细胞利用“生物电”进行协调与集体决策。
内容总结：
生物电：细胞协同决策的“隐秘语言”
长久以来，科学界普遍认为电信号是大脑和心脏等少数器官的“专利”。然而，一项发表于《自然》期刊的最新研究揭示，构成皮肤、器官内壁等保护层的上皮细胞，同样利用生物电信号进行“集体决策”，以维持组织健康。这一发现从根本上拓展了我们对生命体通讯方式的理解。
研究聚焦于一个名为“细胞挤出”的关键过程：当上皮组织生长时，为了维持平衡、防止过度增殖，需要将衰弱、受损或多余的活细胞识别并“驱逐”出去。该过程若出错，可能与癌症、哮喘等疾病相关，但其启动机制一直成谜。
英国伦敦国王学院和弗朗西斯·克里克研究所的乔迪·罗森布拉特团队发现，答案在于生物电。随着细胞密度增加，细胞相互挤压，导致压力敏感的离子通道打开，带正电的钠离子流入细胞内。健康细胞能消耗能量将钠离子泵出，维持正常的细胞膜电位（一种跨膜电压差）。而衰弱、能量不足的细胞则无力补偿，其膜电位随之下降。
这种电位变化如同一次“健康检查”。膜电位降低会触发电压敏感的钾离子通道开放，导致细胞内的水分在数秒内快速流失，细胞体积收缩至少17%，从而被标记并最终被周围细胞挤出。整个过程由电信号率先启动。
“这是一个非常有趣的发现，它表明生物电是细胞挤出过程中最早发生的事件，”未参与该研究的普渡大学遗传学家张广军（音译）评论道，“这为在基础生物学中应用更广泛的电信号视角提供了范例。”
事实上，生物电的运用在自然界中远比我们想象的普遍。从细菌生物膜利用电信号协调群体行为、分配资源，到青蛙胚胎利用电场引导干细胞迁移，再到植物（如捕蝇草）依靠电脉冲触发捕猎动作，电信号已成为跨物种细胞间快速协调与信息交换的通用“工具”。
研究共同作者罗森布拉特强调：“人们过去常把生物电局限于神经元。不——它存在于我们全身。电流始终在体内流动，并执行着重要功能。”
这一发现也暗示了疾病的新机制。例如，癌细胞通常具有异常的膜电位。有观点认为，某些癌症可能源于细胞间电通讯的崩溃，导致衰弱的细胞无法被正常识别和清除，从而引发失控性生长。
科学家们认为，生物电的进化根源可能极为古老，甚至可能与生命起源本身相伴。随着研究的深入，这门曾被忽视的“细胞电生理学”正迎来复兴，有望为我们理解发育、再生与疾病开辟全新的道路。正如德国德累斯顿工业大学的组织生物物理学家埃利亚斯·巴里加所言：“我们现在看到的可能只是冰山一角，仍有大量未知等待发现。”
中文翻译：
细胞利用“生物电”进行协调与群体决策
引言
我们习惯于将大脑视为一个电器官。身体的其他部分呢？似乎并非如此。但若将其他组织视为电惰性的“肉块”，那就大错特错了。最新研究表明，即使是构成皮肤和器官内壁的细胞保护层，也会利用电信号做出决策。
《自然》杂志发表的研究结果显示，细胞利用生物电协调一种名为“挤压”的复杂集体行为。这一关键过程能将病变或衰弱的单个细胞从组织中排出，从而维持健康并控制生长。尽管看似残酷，挤压作用却是维持生命的重要机制。它对保护性上皮组织的健康至关重要，一旦失调则可能导致包括癌症和哮喘在内的疾病。此前，人们一直不清楚细胞如何被筛选出来接受这一过程。
新研究揭示：随着上皮组织生长，细胞排列愈加紧密，导致流经每个细胞膜的电流增强。那些虚弱、衰老或能量匮乏的细胞难以应对这种变化，从而触发应激反应——水分瞬间涌出细胞，使其皱缩并标记为待清除状态。在此过程中，电流如同组织的健康检查系统，引导着细胞修剪程序。
“这项发现非常有趣——生物电竟是细胞挤压过程中最早发生的事件。”普渡大学遗传学家张广军（音）评价道，他研究斑马鱼发育中的生物电信号，未参与此项研究，“这为拓宽电子信号视角在基础生物学中的应用提供了绝佳范例。”
新发现进一步丰富了科学家在神经系统之外发现的生物电现象谱系：从生物膜内细菌的信号交换，到胚胎发育中细胞沿电场定向迁移。电信号正日益显现为生物学中协调各类细胞间信息交换的通用工具。
“人们常将生物电局限在‘这只是神经元的事’。不——它存在于我们全身。”研究作者、伦敦国王学院与弗朗西斯·克里克研究所的上皮细胞生物学家乔迪·罗森布拉特强调，“电流时刻在体内流动，并持续发挥作用。”
生命的火花
《科学怪人》中怪物因电火花获得生命的情节并非偶然。18世纪末，在玛丽·雪莱创作这部科幻杰作的几十年前，意大利外科医生路易吉·伽伐尼通过金属与电刺激无头青蛙腿部跳动的实验震惊科学界。他坚信生命体内流淌着“动物电”。
公共领域；苏黎世联邦理工学院图书馆/科学源
尽管伽伐尼的细节认知后被证实有误，但其方向基本正确。生命之树每个分支上的几乎所有细胞，都会耗费大量能量（某些细胞超过一半）维持跨膜电压。这种被称为膜电位的电压差储存着可后续释放的势能，犹如水坝背后的压力：重力将水向下牵引，水坝则通过蓄积高位水储存能量。类似地，电化学力牵引电荷“顺流而下”——正电荷流向负电荷形成电流。细胞膜等屏障通过阻断这种流动来储存电势能。
我们墙插中的电流是电子流。而在细胞中，“原理相似但不尽相同”，德累斯顿工业大学组织生物物理学家埃利亚斯·巴里加解释道，“我们的能量载体是离子。”
离子是因电子得失而携带电荷的原子或分子，分别呈现正负电性。它们只能通过特化的蛋白质通道和泵进出细胞。正如水电站可利用多余能量将水泵回水库备用，细胞也会消耗化学能量逆电流方向泵送离子。通过控制自然电流并让正负电荷在膜两侧积累，细胞得以维持膜电位。若这部分能量被消耗或泄漏，细胞可消耗更多化学能进行补充。
“细胞建立电位差：内外离子浓度不同，”巴里加说，“这就是生物电的来源。”
神经元利用这种生物电共享信息。通过释放被称为神经递质的信使分子来开闭离子通道，神经元可微调邻近细胞的膜电位。若这些化学信号使神经元膜电位突破阈值，细胞就会产生“峰电位”——电压敏感离子通道瞬间开启，大量带正电的钠离子涌入细胞，引发沿神经元传播的快速电压波动。当信号抵达神经元连接处，电压敏感通道完全打开，触发神经递质向下游更多神经元释放。
肌肉收缩同样始于电压峰值：神经元将电信号传递至肌纤维触发收缩。这正是伽伐尼实验中蛙腿抽搐的原理，也是电击能重启骤停心脏的原因（心脏特化细胞利用电信号设定规律收缩节律）。尽管所有组织都维持膜电位，但研究人员尚未完全明了其功能。巴里加指出，相较于常聚焦心脑电活动的电生理学，研究生物体其他部位电活动的“生物电”领域长期滞后。
“我认为该领域曾陷入停滞，”他说，“但现在可以告诉你，它正以惊人势头回归。”
颠覆性发现
构成皮肤、器官内壁、血管及体腔的上皮组织，默默消耗约25%的可用能量以维持-30至-50毫伏的膜电压。但关注这些组织的研究者通常着眼于机械力、化学信号与基因表达——而非电流与电压，罗森布拉特指出。
她自己直到最近也是如此。25年来，罗森布拉特一直致力于解析上皮细胞挤压过程的细节，这一过程能调控组织生长。由于上皮细胞增殖迅速，细胞分裂与死亡速率的轻微失衡都可能快速累积成肿瘤或损伤。失控的复制可能导致癌症，而过度清除（如哮喘中可能发生的情况）则会损害组织完整性。保持平衡至关重要。
约14年前，罗森布拉特团队发现，过度拥挤的上皮细胞会被活体弹出组织（即挤压），以在新细胞生长时维持组织平衡。这引出一个关键问题：组织如何“选择”要排出哪些活细胞？
在早期工作中，罗森布拉特团队观察到某些细胞在被挤压前会排出水分，变得如葡萄干般皱缩；这种收缩似乎正是挤压过程的起始信号。但研究人员最初并不清楚细胞收缩的诱因。他们未涉足生物电领域，也未意识到其潜在影响。
安东尼奥·塔贝内罗
在后续实验中，他们通过阻断细胞膜上受挤压时开启的压力敏感离子通道，成功阻止了细胞收缩。这促使他们尝试阻断其他离子通道是否也会干扰挤压过程。
“我们得到大量阳性结果时简直难以置信，”罗森布拉特回忆道。其中一种电压门控钾通道（类似神经元产生峰电位时开启的通道）引起她的注意，其“奇特”特性值得深入探究。使用能显示细胞膜电压的特制染料后，科学家发现注定被挤压的上皮细胞（且仅限这些细胞）在收缩和被挤出前约五分钟丧失膜电位。结论显而易见：挤压过程由电信号启动。
与神经元通过神经递质交流不同，密集的上皮细胞通过相互挤压传递信息。随着组织愈发拥挤，挤压加剧，压力敏感离子通道随之开启，带正电的钠离子得以渗入被挤压细胞的膜内。
面对这种挑战，健康细胞会动用化学能量激活泵将钠离子排出，恢复正常电压。但处于应激状态或能量匮乏的不健康细胞无力应对，其膜电压下降，导致那些“奇特”的电压敏感通道敞开。罗森布拉特指出，此时水分在显微镜图像中如“闪电”般涌出细胞。一旦细胞体积减少17%以上，就会被挤压排出。她的工作假说认为：收缩触发的生化级联反应会激活运动蛋白，从而机械性地挤出细胞。
通过这种方式，跨细胞膜的生物电流使组织能检测哪些细胞最不健康，并标记它们以待清除。“它们持续相互推挤、相互竞争，实质是在探查谁是最薄弱环节，”罗森布拉特说，“这是一种群体效应。”
进化中的电工
加州大学圣地亚哥分校生物物理学家居罗尔·叙埃尔研究细菌生物膜中的电现象。这种由单细胞细菌构成的集体既能协同生存，也能独立存活。罗森布拉特团队在人体组织中描述的信号机制，与叙埃尔在微生物中发现的电机制（且在生命之树中反复出现）存在诸多共性。
“这项研究非常精妙，结果出色，”他评价新成果，“从概念上也合乎逻辑。”
叙埃尔实验室
电信号正日益显现为进化过程中整合多元信息流的优选方案。上皮组织用它监测拥挤程度；神经元将多源输入信号编译为峰电位输出；捕蝇草的触觉敏感离子通道对猎物产生反应时，陷阱会迅速闭合——这些通道经过调谐，仅在快速连续多次受刺激时才触发电压峰值并指令关闭。
“膜电位如此基础，又极其迅速，”叙埃尔说。启动或关闭基因、提升蛋白质产量可能需要数分钟甚至数小时，而膜电位翻转只需零点几秒。“它几乎能让你瞬间了解细胞状态。”
十年前，叙埃尔团队证明生物膜中的微生物能像神经元一样通过膜电位峰值进行交流。此后他们进一步揭示：生物膜利用电信号协调任务、抑制过度生长、招募自由游动细菌加入集体。生物电甚至能帮助它们避免陷入“公地悲剧”——共享稀缺食物的两个生物膜可通过电信号协调轮流进食。
多细胞动物同样利用电信号进行自我组织。普渡大学的张广军研究斑马鱼的生物电信号，发现特定离子通道突变会导致斑马鱼发育出超长尾巴，表明电信号能以某种方式指导胚胎发育中的组织生长长度。塔夫茨大学研究员迈克尔·莱文通过阻断细胞通道操控蠕虫胚胎的膜电位，使基因相同的蠕虫发育出不同体型结构。去年，巴里加团队证明青蛙胚胎产生的天然电场能引导特定干细胞迁移至胚胎发育的正确位置。
生物电过程失调可能是被忽视的疾病诱因。癌细胞膜电位通常异于健康细胞，莱文认为某些癌症可能源于多细胞协同崩溃——当细胞无法用电信号协调时，或许再也无法传递“我状态不佳应被清除”的信息，最终导致失控生长乃至肿瘤形成。
叙埃尔确信生物电与生命本身同样古老。事实上，电流驱动着分子涡轮机在所有现存细胞中合成生命通用能量货币ATP。一项主流生命起源假说将深海热液喷口视为生命起点，那里带正电质子的天然电流可能充当原始膜电位，驱动了前生命化学反应。无论生命是否始于这样的电火花，生物电的普遍性暗示其深植于进化历程，而我们才刚刚开始发掘。
“细胞可能正在进行许多有趣的活动，正如这篇论文所揭示的，只是我们尚未知晓，”叙埃尔说，“我们探索到的可能还不到一半……未来仍有大量发现机遇。”
英文来源：
Cells Use ‘Bioelectricity’ To Coordinate and Make Group Decisions
Introduction
We’re used to thinking of the brain as an electric organ. The rest of the body? Not so much. But it would be a mistake to dismiss your other tissues as dumb hunks of electrically inert flesh. Even the protective layers of cells that compose your skin and line your organs use electrical signals to make decisions, according to recent research.
Results published in Nature show that cells use bioelectricity to coordinate a complex collective behavior called extrusion, a vital process that ejects sick or struggling individual cells from tissue to maintain health and keep growth in check. Merciless as it might seem, extrusion helps keep you alive. It’s vital for the health of protective epithelial tissues, and when it goes wrong, it can contribute to disease, including cancer and asthma. Until now, it’s been unclear how cells were singled out for this process.
According to the new results, as epithelial tissue grows, cells are packed more tightly together, which increases the electrical current flowing through each cell’s membrane. A weak, old, or energy-starved cell will struggle to compensate, triggering a response that sends water rushing out of the cell, shriveling it up and marking it for death. In this way, electricity acts like a health checkup for the tissue and guides the pruning process.
“This is a very interesting discovery — finding that bioelectricity is the earliest event during this cell-extrusion process,” said the geneticist GuangJun Zhang of Purdue University, who studies bioelectrical signals in zebra fish development and wasn’t involved in the study. “It’s a good example of how a widening electronic-signaling perspective can be used in fundamental biology.”
The new discovery adds to the growing assortment of bioelectrical phenomena that scientists have discovered playing out beyond the nervous system, from bacteria swapping signals within a biofilm to cells following electric fields during embryonic development. Electricity increasingly appears to be one of biology’s go-to tools for coordinating and exchanging information between all kinds of cells.
“People just kind of relegated [bioelectricity] to ‘This is just neurons.’ No — it’s all of our bodies,” said study author Jody Rosenblatt, an epithelial cell biologist at King’s College London and the Francis Crick Institute. “There are electrical currents going through your body all the time, and they’re doing things.”
Life’s Spark
It’s no coincidence that Frankenstein’s monster sprang to life with a spark. In the late 18th century, just a few decades before Mary Shelley wrote her science fiction masterpiece, the Italian surgeon Luigi Galvani jolted the scientific community with experiments that used metal and electricity to compel disembodied frog legs to kick. He became convinced that there was an “animal electricity” running through life.
Public Domain; ETH-Bibliothek Zurich / Science Source
While Galvani was later proven wrong in the details, he wasn’t totally off. Virtually every cell on every branch of the tree of life expends a hefty chunk of its energy budget — in some cells, more than half — on maintaining a voltage across its membrane. The voltage difference that results, called the membrane potential, stores potential energy that can be released later. It’s like the pressure behind a dam: Gravity tugs water downhill, and dams store energy by holding water at the top of a hill. Like gravity, the electrochemical force tugs charges “downhill” — positive charges stream toward negative charges and vice versa in electrical currents. Blocking that flow, for example with a cell membrane, stores up electrical potential energy.
The electric currents that pour from our wall sockets are streams of electrons. In cells, “it’s quite similar, but not exactly the same,” said Elias Barriga, who studies tissue biophysics at the Dresden University of Technology. “We are fueled by ions.”
Ions are atoms or molecules that carry charge because of extra or missing electrons, which give them negative or positive charges, respectively. They can enter and exit cells only through specialized protein channels and pumps. Just as hydroelectric plants can use surplus energy to pump water back up into the reservoir for later use, cells use their chemical energy to pump ions “uphill” against the electric flow. By controlling the natural current and letting positive or negative charge build up on either side of their membranes, cells maintain their membrane potential. And if this energy is used or leaks away, cells can replenish it by expending more of their chemical energy.
“You generate a potential: what’s inside versus what’s outside, a different concentration of ions,” Barriga said. “That is the source of bioelectricity.”
Neurons make use of this biological electricity to share information. By releasing messenger molecules called neurotransmitters that open and close ion channels, neurons can nudge their neighbors’ membrane potentials up or down. If these chemical nudges push a neuron’s membrane potential beyond a threshold, the cell “spikes” — voltage-sensitive ion channels throw open the floodgates for positive sodium ions, which rush into the cell and cause a rapid voltage swing that ripples along the neuron’s length. When that signal reaches the interface between neurons, voltage-sensitive channels open wide, triggering the release of neurotransmitters to more neurons downstream.
Muscle contraction also kicks off with a voltage spike; neurons send electrical signals streaming into muscle fibers, triggering contractions. This is why Galvani’s electrified frog legs twitched, and why a jolt of electricity can jump-start a stopped heart. (Specialized cells in the heart use electricity to set the pace of its regular contractions.) While all tissues maintain membrane potentials, researchers don’t really know what they do. Compared to electrophysiology, which often focuses on electricity in the brain and heart, the field of bioelectricity — a grab-bag term for electrical activity everywhere else in organisms — has lagged behind, Barriga said.
“I think that at some point it got stuck,” he said. “But now I can tell you that that is coming back like crazy.”
A Shocking Discovery
The epithelial tissues that make up skin and line organs, blood vessels, and body cavities quietly burn about 25% of their available energy to maintain membrane voltages between minus 30 and minus 50 millivolts. But researchers interested in these tissues typically study mechanical forces, chemical signaling, and gene expression — not currents and voltage, Rosenblatt said.
Until recently, that included her. Rosenblatt has spent 25 years piecing together the details of epithelial extrusion, a process that keeps tissue growth in check. Because epithelial cells grow quickly, even a slight mismatch between the rates of cell division and cell death can quickly add up to a tumor or injury. Runaway replication can grow into cancer, while overzealous culling — as can happen in asthma — compromises the integrity of tissues. It’s important to get the balance right.
Around 14 years ago, Rosenblatt and colleagues discovered that overcrowded epithelial cells are popped up and out of the tissue alive — extruded — to maintain that tissue balance as new cells grow. That raised a question: How does tissue “choose” which living cells to expel?
In earlier work, Rosenblatt’s team watched as some cells dumped their water and shriveled up like raisins before being extruded; indeed, this shrinkage seemed to kick off the process. But the researchers didn’t know what caused the cells to shrink in the first place. They didn’t work on bioelectricity and were unaware of any effect it might have.
Antonio Tabernero
In further experiments, they were able to prevent the cells from shrinking by blocking a pressure-sensitive ion channel in the cell membrane that opens when squeezed. They decided to see if blocking other ion channels might interfere with extrusion too.
“We got so many hits, we were just like: Jesus, this is crazy,” Rosenblatt recalled. One of those hits was a voltage-gated potassium channel, like those that open up during a neuron’s voltage spike. It struck Rosenblatt as “weird” enough to follow up on. Using special dyes that reveal the voltage across cell membranes, the scientists found that epithelial cells destined for extrusion — and only those cells — lose their membrane potential about five minutes before shrinking and being extruded. The result was clear: Extrusion kicks off with an electrical signal.
Instead of sending neurotransmitters back and forth like neurons, densely packed epithelial cells squeeze each other. As the tissue gets more crowded, the squeezing intensifies. This opens pressure-sensitive ion channels, which allow positive sodium ions to leak across the squashed cells’ membranes and into the cell.
Faced with this challenge, a healthy cell will use its chemical energy to activate pumps to push sodium back out and restore its normal voltage. But stressed or unhealthy cells without energy to spare can’t keep up. Their membrane voltage falters, throwing open those “weird” voltage-sensitive channels. When that happens, water pours out of the cell in a “lightning” flash clearly visible in microscope images, Rosenblatt said. Once a cell loses 17% or more of its volume, it is extruded. Her working hypothesis is that a biochemical cascade set off by the shrinkage contracts motor proteins, which mechanically extrude the cell.
In this way, bioelectrical flow across cell membranes lets tissues test which cells are the least healthy and mark them for extrusion. “They’re always pushing against each other and bullying each other. And what they’re doing is probing each other for which one’s the weakest link,” Rosenblatt said. “It’s a community effect.”
Evolution as Electrician
At the University of California, San Diego, the biophysicist Gürol Süel studies electricity in bacterial biofilms, which are collectives composed of single-celled bacteria that can also survive independently. The signaling that Rosenblatt and her team described in human tissues has several things in common with electrical mechanisms Süel has described in microbes — and which appear again and again across the tree of life.
“It’s a very elegant study, very nice results,” he said of the new research. “And conceptually, it makes sense.”
Suel Lab
Electricity increasingly appears to be one of evolution’s go-to solutions for integrating multiple streams of information. Epithelial tissues use it to keep tabs on crowding. Neurons compile input signals from multiple sources into a spiking output. A Venus flytrap snaps shut when sensory hairs with touch-sensitive ion channels react to prey. These channels are tuned to trigger a voltage spike and tell the trap to close only if stimulated multiple times in rapid succession.
“The membrane potential is so fundamental, and it is very fast,” Süel said. While switching genes on and off or upping protein production could take minutes or hours, a membrane potential can flip in fractions of a second. “It tells you, in one glance almost, about the state of the cell,” he added.
Ten years ago, Süel and his team showed that microbes in biofilms can spike their membrane potentials to communicate, just as neurons do. Since then, they’ve shown that biofilms use electricity to coordinate tasks, prevent runaway growth, and invite free-swimming bacteria to join the collective. Bioelectricity can even help them avoid falling victim to the tragedy of the commons: Two biofilms sharing scarce food can send electrical signals to each other to take turns eating.
Multicellular animals, too, use electrical signaling to organize themselves. Zhang, of Purdue, studies bioelectrical signaling in zebra fish, which develop striking extra-long tails when a certain ion channel is mutated. This suggests that electrical signaling somehow tells tissues in a developing embryo how long to grow. Michael Levin, a researcher at Tufts University, has blocked cell channels to manipulate the membrane potentials of developing worm embryos, causing genetically identical worms to develop different body plans. And last year, Barriga and his colleagues showed that frog embryos generate natural electric fields that guide the migration of specific stem cells to their proper locations in the developing embryo.
The failure of bioelectric processes might be an overlooked cause of disease. Cancerous cells tend to have different membrane potentials than healthy ones, and Levin has argued that some cancers might result from a breakdown in multicellularity that happens when cells can no longer use electricity to coordinate. For example, maybe they can no longer communicate the message “I’m struggling and should be extruded,” and the result is the uncontrolled growth and, ultimately, a tumor.
Süel is convinced that bioelectricity is as old as life itself. Indeed, an electric current drives the molecular turbines that synthesize life’s universal energy currency, ATP, in every cell alive today. One leading origin-of-life scenario places the beginning at deep-sea hydrothermal vents. There, natural currents of positively charged protons could have served as a kind of primordial membrane potential and powered prebiotic chemical reactions. But whether life started with such a spark or not, bioelectricity’s ubiquity suggests it has deep evolutionary roots that we’re just beginning to unearth.
“There are a lot of interesting things that cells are probably doing, just like this paper showed, that we just don’t know yet,” Süel said. “We have not uncovered even half of this. … There’s a lot of opportunity for discovery.”