内容来源：https://www.quantamagazine.org/a-cell-so-minimal-that-it-challenges-definitions-of-life-20251124/

内容总结：

日本科学家团队今年在太平洋海域发现一种全新古菌，其基因组仅含23.8万个碱基对，创下已知古菌基因组最小纪录。这种被命名为"须久那古菌"的微生物缺失了包括新陈代谢在内的绝大多数生命活动必需基因，仅保留自我复制所需的核心遗传组件，其生存完全依赖宿主细胞供给营养。

研究负责人、筑波大学微生物学家中山卓郎表示，这一发现颠覆了"代谢功能是生命定义核心要素"的传统认知。尽管须久那古菌与病毒同样依赖宿主，但其保留简化核糖体等自主复制能力，与病毒存在本质区别。该微生物可能代表着一类广泛存在的寄生微生物群落，相关研究表明海洋中约25%-50%的细菌可能属于此类寄生生物。

目前科学家尚未直接观测到该微生物的实体形态，其真实宿主及膜蛋白功能仍是未解之谜。该研究提示现有基因测序方法可能因过度筛选而遗漏此类极端简化微生物，预示着微生物多样性认知存在巨大空白。这项发表于生物预印本平台的研究成果，正推动科学界重新思考生命定义的边界。

中文翻译：

一个精简到挑战生命定义的细胞

引言
细胞是生命的基本结构单元，因此细胞的主要活动——处理生物分子、生长、复制遗传物质并产生新个体——被视为生命的标志。但今年早些时候，科学家发现了一种细胞，其基本功能被大幅削减，以至于对生物学家关于何为生物的定义提出了挑战。

该物种是一种单细胞生物，目前仅知其神秘的基因序列。它的基因组小得惊人：在其进化历程中，似乎已丢弃了大部分基因。根据今年五月在预印本网站biorxiv.org上发表该发现的震惊的研究人员称，丢失的基因包括那些对细胞代谢至关重要的基因，这意味着它既不能自行处理营养物质，也无法独立生长。

其他基因组高度简化的细胞仍能编码蛋白质以制造氨基酸、分解碳水化合物获取能量或合成维生素。而这一切似乎都在这细胞中缺失了，它似乎是一种完全依赖宿主或细胞群落来满足其营养需求的寄生生物。迄今为止，这些遗传途径一直被认为是任何细胞生存的基础。

该生物的"复制核心"——自我繁殖所需的遗传组件——依然存在，并构成了其基因组的一半以上。

"代谢通常是我们定义生命的关键要素之一，"日本筑波大学的进化微生物学家、团队负责人中山拓朗说。这种细胞的发现"对此提出了挑战，它表明一个细胞几乎可以在完全没有自身代谢的情况下存在。这证明了细胞生命的多样性远超我们的认知，生物体并不总是遵循我们的定义。"

虽然这种生命形式对科学界来说是新的，但类似它的生物体可能很常见。巴黎法国国家科学研究中心（未参与此项研究）的微生物生态学家普里·洛佩兹-加西亚说，很大一部分微生物生物多样性可能隐藏在寄生微生物与宿主微生物之间错综复杂的相互关系之中。

"看起来属于这些寄生生物超群的古菌和细菌的多样性非常非常巨大，"她说。她推测，对于细菌而言，这类物种可能占其总物种数的25%到50%。

这一发现拓展了我们对细胞生命究竟能变得多小、多简单的认知边界，因为它甚至进化成了几乎算不上活物的形态。

非凡的发现
中山的科学生涯建立在他比通常研究者更为细致的观察之上。他审视一个已经极小的细胞，并思考：是否存在更小的细胞在其中安家落户？

"（寄生细胞与宿主细胞之间的大小）差异有时就像人类与哥斯拉之间的差异，"中山说。他对这些关系中可能蕴含的、数量庞大的未知生物多样性着迷不已，他的实验室就在海水中寻找此类关系。海洋是一个营养贫乏的环境，促使细胞形成交易伙伴关系。有时它们松散地系在一起，随波逐流，交换稀有营养和能量。其他时候，它们的组合则更为有序。

Citharistes regius 是一种全球广泛分布的单细胞甲藻，它有一个带壁的、囊状的外部腔室，用于容纳共生蓝细菌。中山和他的团队通过使用细网从太平洋舀取海水样本，来搜寻这种藻类。一种常见的技术是对此类样本"汤"中能找到的所有DNA进行测序，这种方法被称为宏基因组学。

"这种方法在获取广泛概览方面极其强大，"中山说。"然而，利用这类数据，通常很难维持序列与其来源特定细胞之间的联系，稀有生物体很容易被遗漏。"他的团队采用更具针对性的方法，包括从混合样本中通过显微镜识别并物理分离出单个目标细胞。

回到筑波实验室后，研究人员确认他们获得了C. regius，并对与该单个细胞相关的所有基因组进行了测序。正如预期，他们发现了来自其共生蓝细菌的DNA，但他们还发现了别的东西：属于一种古菌的序列，古菌是生命的一个域，被认为是包括我们在内的真核生物的祖先。

起初，中山和他的同事们认为他们搞错了。这个古菌的基因组极小：头尾相连仅23.8万个碱基对。相比之下，人类有数十亿碱基对，即使大肠杆菌也有几百万。（C. regius的共生蓝细菌有190万个碱基对。）此前，已知最小的古菌基因组是属于Nanoarchaeum equitans的——49万个碱基对，比研究人员发现的新基因组长了一倍多。他们最初认为这个微小基因组——因其过大而不太可能仅仅是统计噪音——是一个更大基因组的片段，被他们的软件错误地组装了。

"起初，我们怀疑这可能是基因组组装过程产生的假象，"中山回忆道。为了验证，团队使用不同技术对该基因组进行了测序，并将数据输入多个能将DNA序列片段组装成完整基因组的计算机程序。各种方法都重建出了完全相同的23.8万碱基对的环状基因组。"这种一致性让我们确信它是真实、完整的基因组，"他说。

这意味着中山和他的团队发现了一种新的生物体。他们根据其异常微小的基因组，将这种微生物命名为Candidatus Sukunaarchaeum mirabile（以下简称Sukunaarchaeum）——"Sukuna"源自日本神道教中以其矮小身材著称的神祇"少彦名神"（Sukuna-biko-na），"archaeum"指古菌，而"mirabile"在拉丁语中意为"非凡的"。

准生命的谱系
当研究团队查阅已知基因数据库来分析这种古菌时，他们发现其微小尺寸是大量基因缺失的结果。

Sukunaarchaeum仅编码自身复制所需的最基本蛋白质，仅此而已。最奇怪的是，除了繁殖所需的基因外，其基因组中没有任何迹象表明存在处理和构建分子所需的基因。由于缺乏这些代谢组件，该生物体必须将生长和维持的过程外包给另一个细胞，即该微生物完全依赖的宿主。

其他共生微生物也丢弃了大部分基因组，包括Sukunaarchaeum的进化亲属。研究人员的分析表明，这种微生物属于DPANN古菌（有时被称为纳米古菌或超小古菌），其特点是体积小、基因组小。DPANN古菌通常被认为是依附在较大原核微生物外部的共生体，其中许多为了适应这种生活方式，基因组已大幅缩减。但直到现在，还没有哪种DPANN物种的基因组缩减到如此程度。而且Sukunaarchaeum在DPANN谱系中很早就分支出来，表明它走过了自己独特的进化历程。

"古菌这个领域总体上相当神秘，"德克萨斯大学奥斯汀分校（未参与此项工作）的微生物生态学家布雷特·贝克说。"[DPANN古菌]在代谢能力上显然有限。"

虽然Sukunaarchaeum可能为其宿主（可能是C. regius、共生蓝细菌，或完全是另一个细胞）提供某些未确定的好处，但它很可能是一种自私的寄生生物。"其基因组的缩减完全由自私动机驱动，这与寄生生活方式相符，"悉尼科技大学（未参与此项研究）的微生物学家蒂姆·威廉姆斯说。它无法提供代谢产物，因此Sukunaarchaeum与任何其他细胞的关系很可能是一条单行道。

其他微生物也进化出了类似的极端、精简形态。例如，生活在吸食树液昆虫肠道内的共生细菌Carsonella ruddii，其基因组比Sukunaarchaeum更小，约为15.9万个碱基对。然而，这些以及其他超小型细菌拥有代谢基因，可以为宿主生产营养物质，如氨基酸和维生素。相反，它们的基因组则抛弃了大部分独立繁殖的能力。

"它们正在变成细胞器的路上。线粒体和叶绿体被认为就是这样进化来的，"威廉姆斯说。"但Sukunaarchaeum走向了相反的方向：其基因组保留了自身增殖所需的基因，但丢失了大部分（即使不是全部）代谢基因。"

中山团队将结果在线发布后不久，就收到了大量反响。"当我们看到预印本时，实验室里真的非常兴奋，"荷兰瓦赫宁根大学与研究中心的进化微生物学家、古菌基因组学专家蒂斯·埃特马（未参与此项工作）说。"（基因组缩减的）这类生物以前也发现过，但没有这么极端。"

一些新闻报道甚至暗示Sukunaarchaeum正在进化成病毒。然而，尽管Sukunaarchaeum和病毒都依赖宿主细胞执行非常基本的生物学功能，但病毒无法自行繁殖。

"Sukunaarchaeum和病毒之间存在根本性的差距，"中山说。"Sukunaarchaeum保留了自身的基因表达核心机制，包括核糖体，尽管是简化形式。这与病毒形成鲜明对比，病毒缺乏核糖体，必须劫持宿主的细胞系统进行复制。"

埃特马说，这些发现融入了关于如何定义生命的更广泛讨论，因为自然界不断演化出挑战简单分类的例外。"它很可能无法独立生存，"他说。"对细菌共生体你也可以这么说。那我们又该如何称呼像线粒体和质体这样的细胞器呢？……到什么程度我们才该称某物为'活'的？"

极简主义生活方式
关于Sukunaarchaeum的许多问题仍未解决。首先，其基因组的大部分由与任何已知序列都不匹配的基因组成。它们似乎编码大型蛋白质，这在如此彻底简化的生物体中并不常见。

中山和他的同事们认为这些大型蛋白质被用于细胞膜上，并以某种方式支持古菌与其宿主之间的相互作用。埃特马说，这也符合其他已研究的DPANN古菌的生活方式，它们通常被认为是外共生体，附着在相对巨大的宿主外部。

虽然Sukunaarchaeum是与甲藻C. regius一起被发现的，但其真正宿主的身份尚不清楚。C. regius是一种真核生物，但DPANN古菌通常与其他古菌相关联。同样存在争议的是：它是像其他DPANN古菌一样附着在宿主细胞外部，还是生活在内部——或者两者兼有？要回答这些问题，需要首次用人类的眼睛亲眼看到这种古菌；目前，仅从一串奇特的遗传数据中知道它的存在。

洛佩兹-加西亚说，也存在一种微小的可能性，即这些基因毕竟还是"丢失的"代谢基因，如果它们进化得离原始序列太远而无法识别的话。"因为该基因组进化速度非常快，也许其中一些功能对应于代谢功能，但（与数据库中的基因）差异太大，我们无法识别出同源物，"她说。

埃特马说，可能还存在更奇特的极简生活方式或更精简的基因组，但研究人员可能会错过它们。他说，调查微生物样本基因组的传统分析方法可能会将其微小基因组标记为不完整或低质量而丢弃，或者完全跳过它们。"（DNA）可能存在于样本中，但在测序后被移除，因此被忽略了。"

当中山和他的同事搜索一个来自世界各大洋的海洋环境序列数据库，以查看这种新微生物是否在其他地方出现时，他们没有找到任何匹配项。但他们确实检测到许多非常相似的序列，很可能来自其近亲。Sukunaarchaeum可能只是一个巨大微生物冰山的尖顶，这个冰山漂浮在微生物多样性的广阔海洋中：微小的微生物依附在稍大一点的微生物上，也许还在其他微生物内部，它们古老关系的故事才刚刚开始被揭示。

英文来源：

A Cell So Minimal That It Challenges Definitions of Life
Introduction
Life’s fundamental structure is the cell, and so the main things that a cell does — processing biomolecules, growing, replicating its genetic material and producing a new body — are considered hallmarks of life. But earlier this year, scientists discovered a cell so severely stripped of essential functions that it challenges biologists’ definitions of what counts as a living thing.
The species is a single-celled organism known only by the mysterious sequence of its genetic code. Its genome is fantastically small: Along the organism’s evolutionary journey, it seems to have gotten rid of most of it. According to the shocked researchers who published the discovery in a preprint uploaded to biorxiv.org in May, the lost genes include those central to cell metabolism, meaning it can neither process nutrients nor grow on its own.
Other cells with highly reduced genomes still encode proteins to create amino acids, break down carbohydrates for energy or synthesize vitamins. All this appears to be absent from the cell, which seems to be a parasite entirely dependent on a host or cellular community to meet its nutritional needs. Until now, these genetic pathways were considered fundamental for the survival of any cell.
The organism’s “replicative core” — the genetic components needed to reproduce itself — remains, making up more than half of its genome.
“Metabolism is one of the key components of how we often define life,” said Takuro Nakayama, an evolutionary microbiologist at the University of Tsukuba in Japan who led the team. The cell’s discovery “challenges this by suggesting a cell can exist almost entirely without its own. It demonstrates that the diversity of cellular life is far greater than we knew and that organisms do not always follow our definitions.”
While this form of life is new to science, it’s possible that organisms like it are common. A huge proportion of microbial biodiversity may be hiding in recursive interrelationships between parasitic and host microbes, said Puri López-García, a microbial ecologist at the French National Center for Scientific Research in Paris who was not involved in the study.
“The diversity of archaea and bacteria that appear to belong to these supergroups of parasitic organisms is very, very large,” she said. For bacteria, it may be between 25% and 50% of the group’s total share of species, she suggested.
The discovery pushes the boundaries of our knowledge of just how small and simple cellular life can become, as it evolves even into forms that are barely alive.
An Extraordinary Discovery
Nakayama has built a scientific career out of looking more closely than other researchers typically do. He considers an already tiny cell and wonders: Are there even smaller cells that make a home there?
“The difference [in size between parasitic and host cells] can sometimes be like that between a human and Godzilla,” Nakayama said. He is fascinated by the potentially vast amount of undiscovered biodiversity these relationships might contain, and his lab looks for such relationships in seawater. The ocean is a nutrient-poor environment that incentivizes cells to form trading partnerships. Sometimes they float along together, loosely tethered, exchanging rare nutrients and energy. Other times their arrangements are more organized.
Citharistes regius is a globally widespread single-celled dinoflagellate that has a walled, pouchlike external chamber for housing symbiotic cyanobacteria. Nakayama and his team searched for the alga by scooping seawater samples from the Pacific Ocean using a fine-mesh net. A common technique is to sequence whatever DNA can be found in the soup of such a sample, an approach called metagenomics.
“That method is incredibly powerful for capturing a broad overview,” Nakayama said. “However, with such data, it is often difficult to maintain the link between a sequence and the specific cell it came from, and rare organisms can be easily missed.” His team’s more targeted approach involves microscopically identifying and physically isolating a single target cell from that mixed sample.
Back on shore in the Tsukuba lab, after the researchers confirmed they had C. regius, they sequenced every genome associated with that one cell. As expected, they found DNA from its symbiotic cyanobacteria, but they found something else, too: sequences that belong to an archaeon, a member of the domain of life thought to have given rise to eukaryotes like us.
At first, Nakayama and his colleagues thought they had made a mistake. The archaeal genome is tiny: just 238,000 base pairs end to end. In comparison, humans have a few billion base pairs, and even E. coli bacteria work with several million. (C. regius’ symbiotic cyanobacteria have 1.9 million base pairs.) Previously, the smallest known archaeal genome was the one belonging to Nanoarchaeum equitans — at 490,000 base pairs, it is more than twice as long as the new one the researchers found. They initially figured that this tiny genome — too large to be merely statistical noise — was an abbreviated piece of a much larger genome, erroneously compiled by their software.
“At first, we suspected it might be an artifact of the genome-assembly process,” Nakayama recalled. To check, the team sequenced the genome using different technologies and ran the data through multiple computer programs that assemble fragments of DNA sequences into a full genome. The various approaches all reconstructed the exact same 238,000-base-pair circular genome. “This consistency is what convinced us it was the real, complete genome,” he said.
This meant that Nakayama and his team had a new organism on their hands. They named the microbe Candidatus Sukunaarchaeum mirabile (hereafter referred to as Sukunaarchaeum) for its remarkably tiny genome — after Sukuna-biko-na, a Shinto deity notable for his short stature, plus a Latin word for “extraordinary.”
The Spectrum of Quasi-Life
When the team consulted databases of known genes to analyze the archaeon, they found its small size was the result of a whole lot that was missing.
Sukunaarchaeum encodes the barest minimum of proteins for its own replication, and that’s about all. Most strangely, its genome is missing any hints of the genes required to process and build molecules, outside of those needed to reproduce. Lacking those metabolic components, the organism must outsource the processes for growth and maintenance to another cell, a host upon which the microbe is entirely dependent.
Other symbiotic microbes have scrapped much of their genomes, including Sukunaarchaeum’s evolutionary relatives. The researchers’ analysis suggested that the microbe is part of the DPANN archaea, sometimes called nanoarchaea or ultra-small archaea, which are characterized by small size and small genomes. DPANN archaea are generally thought to be symbiotes that cling to the outside of larger prokaryotic microbes, and plenty of them have substantially reduced genomes to match that lifestyle. But until now, none of the DPANN species had genomes quite this pared back. And Sukunaarchaeum branched off the DPANN lineage early, suggesting that it had taken its own evolutionary journey.
“This realm of the archaea is pretty mysterious in general,” said Brett Baker, a microbial ecologist at the University of Texas, Austin who was not involved in the work. “[DPANN archaea are] obviously limited in their metabolic capabilities.”
While Sukunaarchaeum may provide some undetermined benefit for its host — which could be C. regius, the symbiotic cyanobacteria or another cell entirely — it’s probably a self-absorbed parasite. “Its genome reduction is driven by entirely selfish motives, consistent with a parasitic lifestyle,” said Tim Williams, a microbiologist at the University of Technology Sydney who was not involved in the study. It cannot contribute metabolic products, so the relationship between Sukunaarchaeum and any other cell would likely be a one-way street.
Other microbes have evolved similarly extreme, streamlined forms. For instance, the bacterium Carsonella ruddii, which lives as a symbiont within the guts of sap-feeding insects, has an even smaller genome than Sukunaarchaeum, at around 159,000 base pairs. However, these and other super-small bacteria have metabolic genes to produce nutrients, such as amino acids and vitamins, for their hosts. Instead, their genome has cast off much of their ability to reproduce on their own.
“They are on the way to becoming organelles. This is the way mitochondria and chloroplasts are thought to have evolved,” Williams said. “But Sukunaarchaeum has gone in the opposite direction: The genome retains genes required for its own propagation, but lost most, if not all, of its metabolic genes.”
Soon after Nakayama’s team posted their results online, they got a big response. “When we saw the preprint, this was really quite exciting in the lab,” said Thijs Ettema, an evolutionary microbiologist and expert on archaeal genomics at Wageningen University & Research in the Netherlands, who was not involved in the work. “These types of organisms [with reduced genomes] have been found before, but not as extreme as this.”
Some news reports went so far as to imply that Sukunaarchaeum is on its way to evolving into a virus. However, while both Sukunaarchaeum and viruses are reliant on a host cell for very basic biological functions, viruses can’t reproduce on their own.
“There is a fundamental gap between Sukunaarchaeum and viruses,” Nakayama said. “Sukunaarchaeum retains its own core machinery for gene expression, including ribosomes, albeit in a simplified form. This is in stark contrast to viruses, which lack ribosomes and must hijack the host’s cellular systems to replicate.”
The findings fit into a larger discussion about how we define life, Ettema said, since nature routinely evolves exceptions that defy simple categorization. “Most likely it cannot live independently,” he said. “You could say the same of bacterial symbionts. And what do we call organelles like mitochondria and plastids? … At what point should we call things alive?”
A Minimalist Lifestyle
Many questions about Sukunaarchaeum remain unresolved. For one, a large portion of its genome is made up of genes that don’t match any known sequences. They seem to encode large proteins, which is uncommon in such radically reduced organisms.
Nakayama and his colleagues think these large proteins are employed on the cell membrane and somehow support interactions between the archaeon and its host. That would fit with the lifestyles of other studied DPANN archaea as well, Ettema said, which are generally thought to be ectosymbionts, adhering to the outside of comparatively immense hosts.
Although Sukunaarchaeum was found in association with the dinoflagellate C. regius, its true host’s identity is unknown. C. regius is a eukaryote, but DPANN archaea generally associate with other archaea. Also up for debate: Is it attaching to the outside of a host cell, like other DPANN archaea, or is it living internally — or both? Answering these questions would require setting human eyes on the archaeon for the first time; at this point it’s only known from a curious string of genetic data.
There is also a slim possibility that these genes are the “lost” metabolic genes after all, López-García said, if they have evolved so far from their original sequences as to be unrecognizable. “Because the genome is so fast-evolving, maybe some of these functions correspond to metabolic functions, but the divergence is so much that we cannot identify the [gene] homologue [in the database],” she said.
Even stranger minimalist lifestyles or more reduced genomes may be out there, but researchers may miss them, Ettema said. Traditional analytical approaches for surveying the genomes of microbial samples could flag their tiny genomes as incomplete or low quality and discard them, or skip them entirely, he said. “[The DNA] might have been present in the samples, but it was removed after sequencing, and hence overlooked.”
When Nakayama and his colleagues searched a database of marine environmental sequence data from the world’s oceans to see if the new microbe popped up anywhere else, they didn’t find any matches. But they did detect many very similar sequences from what are likely to be close relatives. Sukunaarchaeum may be the tip of a very large microbial iceberg, one floating in a vast ocean of microbial diversity: tiny microbes clinging to slightly less tiny microbes, perhaps inside other microbes, the stories of their ancient relationships only beginning to be revealed.