The Ancient Weapons Active in Your Immune System Today

Battles between bacteria and viruses wrote the rules of engagement between host and pathogen — rules our more advanced immune system continue to follow despite billions of years of evolutionary distance.

细菌和病毒之间的战斗书写了宿主和病原体之间的接触规则——尽管进化距离有数十亿年，我们更先进的免疫系统仍然继续遵循这些规则。

E volutionary arms races — where one species is pitted against another, driving the evolution of new or more sophisticated weapons as each tries to gain the upper hand — are ubiquitous in nature.

进化军备竞赛——一个物种与另一个物种竞争，在每个物种都试​​图占据上风的同时推动新的或更先进的武器的进化——在自然界中无处不在。

One of the oldest and fiercest battles has been waged for billions of years between bacteria and the viruses that infect them.

细菌和感染它们的病毒之间最古老、最激烈的战斗之一已经进行了数十亿年。

This escalating warfare has selected for bacteriophage viruses (or “phages”) that devise new ways to invade bacterial cells and, in turn, for bacteria that devise new ways to fend phages off.

这场不断升级的战争选择了设计出新方法入侵细菌细胞的噬菌体病毒（或“噬菌体”），反过来又选择了设计出新方法来抵御噬菌体的细菌。

In their attempts to outmaneuver one another, each species will try anything to stay one step ahead.

在试图战胜彼此的过程中，每个物种都会尝试一切以保持领先。

In recent years researchers have come upon a surprising finding: Some of the machinery that bacteria use to defend against phages exists, almost unchanged, in our own cells.

近年来，研究人员有了一个令人惊讶的发现：细菌用来防御噬菌体的一些机制存在于我们自己的细胞中，几乎没有变化。

According to dozens of discoveries made over the past decade, the rules of engagement between cells and viruses were written billions of years ago and still largely define how our innate immune system, the first responder to infection, defends us against viruses and bacteria today.

根据过去十年的数十项发现，细胞和病毒之间的相互作用规则是在数十亿年前制定的，并且仍然在很大程度上定义了我们的先天免疫系统（对感染的第一反应者）如何保护我们免受病毒和细菌的侵害。

Your immune system fights off today’s viruses with machinery that is billions of years old.

您的免疫系统利用数十亿年前的机制来对抗当今的病毒。

“Seeing that the rules of host-virus interactions are unchanged over billions of years is a really hard thing to digest,” said Philip Kranzusch , a microbiologist at Harvard Medical School who was one of the first researchers to discover that a key component of human immunity also exists in bacteria.

哈佛医学院微生物学家菲利普·克兰祖什 (Philip Kranzusch) 说：“看到宿主与病毒相互作用的规则在数十亿年里没有改变，真是一件很难消化的事情。”他是最早发现人类免疫的关键组成部分也存在于细菌中的研究人员之一。

The pace of evolution for viruses is “insanely high,” he said, compared to that of long-lived, multicellular eukaryotes like ourselves.

他说，与像我们这样的长寿多细胞真核生物相比，病毒的进化速度“快得惊人”。

Indeed, to keep up with the rapid pace of microbial evolution, animals have evolved targeted defenses such as antibodies that adapt to novel viruses as they invade.

事实上，为了跟上微生物进化的快速步伐，动物已经进化出了有针对性的防御能力，例如在新病毒入侵时适应它们的抗体。

And yet, strangely enough, our frontline immune defenses seem to share many antiviral tools with bacteria.

然而，奇怪的是，我们的前线免疫防御似乎与细菌共享许多抗病毒工具。

“Why would the rules be so fixed?” Kranzusch said.

“为什么规则要这么固定？”克兰祖什说道。

Two recent waves of discovery broke this field open.

最近的两波发现打破了这一领域。

First, in 2018, researchers reported a variety of novel bacterial defense systems against viruses , which now number in the hundreds.

首先，2018 年，研究人员报告了多种针对病毒的新型细菌防御系统，目前数量已达数百种。

The second wave, starting around 2019 , showed that some of these bacterial mechanisms exist in plant and animal cells, including our own — and that they still work the same way they did in those distant ancestors.

第二波研究始于 2019 年左右，研究表明其中一些细菌机制存在于植物和动物细胞中，包括我们自己的细胞中，而且它们的工作方式仍然与那些遥远的祖先中相同。

Philip Kranzusch, a microbiologist at Harvard Medical School, was one of the first researchers to discover that a key component of human immunity also exists in bacteria.

哈佛医学院微生物学家菲利普·克兰祖什 (Philip Kranzusch) 是最早发现细菌中也存在人类免疫力的关键成分的研究人员之一。

Courtesy of Philip J.

由菲利普·J. 提供

Kranzusch

克兰祖什

“Those two things combining together is what really made the field explode: There’s lots of new phage defense systems, and, hey, those systems are directly related and relevant and mechanistically going to tell us information about human immunity,” said Kranzusch, who will receive the National Academy of Sciences Award in Molecular Biology for his research in the field at their 163rd annual meeting on April 26, 2026.

Kranzusch 说：“这两件事结合在一起才是真正让这个领域爆炸的原因：有很多新的噬菌体防御系统，而且，嘿，这些系统是直接相关的，它们会机械地告诉我们有关人类免疫的信息。”他将在 2026 年 4 月 26 日举行的第 163 届年会上因其在该领域的研究而获得美国国家科学院分子生物学奖。

These and other discoveries that followed reveal an unexplored landscape of human innate immunity — one that could lead to new medical treatments and biotechnological tools, much as the discovery of the bacterial immune system CRISPR-Cas made genome editing possible.

随后的这些发现和其他发现揭示了人类先天免疫的未开发景观——这可能会带来新的医学治疗和生物技术工具，就像细菌免疫系统 CRISPR-Cas 的发现使基因组编辑成为可能一样。

“There’s a lot to do, and it’s really important to do it,” Kranzusch said, “which is why so many labs have jumped in on it.”

“有很多事情要做，而且做到这一点非常重要，”克兰祖什说，“这就是为什么这么多实验室都参与其中的原因。”

Until the last decade, biologists knew of only two ways that bacteria defend against viruses.

直到过去十年，生物学家只知道细菌防御病毒的两种方法。

In the 1950s, they discovered restriction-modification enzymes, which are bacterial proteins that cut DNA from invading viruses at specific sequences.

20 世纪 50 年代，他们发现了限制性修饰酶，这是一种细菌蛋白，可以按特定序列切割入侵病毒的 DNA。

These enzymes eventually became laboratory workhorses that enabled the revolution in genetic engineering.

这些酶最终成为实验室的主力，推动了基因工程的革命。

Then, in the early 2000s, researchers described CRISPR systems , which also recognize and cut specific DNA sequences and are now widely used for genome editing.

然后，在 2000 年代初，研究人员描述了 CRISPR 系统，该系统还可以识别和切割特定的 DNA 序列，现在广泛用于基因组编辑。

There was this big landscape of new types of defense systems that no one knew about .

没有人知道这种新型防御系统的广阔前景。

.

。

.

。

hiding under our noses in this big vat of data.

隐藏在我们眼皮底下的这个大数据桶中。

Around the time CRISPR was being discovered, Rotem Sorek , a microbial immunologist, was working on bacterial genomics as a postdoc at Lawrence Berkeley National Lab.

在 CRISPR 被发现的时候，微生物免疫学家 Rotem Sorek 正在劳伦斯伯克利国家实验室担任博士后研究细菌基因组学。

“I immediately thought that that’s one of the most interesting things in biology I ever bumped into,” he recalled.

“我立即想到这是我遇到过的生物学中最有趣的事情之一，”他回忆道。

However, it also became clear to him that most bacteria don’t have CRISPR.

然而，他也清楚大多数细菌没有 CRISPR。

In that case, he wondered, how do they fight phages?

在这种情况下，他想知道它们如何对抗噬菌体？

Because both restriction modification enzymes and CRISPR had led to important biotechnological tools, “I thought that if we discovered more immune mechanisms, it might be useful,” Sorek said.

因为限制性修饰酶和 CRISPR 都催生了重要的生物技术工具，“我认为如果我们发现更多的免疫机制，它可能会有用，”Sorek 说。

“That was the source of the motivation.”

“这就是动力的来源。”

A few years later, after he established his own lab at the Weizmann Institute of Science in Israel, Sorek and his team observed that big constellations of immune genes, including restriction-modification enzymes and CRISPR arrays, tended to cluster together in the same region of bacterial genomes.

几年后，Sorek 在以色列魏茨曼科学研究所建立了自己的实验室后，他和他的团队观察到，包括限制性修饰酶和 CRISPR 阵列在内的大量免疫基因倾向于聚集在细菌基因组的同一区域。

He and other labs observed that genes of unknown function within these “ defense islands ” or “ genomic islands ” could potentially represent novel anti-phage mechanisms.

他和其他实验室观察到，这些“防御岛”或“基因组岛”内功能未知的基因可能代表新的抗噬菌体机制。

Rotem Sorek, a microbial immunologist at the Weizmann Institute of Science, spearheaded an approach that investigates bacterial immune systems to predict unknown mechanisms in humans and other eukaryotes.

魏茨曼科学研究所的微生物免疫学家 Rotem Sorek 率先提出了一种研究细菌免疫系统以预测人类和其他真核生物未知机制的方法。

To find out, Sorek’s team developed a computational pipeline to discover more defense islands.

为了找到答案，索雷克的团队开发了一个计算管道来发现更多的防御岛。

Then he experimentally pitted each predicted defense system against a variety of phages, setting up bacteria-versus-phage duels in petri dishes.

然后，他通过实验将每个预测的防御系统与各种噬菌体进行比较，在培养皿中进行细菌与噬菌体的决斗。

In 2018, his team showed that many of the unknown genes in these defense islands did, in fact, function as a variety of anti-phage defense systems .

2018年，他的团队表明，这些防御岛中的许多未知基因实际上确实起到了各种抗噬菌体防御系统的作用。

Through this approach of computational prediction followed by experimental screening, several research teams discovered hundreds of new systems of innate immunity: a veritable “explosion of phage defense,” Kranzusch said.

克兰祖什说，通过这种计算预测和实验筛选的方法，几个研究小组发现了数百个新的先天免疫系统：名副其实的“噬菌体防御的爆炸”。

(Just this month, in April 2026, two research teams used machine learning to identify hundreds of thousands of candidate anti-phage defense systems, and they have already validated dozens of them.)

（就在本月，即 2026 年 4 月，两个研究团队利用机器学习识别了数十万个候选抗噬菌体防御系统，并且他们已经验证了其中数十个。）

“It was so exciting because it suggested that there was just this big landscape of new types of defense systems that no one knew about,” said Alex Gao , a computational biologist at Stanford University who has experimentally verified anti-phage activity in 29 out of thousands of predicted bacterial defenses .

“这太令人兴奋了，因为它表明存在着无人知晓的新型防御系统的大格局，”斯坦福大学计算生物学家亚历克斯·高（Alex Gau）说，他已经通过实验验证了数千种预测细菌防御中的 29 种具有抗噬菌体活性。

“It was hiding under our noses in this big vat of data.”

“它就藏在我们眼皮子底下的这个大数据桶里。”

Soon, the discovery of a critical pathway in human innate immunity would collide with this explosion of phage defense mechanisms, revealing a vast, unexplored territory in plant and animal immunity.

很快，人类先天免疫中一条关键途径的发现将与噬菌体防御机制的爆发相碰撞，揭示动植物免疫中广阔的、未经探索的领域。

How can a cell tell that it has been invaded by a virus?

细胞如何知道它已被病毒入侵？

One sign is the presence of DNA where it doesn’t belong in the cytoplasm — a sign of infection or severe stress.

一个迹象是 DNA 出现在不属于细胞质的地方——这是感染或严重压力的迹象。

In 2013, the biochemist Zhijian “James” Chen and his team at the University of Texas Southwestern Medical Center discovered how human cells generate an innate immune response when they detect this kind of misplaced DNA.

2013年，德克萨斯大学西南医学中心的生物化学家陈志坚和他的团队发现，人体细胞在检测到这种错位的DNA时如何产生先天免疫反应。

When the enzyme cGAS senses DNA in the cytoplasm, it produces a secondary molecule called cyclic GMP-AMP (cGAMP).

当 cGAS 酶感知细胞质中的 DNA 时，它会产生一种称为环 GMP-AMP (cGAMP) 的二级分子。

Then cGAMP activates the STING protein, which sets off a signaling cascade that ultimately turns on immune genes.

然后，cGAMP 激活 STING 蛋白，引发信号级联反应，最终启动免疫基因。

These immune genes kick off an inflammatory response — the first line of defense against an invader.

这些免疫基因会引发炎症反应，这是抵御入侵者的第一道防线。

The STING protein, and the downstream process by which it activates inflammation, were described back in 2008.

STING 蛋白及其激活炎症的下游过程早在 2008 年就已被描述。

But no one knew how STING was activated.

但没有人知道 STING 是如何被激活的。

Chen’s work — describing a new human innate immune pathway called cGAS-STING — filled in the gap.

Chen 的工作——描述了一种名为 cGAS-STING 的新人类先天免疫途径——填补了这一空白。

In 2024, Chen received the Lasker Award for this breakthrough.

2024年，陈因这一突破获得了拉斯克奖。

“Chen’s paper was brilliant — an instant classic,” Kranzusch said.

“陈的论文非常精彩——立即成为经典，”克兰祖什说。

“It made everything else make sense.”

“这让其他一切都变得有意义。”

Almost everything.

几乎一切。

One thing that didn’t quite make sense was how the essential cGAS-STING mechanism could have evolved in humans.

一件不太有意义的事情是，基本的 cGAS-STING 机制是如何在人类身上进化出来的。

“It’s hard to understand how that would come to be,” Kranzusch said.

“很难理解这是怎么发生的，”克兰祖什说。

I always remember that day, because I ran into my adviser’s office and I’m like, ‘You’re not going to believe this.’

我永远记得那一天，因为我跑进顾问的办公室，我说，‘你不会相信这一点。’

Philip Kranzusch, Harvard Medical School

菲利普·克兰祖什，哈佛医学院

To dig into its evolutionary history, he looked for other proteins that produce cGAMP in other species.

为了深入了解其进化历史，他在其他物种中寻找产生 cGAMP 的其他蛋白质。

When he found one — a bacterial enzyme that makes cGAMP , described by John Mekalanos’ lab at Harvard Medical School in 2012 — Kranzusch, who at the time was a postdoctoral fellow at the University of California, Berkeley, worked to understand its molecular structure.

当他发现一种细菌酶（一种产生 cGAMP 的细菌酶，由哈佛医学院 John Mekalanos 实验室于 2012 年描述）时，当时是加州大学伯克利分校博士后的 Kranzusch 致力于了解其分子结构。

The bacterial protein did not share a DNA sequence with the human cGAS.

该细菌蛋白与人类 cGAS 不具有相同的 DNA 序列。

So it was a huge surprise when he found that the two proteins were virtually identical in shape and structure .

因此，当他发现这两种蛋白质的形状和结构几乎相同时，他感到非常惊讶。

“I always remember that day,” he recalled, “because I ran into my adviser’s office and I’m like, ‘You’re not going to believe this.’”

“我永远记得那一天，”他回忆道，“因为我跑进了顾问的办公室，我说，‘你不会相信这一点。’”

In 2016, when Kranzusch launched his own lab at Harvard Medical School, he and Mekalanos, along with postdoctoral fellows Aaron Whiteley and Ben Morehouse , continued the search.

2016 年，当 Kranzusch 在哈佛医学院建立了自己的实验室时，他和 Mekalanos 以及博士后研究员 Aaron Whiteley 和 Ben Morehouse 继续进行研究。

Their careful structural work on a variety of bacterial cGAS-like enzymes, all of which produce cGAMP or related dinucleotide signals, showed that these enzymes look just like human cGAS too.

他们对多种细菌 cGAS 样酶（所有这些酶都产生 cGAMP 或相关二核苷酸信号）进行了仔细的结构研究，结果表明这些酶看起来也像人类 cGAS。

They published their findings in a series of papers in 2019 and 2020 .

他们于 2019 年和 2020 年在一系列论文中发表了他们的发现。

The findings were remarkable.

研究结果非常显着。

After billions of years of evolution, human cGAS and its bacterial equivalents were not recognizably related at the level of DNA or even amino acid sequence.

经过数十亿年的进化，人类 cGAS 及其细菌同类物在 DNA 甚至氨基酸序列水平上都没有可识别的相关性。

Out of a 300-amino-acid-long sequence, the bacterial and human cGAS proteins share only five or six amino acids, said Whiteley, who now runs his own lab at the University of Colorado, Boulder.

Whiteley 表示，在 300 个氨基酸长的序列中，细菌和人类 cGAS 蛋白仅共享五到六个氨基酸。Whiteley 现在在科罗拉多大学博尔德分校经营着自己的实验室。

Yet the shape of the part of the protein that produces the dinucleotide cGAMP signal has remained structurally unchanged for all that time.

然而，产生二核苷酸 cGAMP 信号的蛋白质部分的形状在结构上一直保持不变。

Remarkably, the core machinery of the STING protein (top, protein diagrams) has remained structurally preserved across diverse organisms, although the underlying gene sequence differs widely.

值得注意的是，尽管潜在的基因序列差异很大，但 STING 蛋白的核心机制（顶部，蛋白质图）在不同生物体中在结构上仍然保留。

Some parts of the protein (bottom, dashed outline) have changed over billions of years.

蛋白质的某些部分（底部虚线轮廓）在数十亿年来已经发生了变化。

Courtesy of Philip Kranzusch; Nature 586, 429-433 (2020)

由菲利普·克兰祖施 (Philip Kranzusch) 提供；自然 586, 429-433 (2020)

“The structure, that’s key to function,” Whiteley said.

“结构是功能的关键，”怀特利说。

“The protein can’t change in structure.

“蛋白质的结构不能改变。

But it can change in sequence to try and disrupt all the ways the virus is trying to antagonize the system.”

但它可以改变顺序，试图破坏病毒试图对抗系统的所有方式。”

The discovery of the structural similarity was surprise enough.

结构相似性的发现足以令人惊讶。

But did these bacterial enzymes, like human cGAS, protect against foreign viruses?

但这些细菌酶是否像人类 cGAS 一样能够抵御外来病毒呢？

Yes.

是的。

That same year, Sorek’s team showed that the bacterial cGAS enzymes did in fact work as an anti-phage defense .

同年，Sorek 的团队证明细菌 cGAS 酶实际上起到了抗噬菌体防御的作用。

Both teams eventually found STING in bacteria as well.

两个团队最终也在细菌中发现了刺痛。

When they confirmed that the bacterial STING functioned in immune defense much like the human STING, “all the dots really started to connect,” Kranzusch said.

当他们确认细菌 STING 的免疫防御功能与人类 STING 非常相似时，“所有的点都真正开始联系起来，”Kranzusch 说。

“Then we had everything.”

“然后我们就拥有了一切。”

The hardest part of this work was neither solving the protein structures nor testing their functions.

这项工作最困难的部分既不是解决蛋白质结构，也不是测试它们的功能。

“The dogma in the field was that immune proteins should not be old.

“该领域的教条是免疫蛋白不应该过时。

And that was the really hard part to overcome with the cGAS-STING pathway,” Kranzusch said.

这是 cGAS-STING 途径中真正难以克服的部分，”Kranzusch 说。

“We knew it was conserved, and it was doing the same function, and it was maintained across billions of years of evolution,” he continued.

“我们知道它是保守的，它发挥着相同的功能，并且在数十亿年的进化过程中得以维持，”他继续说道。

“As the data became overwhelming, that broke down the barriers for all sorts of other findings in the field.”

“随着数据变得势不可挡，这打破了该领域各种其他发现的障碍。”

Since the discovery of the uncanny correspondence between bacterial and human cGAS-STING, computational analysis of bacterial defense islands has predicted hundreds of distinct mechanisms of innate immunity.

自从发现细菌和人类 cGAS-STING 之间不可思议的对应关系以来，细菌防御岛的计算分析已经预测了数百种不同的先天免疫机制。

Some of the mechanisms cleave viral DNA or RNA transcripts to kill the viruses; others terminate the reproduction of new viral DNA.

其中一些机制会切割病毒 DNA 或 RNA 转录本以杀死病毒；其他的则终止新病毒 DNA 的繁殖。

“Quite a few of these defense systems turn out to be suicidal,” said Eugene Koonin , an evolutionary biologist at the National Institutes of Health who published a foundational paper on defense islands in 2011.

美国国立卫生研究院的进化生物学家尤金·库宁 (Eugene Koonin) 于 2011 年发表了一篇关于防御岛的基础论文，他说：“其中相当多的防御系统最终证明是自杀性的。”

That is, they cause the cell to self-destruct, thereby preventing further spread in the viral population.

也就是说，它们导致细胞自毁，从而防止病毒群体进一步传播。

The evolutionary biologist Eugene Koonin led foundational research identifying clusters of antiviral genes in bacterial genomes.

进化生物学家尤金·库宁（Eugene Koonin）领导了基础研究，识别了细菌基因组中的抗病毒基因簇。

But over billions of years, phages have evolved ingenious countermoves to evade such defenses.

但数十亿年来，噬菌体已经进化出巧妙的对策来逃避这种防御。

For example, in response to bacterial cGAS-STING, phages deploy molecules that sponge up the cyclic dinucleotide signals (cGAMP) that connect the sensor (cGAS) to the effector (STING).

例如，为了响应细菌 cGAS-STING，噬菌体会部署吸收连接传感器 (cGAS) 和效应器 (STING) 的环状二核苷酸信号 (cGAMP) 的分子。

This effectively short-circuits and overcomes the defense.

这有效地短路并克服了防御。

Countering that, bacteria evolved a mechanism called Panoptes — first described in 2025 by Whiteley, Morehouse, and their colleagues — which constantly generates cGAMP signals that are similar but not identical to those generated by cGAS.

与此相反，细菌进化出了一种名为 Panoptes 的机制（由 Whiteley、Morehouse 及其同事于 2025 年首次描述），该机制不断生成与 cGAS 生成的信号相似但不相同的 cGAMP 信号。

An invading phage then sponges up the cGAMP decoys, allowing the true signal to reach its target (STING) and trigger cellular self-destruction.

然后，入侵的噬菌体吸收 cGAMP 诱饵，让真正的信号到达其目标 (STING) 并触发细胞自我毁灭。

This trick works only because the cGAS and Panoptes dinucleotides are different enough for the cell to distinguish them and similar enough that the phage can’t tell the difference.

这个技巧之所以有效，只是因为 cGAS 和 Panoptes 二核苷酸的差异足以让细胞区分它们，并且足够相似以至于噬菌体无法区分它们。

It’s a dangerous balance — one that probably frequently misfires.

这是一种危险的平衡——一种可能经常失败的平衡。

“This is the marvel of bacteria,” Whiteley said.

“这是细菌的奇迹，”怀特利说。

“They’re replicating so rapidly that they can try a lot of things that don’t work in order to find the very few that do.”

“它们的复制速度如此之快，以至于它们可以尝试很多不起作用的东西，以便找到极少数起作用的东西。”

Another example of fascinating moves and countermoves can be found in a bacterial defense mechanism that depletes NAD, an essential cofactor .

另一个令人着迷的举措和对策的例子是消耗 NAD（一种重要的辅助因子）的细菌防御机制。

NAD is an electron carrier that, every second, greases the wheels of millions of biochemical reactions in the cell.

NAD 是一种电子载体，每秒为细胞中数百万个生化反应提供润滑。

By quickly destroying all cellular NAD, bacteria grind biochemical reactions to a halt, preventing viral replication.

通过快速破坏所有细胞 NAD，细菌使生化反应停止，从而阻止病毒复制。

But phages, not to be outdone, have evolved ways to reconstitute NAD and evade this bacterial defense, Sorek’s team has found.

但 Sorek 的团队发现，噬菌体也不甘示弱，已经进化出重建 NAD 并逃避这种细菌防御的方法。

Then there’s viperin, a human protein that makes modified nucleotides that quickly terminate viral replication; its mechanism of action was deciphered in 2018 .

然后是蝰蛇蛋白，一种人类蛋白质，它可以产生经过修饰的核苷酸，从而快速终止病毒复制。其作用机制于2018年被破译。

Soon after, Aude Bernheim , who was a postdoctoral fellow in Sorek’s lab and now leads her own research group at the Pasteur Institute in Paris, found homologues of viperin in bacteria .

不久之后，索雷克实验室的博士后、目前在巴黎巴斯德研究所领导她自己的研究小组的奥德·伯恩海姆在细菌中发现了蝰蛇蛋白的同源物。

She also showed that they work the same way human viperin does.

她还表明，它们的作用方式与人类蝰蛇蛋白的作用相同。

Gasdermins are immune proteins present in the cytosol that kill the cell when it senses an infection by piercing a hole in the cell membrane.

Gasdermin 是存在于细胞质中的免疫蛋白，当细胞感知到感染时，它会通过刺穿细胞膜上的孔来杀死细胞。

The mechanism for gasdermins in humans was described in 2015.

2015 年描述了 Gasdermin 在人类中的作用机制。

In 2022, Tanita Wein , who trained as a postdoc in the Sorek lab and now leads her own research group at the Weizmann Institute, discovered that gasdermins work the same way in bacteria as they do in humans.

2022 年，在 Sorek 实验室接受博士后培训、现在在魏茨曼研究所领导自己的研究小组的塔尼塔·韦恩 (Tanita Wein) 发现，gasdermin 在细菌中的作用与在人类中的作用相同。

Researchers initially made headway in the field by mapping existing knowledge of human immunity onto bacterial genomes.

研究人员最初通过将现有的人类免疫知识映射到细菌基因组上，在该领域取得了进展。

Now they are doing the opposite: investigating whether the hundreds of new bacterial immune systems can be used to predict still unknown mechanisms in humans and other eukaryotes.

现在他们正在做相反的事情：研究数百种新的细菌免疫系统是否可以用来预测人类和其他真核生物中仍然未知的机制。

This predictive framework has already borne fruit.

这一预测框架已经取得成果。

For example, Sorek’s team discovered a bacterial protein that, upon sensing infection, depletes ATP (molecular energy) from the cell, thus preventing the virus from replicating.

例如，Sorek 的团队发现了一种细菌蛋白，在感知到感染后，会消耗细胞中的 ATP（分子能量），从而阻止病毒复制。

They later found it in the genomes of animals, including corals and insects (though not humans).

他们后来在动物的基因组中发现了它，包括珊瑚和昆虫（尽管不是人类）。

When tested in living tissues, the coral and insect proteins worked the exact same way as they do in bacteria.

当在活体组织中进行测试时，珊瑚和昆虫蛋白的工作方式与在细菌中的工作方式完全相同。

“This is a very strong revelation, because doing research in bacteria is much easier than doing research in humans,” Sorek said.

“这是一个非常有力的启示，因为对细菌进行研究比对人类进行研究容易得多​​，”索雷克说。

“One of the most important influences of our research is this ability to use bacteria to study higher organism immunity.”

“我们研究最重要的影响之一是利用细菌来研究更高的生物体免疫力的能力。”

Although there are hundreds of bacterial defense systems, most bacteria have only about a dozen.

尽管细菌防御系统有数百个，但大多数细菌只有大约十几个。

They are inherently costly and always carry the risk of triggering accidental self-destruction, which limits how many any single bacterium can have.

它们本身成本高昂，而且总是存在引发意外自毁的风险，这限制了单个细菌的数量。

Some mechanisms, like restriction-modification enzymes, are common, while others are relatively rare.

有些机制（例如限制性修饰酶）很常见，而其他机制则相对罕见。

CRISPR exists in about 40% of prokaryotic genomes; viperins are present in only about 0.5%.

CRISPR存在于约40%的原核生物基因组中； viperins 的含量仅为 0.5% 左右。

Bacterial communities are like a cauldron where new molecular weapons are forged and are always evolving.

细菌群落就像一个大锅，新的分子武器在这里被锻造并不断发展。

Many of the most common immune mechanisms in prokaryotes have not been inherited by eukaryotes, while some relatively rare ones have been inherited and have “flourished,” Koonin said.

库宁说，原核生物中许多最常见的免疫机制尚未被真核生物遗传，而一些相对罕见的免疫机制已经被遗传并“蓬勃发展”。

The question is: Why?

问题是：为什么？

Why don’t our cells have CRISPR?

为什么我们的细胞没有 CRISPR？

And why did cGAS-STING, a relatively rare immune mechanism in bacteria, become such a central tool in our arsenal?

为什么 cGAS-STING 这种细菌中相对罕见的免疫机制会成为我们武器库中如此重要的工具？

In some cases, bacterial defense mechanisms could have been acquired by eukaryotes about 2 billion years ago, when an archaeal cell first engulfed a bacterial one — which eventually settled in as a mitochondrion organelle — and seeded the eukaryotic lineage .

在某些情况下，细菌防御机制可能是在大约20亿年前由真核生物获得的，当时古细菌细胞首先吞噬了细菌细胞——最终以线粒体细胞器的形式定居下来——并为真核细胞谱系播种。

Other mechanisms may have been acquired later through horizontal gene transfer, a mechanism commonly used by bacteria to swap chunks of DNA, which occurs with less frequency in eukaryotes .

其他机制可能是后来通过水平基因转移获得的，水平基因转移是细菌常用的交换 DNA 块的机制，这种机制在真核生物中发生的频率较低。

The acquisition “in itself is not such a big problem,” Koonin said.

库宁表示，此次收购“本身并不是一个大问题”。

“How and why [rare defenses] replaced the most common prokaryotic defenses — that is more intriguing and, of course, not entirely clear.”

“[稀有防御]如何以及为何取代了最常见的原核防御——这更有趣，当然，还不完全清楚。”

One possibility is that in bacteria, defenses often come with several genetic components organized in small arrays, or operons, that are regulated together.

一种可能性是，在细菌中，防御通常伴随着以小阵列或操纵子形式组织的多个遗传成分，这些遗传成分受到共同调节。

Restriction-modification enzymes, toxin-antitoxin genes, CRISPR and Cas, cGAS and STING — each is a system made of genes that sit next to each other in bacterial genomes.

限制性修饰酶、毒素-抗毒素基因、CRISPR 和 Cas、cGAS 和 STING——每一个都是由细菌基因组中彼此相邻的基因组成的系统。

This makes it easy for bacteria to share the entire toolkit.

这使得细菌很容易共享整个工具包。

But in eukaryotes, because of the more complicated way our genomes are organized and regulated, genes’ operon organization is often disrupted.

但在真核生物中，由于基因组的组织和调节方式更加复杂，基因的操纵子组织经常被破坏。

“Once you lose an operon, you are very unlikely to reacquire it by horizontal transfer,” Koonin said.

“一旦你失去了一个操纵子，你就不太可能通过水平转移重新获得它，”库宁说。

“Once it is disrupted, it is effectively gone.”

“一旦它被破坏，它实际上就消失了。”

The evolutionary immunologist Tera Levin studies how arms races between bacteria and viruses create new immune mechanisms.

进化免疫学家泰拉·莱文（Tera Levin）研究细菌和病毒之间的军备竞赛如何创造新的免疫机制。

When Tera Levin and Edward Culbertson, a postdoctoral fellow in her lab at the University of Pittsburgh, surveyed cGAS and STING proteins across a broad swath of eukaryotes, they found that it’s quite common to find one or the other missing.

当 Tera Levin 和匹兹堡大学实验室的博士后 Edward Culbertson 对大量真核生物中的 cGAS 和 STING 蛋白进行调查时，他们发现其中一种缺失是很常见的。

That begs the question of what one piece is doing when the other isn’t there.

这就引出了一个问题：当另一块不存在时，其中一块在做什么。

“These components either aren’t there, or aren’t there in the combinations I expected — what are they possibly doing?” Levin said.

“这些组件要么不存在，要么不存在于我预期的组合中——它们可能在做什么？”莱文说。

“That is a question we encounter over and over again in this part of the field.”

“这是我们在该领域反复遇到的一个问题。”

It’s possible that the pieces evolved entirely new functions.

这些部件有可能进化出全新的功能。

For example, more than a decade ago, the evolutionary biologist L.

例如，十多年前，进化生物学家 L.

Aravind showed that some restriction-modification enzymes became essential enzymes in eukaryotic epigenetics, where they place (or remove) epigenetic marks at specific locations on the chromatin.

Aravind 表明，一些限制性修饰酶成为真核表观遗传学中的必需酶，它们在染色质的特定位置放置（或去除）表观遗传标记。

In 2025, his team showed that Wnt proteins , essential signaling molecules in animal development, also originate in bacterial conflict systems.

2025 年，他的团队证明，动物发育中必需的信号分子 Wnt 蛋白也起源于细菌冲突系统。

In this way, bacteria serve as a kind of “maker space” for accelerated evolutionary experimentation and innovation, generating novelty that then is seeded across life.

通过这种方式，细菌充当了一种加速进化实验和创新的“创客空间”，产生新奇的东西，然后在生命中播种。

This seeding is not just a thing of the distant past: Eukaryotes have continued to beg, borrow, and steal from bacteria and phages in more recent evolutionary time.

这种播种不仅仅是遥远的过去的事情：真核生物在最近的进化过程中继续向细菌和噬菌体乞讨、借用和窃取。

Several million years ago, the wild fruit fly Drosophila ananassae horizontally acquired a viral toxin gene that cuts DNA, probably from phages of endosymbiotic bacteria.

几百万年前，野生果蝇 Drosophila ananassae 水平获得了一种切割 DNA 的病毒毒素基因，该基因可能来自内共生细菌的噬菌体。

In 2025, Noah Whiteman , a biologist at Berkeley, and his team discovered that the fruit fly uses this phage toxin not to kill viruses but rather to poison parasitic wasps that lay eggs inside fly larvae.

2025 年，伯克利分校的生物学家诺亚·怀特曼 (Noah Whiteman) 和他的团队发现，果蝇使用这种噬菌体毒素不是为了杀死病毒，而是为了毒害在蝇幼虫体内产卵的寄生黄蜂。

Amazingly, the fly manages to wield this powerful new weapon without poisoning its own cells.

令人惊讶的是，苍蝇成功地运用了这种强大的新武器，而没有毒害自己的细胞。

Unlike bacteria that can easily swap genes with their neighbors and evolve at warp speed, multicellular organisms are stuck with sexual reproduction — which means that evolution proceeds at a slower pace.

与可以轻松地与邻居交换基因并以极快的速度进化的细菌不同，多细胞生物受有性繁殖的束缚——这意味着进化的速度较慢。

By taking advantage of the rapid evolution of bacterial and viral weapons, insects and other eukaryotes can accelerate their own evolutionary process to stay a step ahead of their enemies.

By taking advantage of the rapid evolution of bacterial and viral weapons, insects and other eukaryotes can accelerate their own evolutionary process to stay a step ahead of their enemies.

“When you borrow a gene from another organism that’s evolving very rapidly, that’s a great strategy, because you can borrow tools at a faster rate than you could ever make them,” Whiteman said.

怀特曼说：“当你从另一种进化非常快的生物体借用基因时，这是一个很好的策略，因为你借用工具的速度比你制造工具的速度还要快。”

It’s now clear that bacterial communities are like a cauldron where new molecular weapons are forged and are always evolving.

现在很清楚，细菌群落就像一个大锅，新的分子武器在这里被锻造并不断进化。

This microbial arsenal contains hundreds, perhaps thousands, of different defense systems.

这个微生物库包含数百个甚至数千个不同的防御系统。

Diverse eukaryotic lineages, from unicellular eukaryotes to plants and animals, have repeatedly borrowed, adapted, and lost defenses from this arsenal over evolutionary time.

Diverse eukaryotic lineages, from unicellular eukaryotes to plants and animals, have repeatedly borrowed, adapted, and lost defenses from this arsenal over evolutionary time.

In this cauldron, the rules of all evolutionary warfare — microbial, animal, vegetal — continue to be written.

在这个大锅里，所有进化战争的规则——微生物、动物、植物——继续被书写。

Update : April 20, 2026 In the graphic, a label was updated to clarify confusing wording around cell type.

更新：2026 年 4 月 20 日 在图中，更新了标签以澄清有关细胞类型的令人困惑的措辞。

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《Quanta》杂志对评论进行审核，以促进知情、实质性、文明的对话。

Abusive, profane, self-promotional, misleading, incoherent or off-topic comments will be rejected.

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。