生物与医学2022nature.com编辑精选
人类免疫系统的物理接线图
A physical wiring diagram for the human immune system
专业 · 约 90 分钟读完前置知识：免疫学基础、受体-配体相互作用、计算建模基础
导读
这篇 Nature 论文系统绘制了人类免疫系统的“物理接线图”：通过大规模实验鉴定免疫细胞表面受体之间的相互作用（包括约 30 种此前未知的受体互作），并结合定量计算模型模拟免疫细胞在体内的动态连接方式。作者称这套方法为未来系统性地解析免疫及其他领域的细胞回路提供了框架。
HN 关注点：是因为单篇论文的信息量惊人——新受体互作、体内定位和计算建模结合，被视为免疫学系统级理解的里程碑，也引发了对生物系统安全性的讨论。
HN 评论精选
这几条评论里：支持 1 补充 2 亲历 1
支持惊叹论文信息量：约30种新受体互作加定量建模，并附补充材料链接
这相当震撼。他们似乎发现了约 30 种此前未知的免疫细胞受体相互作用（图1），然后建立了定量模型，研究这些相互作用在体内的定位等。单篇论文的信息量真是惊人。免疫系统是一个分布式系统，不固定于某个器官，而是由众多特化细胞类型组成，需要灵活组织细胞间连接来应对病原体。他们提供的受体互作网络中每一项都值得单独深入研究。对计算建模感兴趣的人可以看补充材料 PDF，其内容本身就够一篇论文。
photochemsyn查看英文原文
This is kind of stunning. They appear to have discovered something like 30 novel (previously unknown) immune cell receptor interactions (Fig 1). Then they built a quantitive model, looked into where these interactions are localized in the body, and lots more beside. A truly ridiculous amount of information for a single paper. This seems to be the 'what's it all about' paragraph in the paper: > "The immune system is distinctive for being a distributed system. It is not fixed to a single localized organ in the body, but rather is made up of numerous specialized cell types that must adaptably organize their intercellular connections to respond to pathogens and other threats wherever they may appear. We provide a systematic and quantitative view of the cell-surface proteins that enable immune cells to dynamically wire their interactions. The receptor interactions that we report in our network each merit further individualized study to characterize their full roles in health and disease." For those interested in computational modeling (basically they simulate immune cells circulating freely within the body and interacting based on their receptor types), here's the supplementary description link (pdf), which is enough for a whole paper on its own. https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-022-05028-x/MediaObjects/41586_2022_5028_MOESM1_ESM.pdf
亲历患者视角：兴奋于前所未有的综合模型，但担心转化到临床太慢
作为一个被模糊的免疫系统问题困扰、疑问多于答案的患者，我很惊讶这里展示了如此多的免疫系统知识。我立刻想知道如何用这些知识理解自己的免疫问题，可惜我的生物化学知识不够。论文结尾令人鼓舞：他们开创的整合方法为未来系统性研究提供了框架，也许我们终于能开始理清免疫中的细胞回路，从单个蛋白分子 bridging 到多细胞行为。这似乎是前所未有的综合模型，我只希望它不要花几十年才传导到能真正帮助患者的医生手中。
yosito查看英文原文
As someone who struggles with some vague immune system issues with more questions than answers, I was shocked at how much knowledge of the immune system is presented here. I was immediately curious about how I can apply this knowledge to help me understand my own immune issues. Unfortunately, I don't know enough about biology and chemistry to understand much of this. But I found this bit near the end encouraging, and a helpful summary of what is presented here: > More broadly, the integrated approaches that we pioneered here for disentangling the immune system provide a framework for future systematic investigations ... Our analysis and the methods that we developed provide a template for future studies looking at physical cell wiring networks in detail. From these combined approaches, we may finally begin to disentangle cellular circuits in immunity and beyond, bridging from individual protein molecules to multicellular behaviour. This seems to be a comprehensive model on a level that has never been seen before, so in that sense, I'm very excited about it. I just hope it doesn't take decades to trickle down into providers' hands who can actually do something to help patients.
补充分享相关数据库资源：VMH 代谢图谱、BioModels、Human Protein Atlas
我非常期待有一天我们能大规模、有意义地增强或操纵免疫系统。喜欢可视化人类知识全貌的人可以看看虚拟代谢人数据库（VMH），它展示了不断更新的人类代谢图谱，另外 BioModels 和 Human Protein Atlas 也很好。
WebbWeaver查看英文原文
I am really, really excited for the day we are able to augment or manipulate the immune system in a large and meaningful way. For anyone who likes to visualize the whole kit and kaboodle of current human knowledge check out the virtual metabolic human database. They display an updated map on human metabolism Recon human metabolism map https://www.vmh.life/#reconmap2 Paper overview of vmh https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323901/ API Root of vmh https://www.vmh.life/_api and obviously https://www.ebi.ac.uk/biomodels/ is pretty good too human protein atlas https://www.proteinatlas.org/humanproteome/metabolic
补充以信息安全视角类比：生物系统防御架构薄弱，令人担忧智能设计的生物攻击
从信息安全工程师的角度看，生物系统的架构安全极其薄弱。任何一段 DNA 代码只要进入细胞核，就会被加入细胞“运行时”并获得 root 权限。生物防御依赖多层安全——物理的皮肤和化学的蛋白“密码”——但都容易被绕过：物理层有弱点，蛋白密码是静态低熵的，容易被拥有感染宿主“僵尸网络”的敌人暴力破解。一旦感染发生，身体的应对就像清理一台被奶奶用了二十年没重装过的 Windows 98，混乱而极其复杂。如果智能且理性的敌人（人类或 AI）获得知识、工具和动机去智能设计攻击载体，我们最珍贵的系统是完全敞开的。
manholio查看英文原文
In terms of information security, as viewed by an infosec engineer, biological systems seem to have incredibly weak architecture. Hear me out, please. If any piece of DNA code manages to find its way into the nucleus, it's happily added to the cell "runtime" and has root access to the system. To defend against this, biology relies on multiple layers of security, both physical, like the skin, and chemical, like the secret protein password it requires to allow foreign DNA to breach the cell membrane. But both are easily circumvented, for example weak points exist in the physical layer and the protein passwords are static and low entropy, easy to bruteforce by an enemy that already has a botnet of infected hosts which produce random permutations of these keys. And once infection happens, the body response is sort of like the experience of cleaning a Windows 98 which has been used by your grandma to surf the internet for the last two decades, without the option to do a fresh install (kill the host). It's messy and insanely complex - the sort of thing you would expect blind evolution to generate against a blind, brute-forcing script kiddie. You just have to wonder what are our chances on this planet if intelligent and rational enemies, be they human or AI, gain the knowledge, tools and motivation to attack biological systems and intelligently design sophisticated attack vectors. Our most precious systems are wide open, folks. Perhaps some day, to prevent such attacks, we will take control of this complex immune machinery and inject ourselves with highly engineered "anti-viruses" built on the same info-sec principles we build software on.
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