的生物学家。

但是，研究真核细胞（构成我们身体和其他多细胞生物体的那种细胞）的物理学提出了一个挑战：如何研究深埋在人体、小鼠甚至简单蠕虫体内的单个细胞？

起初，科学家们通过从人类和动物体内取出这些细胞，在试管或培养皿中培养它们来规避这个问题。早期研究暗示细胞受到"金发姑娘现象"的影响：当它们的细胞质——细胞膜内的一切，包括细胞器、核糖体等分子结构，以及凝胶状的细胞质溶胶及其溶解的分子——具有某种程度的拥挤，但不过度时，它们的功能最佳。20世纪80年代，一个研究团队发现，即使将青蛙卵中提取的细胞质稍微稀释一点，有丝分裂和DNA复制等重要生化反应就会停止。其他研究发现，过度拥挤同样可能是灾难性的，会导致生命的化学机制陷入停滞。

细胞不断消耗能量来搅动物质，保持细胞质溶胶流动，并促使分子比单纯通过扩散更频繁地碰撞和反应。即便如此，细胞生命似乎行走在刀刃边缘。如果细胞不那么拥挤，分子会漫无目的地游荡，很少遇到为生命提供动力的化学反应（新陈代谢、蛋白质合成、生长、分裂等）中的伙伴（或多个伙伴）。在这种情况下，细胞生命将会枯萎。另一方面，如果细胞拥挤得多，分子会被困在原地，几乎无法移动，更不用说遇到它们的反应伙伴了。生命将陷入停滞。

霍尔特说，进化似乎在过度拥挤和不够拥挤之间达成了微妙的平衡，像核糖体这样的大分子通常占细胞质溶胶中溶解大分子体积的30%到40%。"似乎许多生物学过程都调整到了非常相似的拥挤水平。"但要证实这一观点，研究人员需要找到一种方法来追踪分子在细胞内的移动。他们需要一个大小合适的示踪剂。

拥挤控制

拥挤是相对的。虽然一个人可能在霍尔特想象的午夜俱乐部里行动困难，但一只猫或老鼠可能不会觉得太拥挤而难以穿行。为了研究细胞内的拥挤，生物学家需要一个大小范围相当的替代分子——一个与参与大多数细胞反应的大分子大致相同大小的示踪剂。

在2010年代中期，霍尔特引入了基因编码的多聚体纳米颗粒（GEMs），这是一种天然存在的球形蛋白质，直径约40纳米——与构建蛋白质的分子机器核糖体大小相近。利用基因工程，研究人员可以在GEMs表面装饰发绿色荧光的标签，然后在显微镜下追踪它们在细胞质中的运动。

2018年，这种方法让霍尔特和他的同事们对细胞如何管理其拥挤度有了新的认识。他们将GEMs放入培养的酵母和人类细胞中，测量了这些颗粒渗透到细胞不同区域所需的时间。奇怪的是，在不同营养条件下生长的细胞中，整个细胞的拥挤度似乎会发生变化。"这让我想问发生了什么，"霍尔特说。

他怀疑mTORC1参与其中。mTORC1是真核细胞中主要的营养感受器，是细胞生长的主调控因子；根据营养水平，它可以促进核糖体的生产，以更快地制造更多蛋白质。"生物体生长的速度从根本上受限于它们能产生多少核糖体，"霍尔特说。确实，当他的团队化学抑制mTORC1时，核糖体的浓度下降，GEMs在细胞质中的流动变得容易得多。

进一步的实验表明，细胞可以利用核糖体——细胞中最丰富的分子之一——以及调控它们的遗传通路，来控制它们的分子拥挤度。霍尔特称mTORC1为"细胞质物理特性的动态控制旋钮"。

霍尔特团队关于细胞如何管理其内部环境的工作启发了进一步的实验。这篇论文（目前已被引用近500次）"极具影响力"，匹兹堡大学的细胞生物学家阿罗汉·苏布拉马尼亚说。霍尔特表明"核糖体充当了天然的拥挤剂"。

霍尔特说，其结果是一个生化系统，其中细胞质的拥挤度反映了细胞的生长和健康状况。"如果生物体在完美条件下快速生长，它们会用非常高浓度的核糖体填满细胞质。"

然而，他的团队是在单细胞酵母和培养的人类细胞中做出这一发现的。生物物理学家G.W. 甘特·勒克斯顿想知道，在更复杂的活体多细胞生物环境中，细胞是否遵循相同的规则。

拥挤不堪

2018年夏天，勒克斯顿和霍尔特在马萨诸塞州伍兹霍尔海洋生物实验室访问时见面喝咖啡。勒克斯顿只花了几分钟就看到了如何在自己的工作中使用霍尔特的GEMs——但他需要更多帮助。他联系了一位同事，遗传学家丹尼尔·斯塔尔，看他是否有兴趣将这些颗粒工程化到秀丽隐杆线虫（一种微型蠕虫）中。关键的是，这种常用的模式生物是透明的，允许生物学家观察实验性荧光，例如GEMs发出的荧光。

斯塔尔同意了。在获得项目资助后，勒克斯顿将他的实验室搬到了加州大学戴维斯分校，组建了斯塔尔-勒克斯顿实验室。勒克斯顿和斯塔尔花了几个月时间让线虫产生GEMs，又花了数年时间才弄清楚如何成像和分析数据。但最终，他们能够看到并测量这些颗粒在线虫肠道和皮肤细胞中发出的荧光。

一旦进入细胞，这些颗粒几乎不动。测量显示，线虫细胞质中核糖体的拥挤程度大约是霍尔特培养细胞的50倍。起初，进行实验的研究生以为他们犯了错误。

"这简直让我震惊，"勒克斯顿说。"为什么这些探针不动？"

另一位研究生评论说，培养细胞的稠度像蜂蜜，而更稠的线虫细胞质则像"草莓酱"。

"这是一个非常令人惊讶的结果，"该论文（于2025年9月发表在《科学进展》上）的合著者霍尔特说。"我从未见过像蠕虫上皮细胞中那样戏剧性的情况。"

对勒克斯顿来说，这个结果立即引发了问题。首先，如果活细胞内部像果酱一样稠密，一个给定的分子如何能充分移动以遇到它需要与之反应的另一个分子？"我不知道任何东西如何能找到任何东西，"他说。

研究人员还注意到，GEMs似乎卡在细胞的某些区域。但当勒克斯顿和斯塔尔的团队破坏了一种名为ANC-1的大型蛋白质（它在细胞内充当支架）的功能时，GEMs开始移动。这表明细胞进化出了多种机制来管理细胞质中的拥挤。

"把细胞想象成一个盒子，核糖体想象成填充花生，"勒克斯顿说。"你可以通过填充花生来改变拥挤度……但你也可以改变盒子的大小。看起来ANC-1控制着这方面的因素。"

"这表明控制拥挤的方式非常不同，"他继续说。"组织中的细胞可能比我们从研究培养细胞中所认识到的，更依赖于空间组织——区室化、支架结构、酶之间底物的通道化。"

一个新的子领域

自关于ANC-1的论文发表以来，勒克斯顿和他的团队已将GEMs放入线虫神经元和其他类型的细胞中，包括患病和衰老的细胞，以收集不同组织细胞质生物物理特性的基线数据。"我们一直在构建一个线虫图谱，"他说。与一位合作者一起，他们也开始将GEMs放入斑马鱼（另一种常见的模式生物）中。他们发现细胞内存在一系列拥挤度水平，这使霍尔特关于细胞倾向于用分子填充其体积30%到40%的图景变得复杂。这项研究强调了在活体生物（在不同条件下运作）中验证细胞培养结果的重要性。

"细胞找到了不同的方法来应对不同程度的拥挤，"勒克斯顿说。"你看哪里真的很重要，并非所有组织都是一样的。"

霍尔特表示同意。"似乎不是存在一个普遍的最佳拥挤水平，而是不同的细胞类型和组织会调整其拥挤度以适应其特定需求，"他说。例如，一个需要反复收缩和放松的肌肉细胞，其机械特性与主要工作是储存能量的脂肪细胞不同，这是有道理的。

另一研究方向涉及将GEMs放入类器官中——类器官是三维实验室培养的结构，可以模拟各种组织和器官。因为类器官是3D的，勒克斯顿认为它们比漂浮在试管中的细胞更能近似活体动物。他和同事们正在将GEMs放入胰腺癌类器官中，寻找可用于区分癌细胞和健康细胞的生物物理差异。

科学家们早就知道癌细胞在物理上是不同的。"癌症是一个发生巨大机械变化的例子，"霍尔特说。"你发现肿瘤的方式，是寻找一个肿块——一个比应有体积更大的细胞团。就像给轮胎打气一样。细胞被挤压；它们变得更拥挤。"他提出，这会改变它们的生物物理特性。

这是一个令人兴奋的时代，生物物理学、显微镜学和基因工程领域的创新汇聚在一起，在已有数百年历史的细胞科学中开辟了一个新的子领域。

"这有点像潘多拉魔盒，"勒克斯顿说。"每当我们观察不同的组织时，我们都会看到一些意想不到的东西。"

英文来源：

The Biophysical World Inside a Jam-Packed Cell
Introduction
It’s a familiar image, reprinted in countless biology textbooks: an illustration of a typical cell, halved like a grapefruit to reveal its innards. Strands of endoplasmic reticulum encircle a nucleus that floats in the center like a raft. RNA molecules wait patiently at ribosomes to deliver recipes for making proteins. A few vacuoles and Golgi bodies bob about. A mostly deserted cytosol offers a blank backdrop. These are scenes of a calm, rarefied order, as if a cell were a tidy factory with workers individually going about their focused tasks.
Scrub that picture from your mind right now: Cells are anything but calm or rarefied. If you were trapped inside a cell, you would feel like a dancer in a thronged nightclub, constantly jostled by neighbors.
Over the past few years, thanks to stunning advances in imaging and genetic engineering, scientists have been able to observe and measure crowding inside cells in living organisms for the first time. The experiments have revealed a more dynamic and crowded place than anyone expected, and are the latest evidence that cells actively regulate their internal crowdedness to optimize for the chemical reactions required for life.
Far from being a biophysical accident, the packing of molecules into tiny spaces is emerging as a fundamental way that cells have evolved to harness physics to bring molecules together for the estimated 1 billion biochemical reactions that occur every second in every cell of our bodies.
Deb Bemis
“If you’re in a bar or nightclub that’s not very crowded, you might not talk to anyone or dance with anyone,” said Liam Holt, a cell biologist at New York University Langone Health. “But at midnight when the bar is jam-packed, you’re more likely to talk or dance with someone next to you. But if you see someone across the room, it’s harder to get to them.”
The new findings are confounding scientists’ expectations, raising questions about how exactly molecules can encounter their reactive partners in a teeming, crowded space — and therefore how cells can possibly function.
The Biophysical Knife’s Edge
Cells may be biological entities, but they are not exempt from the laws of physics. In his 1944 book What Is Life? The Physical Aspect of the Living Cell, the quantum physicist Erwin Schrödinger argued that living things, like their nonliving counterparts, must submit to governance by physical laws. His vision has inspired biology-minded physicists and physics-minded biologists ever since.
But studying the physics of eukaryotic cells — the kind that make up our bodies and those of other multicellular organisms — presented a challenge: How do you study an individual cell buried deep within the body of a person, a mouse, or even a simple worm?
At first, scientists got around this problem by removing those cells from humans and animals and growing them in test tubes or petri dishes. Early studies hinted that cells are subject to a Goldilocks phenomenon: They function best when their cytoplasm — everything enclosed by a cell’s membrane, including organelles, molecular structures such as ribosomes, and the gel-like cytosol and its dissolved molecules — has some level of crowding, but not too much. In the 1980s, a team of researchers found that if they diluted the cytoplasm extracted from frog eggs even a little bit, vital biochemical reactions such as mitosis and DNA replication ceased. Other studies found that overcrowding could be equally disastrous, causing the chemical machinery of life to freeze up.
Cells are constantly churning through energy to stir things up, keep the cytosol fluid, and encourage molecules to collide and react more often than they would through simple diffusion. Even so, cellular life appears to balance on a knife’s edge. If cells were any less crowded, molecules would wander aimlessly and only rarely encounter their partner (or partners) in the chemical reactions that power life — metabolism, protein synthesis, growth, division, and more. In that situation, cellular life would wither. If, on the other hand, cells were much more crowded, molecules would be stuck in place, unable to move much at all, let alone come across their reaction partners. Life would grind to a halt.
Evolution seemed to have struck a delicate balance between over- and undercrowding, with large molecules such as ribosomes typically representing between 30% and 40% of the volume of dissolved macromolecules in the cytosol, Holt said. “It seems that much of biology is tuned to have a very similar level of crowding.” But to confirm this view, researchers would need to find a way to track molecules moving through a cell. They would need a tracer of the right size.
Crowd Control
Crowding is relative. While a person might have trouble moving through Holt’s imagined club at midnight, a cat or mouse would not find it too crowded to navigate. To study crowding in cells, biologists needed a proxy molecule in the same size range — a tracer roughly as large as the large molecules involved in most cellular reactions.
In the mid-2010s, Holt introduced genetically encoded multimeric nanoparticles, or GEMs, which are naturally occurring spherical proteins about 40 nanometers in diameter — around the same size as ribosomes, the molecular machines that build proteins. Using genetic engineering, researchers can decorate the surfaces of GEMs with glowing green fluorescent tags and then track their movements through a cell’s cytoplasm under a microscope.
In 2018, this approach gave Holt and his colleagues fresh insight into how cells manage their crowdedness. They put GEMs inside yeast and human cells in culture and measured how long it took the particles to percolate through different areas of the cell. Strangely, in cells grown under different nutritional conditions, the crowding of the entire cell seemed to change. “This led me to ask what was going on,” Holt said.
He suspected that mTORC1 was involved. The main nutrient sensor in eukaryotic cells, mTORC1 is a master regulator of cell growth; based on nutrient levels, it can boost production of ribosomes to build more proteins faster. “The rate at which organisms can grow is fundamentally limited by how many ribosomes they can produce,” Holt said. Indeed, when his team chemically suppressed mTORC1, the concentration of ribosomes decreased, and GEMs flowed through the cytoplasm much more easily.
Further experiments suggested that cells can use ribosomes — one of the most abundant molecules in a cell — and the genetic pathways that regulate them, to control their molecular crowds. Holt calls mTORC1 “a dynamic control knob for cytoplasmic physical properties.”
Holt’s team’s work on how cells manage their internal environment inspired further experiments. The paper, now cited almost 500 times, was “incredibly influential,” said Arohan Subramanya, a cell biologist at the University of Pittsburgh. Holt showed that “ribosomes act as natural crowding agents.”
The result is a biochemical system in which the crowdedness of the cytoplasm reflects a cell’s growth and health, Holt said. “If organisms are growing quickly and in perfect conditions, they pack their cytoplasm with a very high concentration of ribosomes.”
However, his team made their discovery in single-celled yeast and cultured human cells. G.W. Gant Luxton, a biophysicist, wanted to see if cells followed the same rules in the more complex environment of a living multicellular organism.
Jam-Packed
In summer 2018, Luxton and Holt met for coffee while both were visiting the Marine Biological Laboratory in Woods Hole, Massachusetts. It took only a few minutes for Luxton to see how to use Holt’s GEMs in his work — but he would need more help. He contacted a colleague, the geneticist Daniel Starr, to see if he would be interested in engineering the particles into Caenorhabditis elegans, a microscopic worm. Crucially, this workhorse model organism is transparent, allowing biologists to observe experimental fluorescence such as that given off by GEMs.
Starr said yes. After receiving funding for the project, Luxton moved his lab to the University of California, Davis, to form the Starr-Luxton lab. It took months for Luxton and Starr to make the worms produce GEMs, and years to figure out how to image and analyze the data. But eventually they could see and measure the particles glowing in the worms’ gut and skin cells.
Once inside the cells, the particles hardly moved. The worm cytoplasm, measurements showed, was around 50 times more crowded with ribosomes than that of Holt’s cultured cells. At first, the graduate student conducting the experiments thought they had made a mistake.
“It just kind of blew my mind,” Luxton said. “Why aren’t these probes moving?”
Another graduate student remarked that while cultured cells had the consistency of honey, the thicker worm cytoplasm resembled “strawberry jam.”
It was “a very surprising result,” said Holt, a co-author on the paper, which was published in September 2025 in Science Advances. “I’ve never seen anything as dramatic as in the epithelium of the worm.”
For Luxton, the result immediately raised questions. For one thing, if the interior of living cells is thick like jam, how does a given molecule move around enough to encounter another molecule it needs to react with? “I don’t know how anything ever finds anything,” he said.
Joaquin Benitez, UC Davis
The researchers also noticed that the GEMs seemed stuck in certain regions of the cell. But when Luxton and Starr’s team disrupted the functioning of a large protein called ANC-1 that acts as scaffolding inside cells, the GEMs started moving. This suggested that cells have evolved multiple mechanisms to manage crowding in the cytoplasm.
“Think of the cell as a box and ribosomes as packing peanuts,” Luxton said. “You can change crowding through the packing peanuts … but you can also change how big the box is. It looks like ANC-1’s controlling that aspect of this.
“It shows there’s very different ways to control crowding,” he continued. “Cells in tissues may depend much more on spatial organization — compartmentalization, scaffolding, channeling of substrates between enzymes — than we appreciate from studying cells in culture.”
A New Subfield
Since the publication of the paper on ANC-1, Luxton and his team have put GEMs in worm neurons and other kinds of cells, including diseased and aging ones, to gather baseline data on the cytoplasmic biophysical properties of different tissues. “We’ve been building an atlas of worms,” he said. With a collaborator, they’ve also started to put GEMs in zebra fish, another common model organism. They are finding a range of crowdedness levels within cells, complicating Holt’s picture that cells prefer to fill 30% to 40% of their volume with molecules. The research underscores the importance of confirming cell culture results in living organisms, which operate under different conditions.
“Cells have found different ways to deal with a continuum of crowdedness,” Luxton said. “It really matters where you’re looking, and not all tissues are created equal.”
Holt agrees. “Rather than one universal optimal crowding level, it appears that different cell types and tissues tune their crowding to suit their particular needs,” he said. It makes sense that, say, a muscle cell that needs to repeatedly contract and relax would have different mechanical properties than a fat cell whose main job is to store energy.
Another line of research involves putting GEMs in organoids — three-dimensional lab-grown structures that can be made to mimic various tissues and organs. Because organoids are 3D, Luxton believes they better approximate living animals than cells floating in test tubes. He and colleagues are putting GEMs into pancreatic cancer organoids and looking for biophysical differences that could be used to distinguish cancer cells from healthy ones.
Scientists have long known that cancer cells are physically distinct. “Cancer is an example where you have big mechanical changes,” Holt said. “The way you find a tumor, you look for a lump — a larger cell mass than should be there. It’s like pumping air into a tire. Cells are getting squished; they get more crowded.” This, he suggested, would change their biophysical properties.
It’s a heady time, with innovations in biophysics, microscopy, and genetic engineering coming together to open up a new subfield within the centuries-old science of cells.
“It’s kind of like Pandora’s box,” Luxton said. “Every time we look at a different tissue, we see something we don’t expect.”