首次，从零构建的细胞实现生长与分裂
内容总结：
全球首次！人工合成细胞实现自主生长与分裂
在合成生物学领域，科学家首次将非生命物质逐一组装成类似细胞的膜结构，并亲眼目睹这一“分子包裹”开始展现出生命行为。由明尼苏达大学合成生物学家凯特·阿达马拉领导的研究团队成功制造出一种人工合成细胞，它能够生长、复制自身DNA并完成分裂，完整模拟了细胞周期的基本功能。
这一成果被认为是向“从零制造生命”这一终极目标迈出的重大一步。尽管该细胞尚不能完全独立生存，仍需持续供应“食物”和核糖体等蛋白质合成机器，且缺乏防御和废物处理系统，但它首次证明：从非生命物质中创造出具备生命基本特征的体系是可行的。
研究团队从零开始，将所有分子部件在实验室中手工打造，并组装进由脂质膜包裹的空心囊泡中。他们首先构建了DNA复制系统，并整合了36种酶的商业试剂盒，使细胞能够读取DNA并制造蛋白质。经过反复调试基因组合与分子浓度，这些遗传系统最终成功协同工作。
最关键的突破在于细胞分裂。此前，合成生物学界一直难以攻克这一难题。阿达马拉团队放弃了传统的细胞骨架方案，转而采用一种特殊的膜蛋白标记技术，吸引其他蛋白聚集并物理挤压细胞膜，从而迫使细胞分裂。经过多次尝试，该机制成功奏效。
研究还初步展示了细胞的进化潜力：通过人工诱导遗传变异，那些体积更大的细胞产生了更多子代细胞，并在群体中逐渐占据优势，迈出了自然选择的第一步。不过，该细胞目前仍缺少关键的自维持能力，例如无法自主制造核糖体，且分裂过程能耗较高。
阿达马拉将这一成果比作“莱特兄弟的飞行器”——虽然简陋，却是里程碑式的突破。她表示：“现代细胞如同波音787梦幻客机，而我们造出的只是第一架能飞100英尺的自行车框架翅膀。”
与此同时，阿达马拉与其他合成生物学家共同宣布成立非营利组织“Biotic”，向全球研究人员开放其合成生物学工具、数据和方法。未来数十年，这类合成细胞有望用于制造无化石燃料塑料、肥料或药物，也将帮助科学家探索生命起源等根本性问题。正如一位未参与研究的系统化学家所言：“如果你想知道生命是什么，首先得去建造生命。”
中文翻译：
首次实现：从零构建的细胞能够生长分裂
引言
生物学家首次将非生命组分逐一封装进类细胞膜结构，见证这袋分子开始展现生命特征。实验室制造的人造细胞成功实现生长、DNA复制与分裂，完整呈现了细胞周期的基本功能。
“这是令人瞩目的突破，”未参与该研究的芝加哥大学生命起源研究学者杰克·绍斯塔克评价道，“据我所知，还没有其他用生物组分制造人造细胞的尝试能达到如此水平。”
该细胞在任何定义下都不算生命体。它必须持续获取养分和核糖体（蛋白质合成必需的分子机器）才能存活，缺乏防御机制和有效的废物处理系统。但这项成果有力地证明了从非生命物质创造生命是可能的——这正是合成生物学家数十年来追逐的目标。
“这是迈向‘用死物造活物’这一圣杯的巨大进步，”未参与该研究的荷兰斯特拉廷化学研究所系统化学家西布伦·奥托表示，“虽然尚未完全实现，但确实非常接近了。”
由于这些细胞从零开始拼装，所有分子部件均在实验室中制造，科学家可以随意调整系统、替换组件。“我拥有蓝图和完整的化学成分清单，”领导该未同行评审研究的明尼苏达大学合成生物学家凯特·阿达马拉说。凭借这种灵活性，这类合成细胞未来或可被诱导制造新材料（如生物燃料和药物），并助力疾病研究。
它也可能为一些最深层的存在性命题提供线索：维持生命所需的最小要素是什么？生命如何起源？若改变构成现今地球生命的生物学机制，会发生什么？
或如阿达马拉所言：“生物学还能创造什么？”
构建生命
约40亿年前，一群非生命分子聚合形成最初的原细胞。它们摄取营养、生长、分裂，随后演化进程逐渐浮现，使这些细胞分化出万千形态，在荒芜世界点缀出奇异生命。纯粹化学的世界绽放出生物学光芒。科学家对非生命向生命转化（即生命起源）的机制尚未达成共识，但部分研究者已转向在实验室复现这一过程。
数十年来，研究者采用不同路径应对这一挑战。J.克雷格·文特尔研究所的合成生物学家约翰·格拉斯等人正剥离细菌细胞至最小基因组，以揭示细胞存活的最低要求。奥托等人则尝试用不同于地球生物学的分子构建细胞。
阿达马拉同样从零开始，但采用现今自然界存在的生物分子。2016年启动实验室时，她设想组装一个能利用自身基因组完成完整分裂周期的合成细胞作为概念验证。
她以所有已知细胞的共同特征为蓝图：生长、DNA复制、分裂、演化。细胞将DNA转录为RNA，进而制造蛋白质执行维持生命所需的任务（如代谢分子获取能量）。这一切发生在脂质膜内，该膜将必须物质集中于一室。阿达马拉团队需为合成细胞构建基因组，并提供执行上述任务的所有物质。
他们开发并优化了多种成分（多数受其他实验室启发），最终将其组合进脂质体——由简单脂质膜包裹的空心囊泡，作为细胞体。
团队首先攻克细胞最基础的系统：DNA复制及传递给子代的机制。他们采用合成生物学家汉内斯·穆奇勒和克里斯托夫·达内隆首创的DNA复制系统，经调整后与其他系统协同运作，包括一套含36种酶的商业试剂盒，使细胞能读取DNA并制造蛋白质。阿达马拉团队反复调整细胞配方，替换基因并调节分子浓度，最终让承载信息与蛋白质合成的遗传系统协调运转。
他们微小的合成基因组不编码代谢基因（负责处理食物与能量）及细胞所需的大部分复杂分子。因此，研究人员同步制备了补给包。
他们将其他脂质体填充糖类、脂质、酶及转运RNA（tRNA）和核糖体等复杂分子——这些物质协同将遗传指令转化为蛋白质。为让原细胞接纳关键补给，团队还改造了一种嵌在细胞膜中的蛋白，使其能吸引脂质气泡。当气泡与细胞碰撞时，膜会融合，将补给释放进细胞内部。
让所有遗传系统成功协作并非易事。经反复调整优化后，细胞开始生长并复制DNA。
“我几乎要说‘完成了，可以发表了’，”阿达马拉回忆道。但她的合成细胞构想还有最后一步：分裂。
这正是该领域长期停滞的环节。此前研究者已找到多种方法喂养、培养合成细胞并复制其DNA，但细胞分裂是另一回事。典型细胞会重组细胞骨架（提供结构支撑的蛋白纤维网络）以均分DNA并分裂。合成生物学家始终无法让细胞完成这一复杂过程。
阿达马拉决定放弃细胞骨架。某日翻阅文献时，她发现一篇论文中的有趣机制：马克斯·普朗克胶体与界面研究所的合成生物学家莱因哈德·利波夫斯基通过将蛋白标签附着在细胞膜上，吸引其他蛋白聚集并物理挤压膜结构，迫使细胞分裂。阿达马拉借鉴此法，改造了一种细胞膜蛋白并在原细胞中测试。多次尝试后终获成功。
“我一度不敢相信，”她说，“就像‘天哪，我真的造出了会分裂的细胞？’……反复验证多次后，终于确信‘这是真的’。”
未参与该研究的慕尼黑工业大学系统化学家约布·布克霍芬表示，这篇论文“完美演示了分裂机制，是巨大成就。”
通过整合不同实验室的灵感（DNA复制、滋养脂质体、聚集诱导分裂蛋白）并优化其协同性，阿达马拉团队证明了在实验室引导化学世界形成生物世界是可行的。
“整合所有这些系统是惊人的技术成就，”格拉斯说，“这将成为合成细胞领域乃至整个生物学的分水岭。”
未参与研究的亚利桑那州立大学演化生物学家迈克尔·林奇深表赞同，称其为“合成生物学的杰作”。但他也提醒不应过度炒作，毕竟该细胞尚无法自给自足。
合成细胞诞生后，学生和同事们开始称其为“阿达马拉细胞”——这个称呼让她深恶痛绝。她坚持要用其他名字命名，开玩笑建议叫“土豆”。于是学生们开始称它们为“薯细胞”。“我是波兰人，身体几乎由土豆构成，所以这名字挺合适，”阿达马拉笑道。
每个细胞都极其微小，基因组远小于细菌，外观平平无奇。“对我来说它很美，因为我为之狂热，”阿达马拉说，“但若在显微镜下看，就是个‘小团子’。”
演化与未来
细胞能生长分裂，但能否通过演化向生命迈进一步？
研究人员开始篡改合成细胞DNA，试图让部分细胞长得更大或分裂更快——实质上是在细胞群体中创造遗传变异。他们发现长得更大的细胞产生更多子代，数量逐渐占优。换言之，这些特征开始在群体中被选择——这是演化的第一步。
阿达马拉团队展示的并非严格意义上的自然选择（驱动演化的主要机制，即更适应环境的生物更易存活）。即使她让细胞产生更多子代，也不认为会导向演化。因为团队需人工制造遗传变异，而非允许DNA随机突变。负责构建新DNA链的酶“过于完美”，无法在序列中引入有意义突变。他们需要找到更易出错的酶——但不能错到破坏基因组完整性和细胞功能。
“生物学需要足够快的变化，但不能太快，”阿达马拉说。她引用宾夕法尼亚大学荣休教授、生物化学家及复杂性理论家斯图尔特·考夫曼的“混沌边缘”理论，称需在有序与混沌间找到平衡点。
布克霍芬认为，清晰展示演化过程“显然是缺失的环节，也是下一步重大突破”。其他研究者已展示其他类型合成细胞的适应性演化，但那些细胞是剥离到仅剩基础基因的细菌——并非从零构建。
这些细胞还需依赖外部供给原料。绍斯塔克指出，细胞无法像天然细胞那样自主制造核糖体，“限制了其生长和持续繁殖的潜力。若系统能生成自身核糖体及其他蛋白质和RNA，将更接近细菌等现有生物细胞。”
阿达马拉也认为需添加细胞骨架以改进复制系统。目前细胞需消耗大量能量和时间吸引分子聚集辅助分裂。
总而言之，科学家距离制造接近现代活细胞的实体仍路途遥远——但这款新细胞仍是最接近生命的。“现代细胞就像梦想客机（波音787），”阿达马拉比喻道，“我们造出了莱特飞行器……首个能飞100英尺的带翼自行车架。”
除公布新成果外，阿达马拉与其他合成生物学家宣布成立非营利组织Biotic，向全球研究人员开放合成生物学工具。团队公开数据和方法，以便他人改进这些细胞。希望数十年后，这些工作能用于制造无化石燃料的塑料、肥料或药物。
这些合成细胞也可能回溯过去，通向生物学起源本身。地球生命可能起源于比薯细胞所用分子简单得多的物质。尽管如此，阿达马拉用非生命材料创造合成细胞系统，仍将研究者向实验室中探索生命起源与本质的深层问题更推进一步——这也是她与同行共有的梦想。
“若想理解何为生命，”布克霍芬说，“必先亲手构建生命。”
英文来源：
For the First Time, a Cell Built From Scratch Grows and Divides
Introduction
For the very first time, biologists packed nonliving components into a cell-like membrane, piece by piece, and witnessed the bag of molecules start to behave like life. The lab-made synthetic cell grew, replicated its DNA, and divided, demonstrating the basic functions of a cell cycle.
It’s “an impressive step,” said Jack Szostak, who studies the origins of life at the University of Chicago and was not involved in the research. “I don’t know of any other effort to put together an artificial cell from biological components that has progressed so far.”
The cell is not alive by any definition. It can’t survive without constant deliveries of food and ribosomes, the machinery needed to make proteins. It has no defenses or a good waste removal system. But it’s the strongest demonstration yet that it is possible to generate life from nonlife, a goal that synthetic biologists have been chasing for decades.
“It’s a big step forward to this holy grail of making a living thing out of dead components,” said Sijbren Otto, a systems chemist at the Stratingh Institute for Chemistry in the Netherlands who was not involved in the work. “It’s not completely there yet, but it’s definitely getting quite close.”
Since these cells were pieced together from scratch, and all the molecular parts were crafted in the lab, scientists can tinker with the system and switch components in and out. “I have a blueprint, I have a full chemical ingredient list of every component,” said Kate Adamala, a synthetic biologist at the University of Minnesota who led the new study, which is not yet peer-reviewed. With such flexibility, this kind of synthetic cell could eventually be coaxed to create new materials, such as biofuels and drugs, and help researchers study disease.
It could also give scientists insight into some of their deepest existential questions: What is the minimum needed to sustain life? How could life start? What happens if we alter the biology that composes life on Earth today?
Or, as Adamala put it: “What else can biology do?”
Building Life
Some 4 billion years ago, a bunch of nonliving molecules got together to form the first protocells. They fed, grew, and divided. Then, over time, evolutionary processes emerged that let these cells change and diversify into many different types, decorating a barren world with all manner of strange beings. A purely chemical world blossomed into a biological one. Scientists cannot agree on how this shift from nonlife to life, or abiogenesis, happened, but some have turned their sights on trying it out for themselves in the lab.
For decades, researchers have taken different approaches to this challenge. Some, like the synthetic biologist John Glass at the J. Craig Venter Institute, are stripping down bacterial cells to their smallest, barest genomes to reveal a cell’s minimum requirements to stay alive. Others, like Otto, try to build cells with molecules that differ from those found in Earth biology.
Adamala also works from the ground up, but with biological molecules found in nature today. When she started her lab in 2016, she envisioned assembling a synthetic cell, a proof of concept, that could undergo a complete cycle of cell division using its own genome.
She found an instruction manual in what all known cells have in common: They grow, they duplicate their DNA, they divide, and they evolve. They transcribe their DNA into RNA and then make proteins to carry out these tasks and others that keep a cell running, such as metabolizing molecules for energy. All of this is done inside a lipid membrane, which holds all the necessary materials in one place. Adamala’s team needed to build their synthetic cell a genome and supply it with all the materials to carry out those tasks.
They developed and optimized different ingredients, most inspired by other labs, before combining them together inside liposomes — hollow sacs enclosed by a simple lipid membrane. This would serve as the cellular body.
They started with a cell’s most fundamental system: its mechanism for copying its DNA and passing it down to daughter cells. They adopted a DNA replication system, pioneered by the synthetic biologists Hannes Mutschler and Christophe Danelon, and tweaked it to work alongside other systems, including a commercial pack of 36 enzymes that let the cell read DNA and make proteins. Adamala’s team fiddled with their cellular brew, switching genes in and out and adjusting concentrations of various molecules, to get the crucial information-carrying and protein-making genetic systems to jibe.
Their tiny synthetic genome did not encode any metabolic genes, which would let the cell process food and energy, or many of the complex molecules a cell needs. So, in parallel, the researchers prepped some supply packs.
They filled other liposomes with sugar, lipids, and enzymes, as well as complex molecules, such as transfer RNA (tRNA) and ribosomes, which work together to translate genetic instructions into proteins. For their protocell to accept these crucial supplies, the team also modified a protein that would sit in the cell membrane and attract the lipid bubbles. When a bubble bumped into the cell, their membranes would fuse, releasing the supplies inside.
It wasn’t easy to get all these genetic systems to work together successfully. After some more tweaking and optimizing, the cell started growing and replicating its DNA.
“I was almost ready to say ‘Done’ and ‘We’re going to publish it,’” Adamala recalled. But her vision for a synthetic cell had one more step: division.
This was where the field had been stuck for some time. Researchers before Adamala had figured out different ways to feed and grow synthetic cells and to replicate their DNA. But cell division is a different beast. A typical cell reorganizes its cytoskeleton — a network of protein fibers that provide structural support — to halve its DNA and split. Synthetic biologists could not figure out how to get their cells to undergo this complex process.
So Adamala decided to ditch the cytoskeleton. One day, while tearing through the literature, she came across an interesting mechanism in a paper. By attaching protein tags to a cell membrane, the synthetic biologist Reinhard Lipowsky at the Max Planck Institute of Colloids and Interfaces attracted other proteins to crowd around and physically bend the membrane, forcing the cell to divide. Following this approach, Adamala tweaked a cell-membrane protein and tested it in her protocells. After several tries, it worked.
“I wasn’t allowing myself to believe it for a while,” she said. “It was like, ‘Holy shit, did I actually make a dividing cell?’ … At some point, you’ve been checking enough that [you think], ‘OK, now it’s real.’”
This paper “beautifully demonstrates this division mechanism,” said Job Boekhoven, a systems chemist at the Technical University of Munich who was not involved in the study. “That has been a huge achievement.”
By putting together systems inspired by different labs — DNA replication; feeder liposomes; and swarming, division-inducing proteins — and then optimizing them to work together, Adamala’s team showed that it is possible to induce the chemical world to form a biological one in the lab.
“Combining all of these things is a staggering technical accomplishment,” Glass said. “I think it will prove to be a watershed event for the synthetic-cell field and biology in general.”
Michael Lynch, an evolutionary biologist at Arizona State University who was also not involved in the study, agreed. It is “a synthetic biology tour de force,” he said. However, he also cautioned against over-hyping the cell since it’s not yet self-sustaining.
Once the synthetic cells were created, her students and others started calling them Adamala cells — a moniker she hated. She insisted that they name the cells after anything else, jokingly suggesting potatoes. So her students started calling them spudcells. “I’m Polish, I’m mostly made of potatoes, so that’s fine with me,” Adamala said.
Each cell is tiny. Its genome is way smaller than bacterial genomes, and it doesn’t look like anything special. It’s “beautiful to me because I’m super excited about it,” Adamala said. “But if you look at it under the microscope, it’s like, ‘OK, it’s a blob.’”
Evolution and Beyond
The cell could grow and divide. But could it take the next step toward life by evolving?
The researchers started fiddling with the synthetic cell’s DNA to see if they could get some cells to grow larger or divide faster — in effect, creating genetic variation in the cell population. They found that the cells that grew bigger also had more daughter cells and started to become more populous. In other words, those traits started being selected for within the population, the first step toward evolution.
What Adamala’s team demonstrated was not quite natural selection, the primary mechanism that drives evolutionary change, in which organisms that are better adapted to their environment are more likely to survive. Even if she got their cell to produce more daughter cells, she doesn’t think it would lead to evolution. That’s because Adamala’s team had to create genetic variation synthetically, instead of allowing for random mutations in DNA. The enzyme that builds new DNA strands works too well, she said; it doesn’t introduce meaningful mutations into the sequence. They will need to find an enzyme that is more error-prone — but not so error-prone that the genome’s integrity and the cell’s function is lost.
“Biology needs to change fast enough, but not too fast,” Adamala said. She said that she needs to find the sweet spot between order and chaos, referencing the biochemist and complexity theorist Stuart Kauffman, a professor emeritus at the University of Pennsylvania, who argues that biology works best at the “edge of chaos.”
A clear demonstration of an evolutionary process is “clearly something that’s missing,” Boekhoven said. “I’m sure that that’s the next big step.” Other researchers have shown adaptive evolution in other types of synthetic cells. But those cells were bacteria stripped of all but the bare minimum of genes — they weren’t built from the ground up.
The cells are also limited by the fact that they need to be fed many of their raw materials. That the cells can’t make their own ribosomes, the way natural cells do, “limits [their] potential for growth and sustained reproduction,” said Szostak, who was Adamala’s doctoral adviser. “If their system was able to generate its own ribosomes and other proteins and RNAs, it would be much closer to existing biological cells such as bacteria.”
Adamala also thinks they will need to figure out a way to add a cytoskeleton to improve their replication system. Currently, the cells waste a lot of energy and time attracting molecules to crowd around and help them divide.
All told, scientists are far from building anything remotely close to a modern living cell — but this new one is still the most lifelike yet. “The modern cell is like a Dreamliner,” Adamala said, referring to the Boeing 787 airplane. “We built a Wright flyer… the first bike frame with wings that flies 100 feet.”
Alongside sharing the new results, Adamala and other synthetic biologists announced the formation of a nonprofit called Biotic, which they will use to make their synthetic biology tools available to researchers around the world. The team is releasing their data and methods so that synthetic biologists can start building and improving on their cell. The hope is that the work can be used, decades from now, to create plastics without fossil fuels, for example, or fertilizers or drugs.
These synthetic cells could also pave the way to the past, to the origins of biology itself. Life on Earth would have started from much simpler molecules than the ones that spudcells use. Still, Adamala’s creation of a synthetic cell system from non-living materials brings researchers a step closer to exploring, in the lab, deeper questions about life’s origins and requirements, a dream she shares with others.
“If you want to understand what life is,” Boekhoven said, “you need to first build life.”