第 350 期·中文精讀

貝圖爾·卡查爾:生命起源、古 DNA、胚種論與外星人

Betül Kaçar: Origin of Life, Ancient DNA, Panspermia, and Aliens

生物學家貝圖爾·卡查爾談生命起源的實驗探索、古 DNA 研究、胚種論與外星生命可能性。

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中文精讀由 AI 基於原始訪談改寫,非官方翻譯,可能存在偏差或錯誤;表述以原音訊與官方文稿為準。說明

地球上所有活著的細胞,從人腸道里的大腸桿菌到藍鯨的肌肉纖維,用的都是同一臺機器。這臺機器讀四個字母,把讀到的序列翻譯成二十種氨基酸,再摺疊成能幹活的立體結構。它只有一個起始訊號,永遠是同一個,甲硫氨酸;它有三個終止訊號,用來告訴工廠這活幹完了。

翻任何一本教科書,那套 64 個密碼子對應 20 種氨基酸的表格,在細菌身上和在人類身上沒有任何偏差。四十億年的分岔、滅絕、重組之後,這一頁表格沒動過一個格子。

貝圖爾·卡查爾(Betül Kaçar)在威斯康星大學做天體生物學,博士唸的是化學,現在做的事是拿今天的基因序列往回推,把幾十億年前的蛋白質在實驗室裡重新合成出來。她管這段歷史叫“霧”,越往遠處看霧越濃,但她偏偏喜歡往最濃的地方走。

生命之樹最浪漫的地方,是它必須從枝頭倒著畫

卡查爾說,系統發生樹可能是生物學裡最浪漫、最漂亮的一個概念。它把生命之間的親緣關係畫成一張圖,所有活著的東西都站在這張圖不同的枝頭。

但這棵樹有個容易搞反的地方。你以為是先有根,再有枝,其實畫的時候是反的。你先看到的是枝頭,是今天活著的這些生物身上拿到的東西。根在哪裡,是由枝頭上放了什麼決定的。

所以做古基因重建的人,乾的是逆向工程。手裡只有葉子,要猜樹幹長什麼樣,要猜那些早就死透的祖先當年靠什麼活著。卡查爾的原話是,先看今天有什麼,然後開始反推,往時間的上游走。

樹的解析粒度也可以自己挑。想搞清楚某段 DNA 是不是在進化路上從別的物種那兒偷來的,就按這個目的建一棵樹;想復活一段古蛋白,就同時建三棵,一棵用基因序列,一棵用蛋白質序列,一棵用物種關係,然後互相對照。三棵樹說法一致的地方,可信度就高一些。

侏羅紀公園拍不出來,真正有意思的部分比恐龍早得多

Lex 直接把那個沒法正經問的問題扔了出來:侏羅紀公園有多現實?

卡查爾的回答裡藏著一個轉向。她說恐龍也好,那些大型哺乳動物也好,等她真正關心的東西出場時,這些早就演完了。她感興趣的是兩段時間。

第一段是生命起源,第一個細胞長什麼樣。第二段是某些漫長的地質時期裡,看上去什麼重大創新都沒發生,也沒在岩層裡留下任何記錄。她想知道的是,那些空白裡到底丟了什麼。

這裡面有一串被大眾忽略的事件。光合作用,真核細胞,多細胞生物,還有那次把整個星球大氣改寫的氧氣事件。全部發生在這類“原始長相”的單細胞身上,全部沒有好記錄。你我今天能坐在這兒對話,靠的就是這些事件。

人類對這顆星球過去的生物學創新,理解得極少。手裡只有兩類材料:岩石裡留下的印痕,和用今天的序列推出來的樹。地質學給一點,生物學給一點,兩邊都有各自的盲區,中間那段得靠推理縫起來。

生物學這門學問,最麻煩的地方是它會自己擦掉自己的歷史

卡查爾講了一句很實在的話:生物學研究的,廣義上講就是倖存者。你手裡只有活到今天的這些東西,然後試圖用它們拼出一部歷史。

DNA 是一份四十億年的產品,是一團非常活躍、一直在變的化學物質。它會給你資訊,但前提是你知道該往哪兒看。因為它一直在響應環境,一直在重寫自己。

這就導致一個別的歷史學科沒有的困境。地質學家能去看地層,考古學家能去挖遺址,生物學家的“史料”本身就帶著篡改痕跡,而且篡改得很勤奮。

Lex 用了“霧”這個比喻,卡查爾接了過去。她說確實很霧,而且越往遠看越霧。

細菌不需要人類的道歉,它們需要的是被承認

聊到這裡,卡查爾主動替細菌說了幾句好話。她說細菌一點都不原始,我們今天看到的細菌,是幾十億年殘酷篩選之後的勝出者,比任何大型動物都更老練、更抗折騰。

她還引了道格拉斯·亞當斯那句玩笑:人類不喜歡自己的祖先,很少請他們來家裡吃飯。可細菌就在你的飯裡,在你的腸道里,一路幫你把日子過下去。某種意義上,它們自己找到了被邀請的方式。

這句話不是單純的幽默。它背後有個認知上的坑:人們習慣把“簡單”和“原始”劃等號,覺得單細胞是低配版的生命。實際上單細胞是一個在極端環境裡跑了幾十億年、從沒宕機過的系統。複雜度的評價標準如果是“能不能活下去”,那贏家一直是它們。

實驗室裡養的那幾只“寵物”,各自負責回答不同的問題

卡查爾實驗室的工作方式很直接:改造細菌。選誰當物件,取決於想問什麼。

想連線生物學和地質學,搞清楚幾十億年前那些基礎創新,藍細菌(cyanobacteria)是首選。它的基因組可以改,可以往裡塞設計好的外源 DNA,改動它自己的代謝功能。

想搞清楚細胞最基本的功能,用大腸桿菌。這是研究得最透的模式生物,做克隆、做基礎驗證都靠它。

還有一類叫固氮菌(diazotrophs),專門負責把大氣裡的氮變成生物能用的形式。她們的做法是把一條用計算和系統發生工具“復活”出來的古老固氮代謝通路,裝進今天還活著的固氮菌裡。

整個生物圈只發明過一次固氮,碳的路子卻有七八條

氮氣在空氣裡佔了差不多八成,但那個三鍵穩得離譜,細胞沒法直接用。要把它變成氨,才能進入下游的代謝。這個過程叫固氮。

氮的重要性容易被低估。它在 ATP 裡,在葉綠素裡,是生命用量最大的元素之一。地球上有大量含氮的化合物,缺了這一道轉化,全部堵在門口。

關鍵點在這兒:到目前為止,人類只知道一條生物固氮路徑。對比一下碳,微生物發明了七八種不同的固碳方式,各走各的路。氮這邊,地質時間尺度上看,就一個解。卡查爾管它叫“奇點”。

這條唯一的路徑大約出現在 27 億年前,也可能接近 30 億年。核心是一個叫固氮酶(nitrogenase)的酶,配合電子供體、ATP,還有大量的氫,硬生生把三鍵撬開。

沒有這一步,今天的世界不存在。Lex 問,如果生命沒發明固氮會怎樣。卡查爾的回答很乾脆:她想不出另一種可能。你我此刻能說話,是因為生命找到了這條路。

人類自己也發明了一次,而且現在供應著你體內一半的氮

非生物的固氮方式其實有。閃電就能把大氣裡的氮變成氨,一場雷雨就是一次小規模的化肥生產。

人類的那次發明大約在一百年前,一戰前後,哈伯-博施法(Haber-Bosch process)。原理不復雜,用極高的壓力把氮和氫壓成氨。今天農業用的尿素來自這個流程,糧食來自這些化肥。

有個數字值得停一下:人體內的氮,大約有一半來自人類自己合成的氨。 換句話說,現代人的身體裡有相當一部分原子,走的是一條一百年前才被工業打通的路徑,而不是那條 27 億年前演化出來的酶促路徑。

卡查爾對此的評價是,人類用最笨的方式復刻了自然最精巧的發明。生命靠一個酶、一堆 ATP、一些氫,在常溫常壓下完成的事,工業得靠高溫高壓。這個對比擺在任何一次關於“技術是否已經足夠先進”的討論裡,都挺有說服力。

她還提到生命依賴的五種元素:碳、氫、氧、氮、硫。這是一杯雞尾酒的基本配料。至於這五種是不是宇宙裡唯一能撐起生命的組合,她明確說不知道。地球只是給出了一個樣本。

細胞裡真正的中樞,是那臺把序列變成形狀的機器

訪談的重心在這裡轉向。卡查爾說,如果只能挑一個子系統來講,她選翻譯機器(translation machinery)。

人們習慣把細胞當成生命的基本單位,但在她看來,細胞裡發生的一切,某種程度上都在為翻譯服務。有一篇論文的說法是,整個細胞對這種位於核心的資訊、計算、生物化學系統“無可救藥地上癮”。

這臺機器乾的事,是把 mRNA 的線性序列變成摺疊好的蛋白質。過程分成起步、延伸、終止、回收幾個階段,每一步都在處理離散的資訊單位。

卡查爾給了一個很好用的比喻:它像一臺印表機,讀圖紙,造出三維的實物。Lex 順著說,更像一座工廠,圖紙進去,產品出來。

這臺機器由大約一百個不同的元件構成。核心位置是一段 RNA,它同時充當資訊載體和酶。剩下的是各種蛋白,靠 ATP 或 GTP 供能,各司其職。

拆成五個學科看,它比任何一臺人造計算機都難對付

卡查爾把翻譯機器拆成五個層面,這一段是她整個思路的骨架。

  • 化學的:構成它的全是化學物質,速率常數、結合親和力、反應條件,一條都不能越界。
  • 物理的:它要消耗能量,要在真實空間裡挪動真實的分子,是個機械活。
  • 資訊的:它處理的是位元,是四個字母排出來的序列。
  • 計算的:處理資訊的過程中,系統進入一個個離散狀態,這本身就是計算。
  • 生物的:複製不完美,於是有了變異,有了遺傳,有了演化。

這五層裡的任何一層被破壞,系統就塌。速率太快,下一條資訊遞不進來;速率太慢,整個流程卡死。每個元件都有自己的容錯區間,區間外就是崩潰。

卡查爾用了爵士樂隊的比喻。所有樂手都在同一個場子裡,各自有即興空間,但整體必須咬合。Lex 說這更像一場派對,每個人都收到邀請,還得跳同一支舞。

對比一下人造計算機,差別很清楚。計算機有資訊層,有計算層,但沒有化學層、物理層、生物層。更要命的是,計算機裡的資訊和功能是松耦合的,翻譯機器裡兩者死死綁在一起。 序列一變,蛋白質的形狀就變,功能就變,沒有中間商。

這臺機器可以被整個拔出來,放進試管裡照樣工作

有個實驗事實很能說明問題。把翻譯機器從細胞裡取出來,放到無細胞體系裡,它照樣翻譯。它不需要細胞的其他部分配合,只需要有人餵給它資訊。

這一點挺關鍵。它說明翻譯機器在功能和結構上有相當的獨立性,不是一個必須依附於完整細胞才能存在的脆弱環節。這讓研究它變得可行,也讓“在實驗室裡從零造一臺翻譯機器”這個目標看起來不完全是妄想。

但卡查爾承認,這個目標還沒實現。她還提了一句,做生命起源的化學家一直在找那個“鍋”,一鍋下去能煮出這套東西的配方,到現在也沒找到。因為這套東西遠不止化學。

說到“鍋”,她解釋了一下什麼叫單鍋化學(single-pot chemistry)。就是你把這套配方需要的所有原料按比例扔進一個容器,知道在什麼環境下會得到什麼產物。到這一步,運氣就不參與運算了,輸入決定輸出,像一道已經解出答案的數學題。

她把這類化學家稱作某種廚師。他們不是碰運氣,是在設計一份能重複的菜譜。

那張遺傳密碼錶,是生命的字母表

訪談裡有一段非常適合邊看邊聽。Lex 調出了標準遺傳密碼錶,圓盤形,外圈是二十種氨基酸,內圈是鹼基組合。

四個字母,三個位置一組,4×4×4,一共 64 個可能的狀態。生命的做法是:拿掉一個起始訊號和三個終止訊號,剩下的用來編碼 20 種氨基酸。

起始訊號只有一個,AUG,對應甲硫氨酸。卡查爾對這一點特別著迷:所有生命從同一個起始碼開始,沒有第二種寫法。 AUG 一到,翻譯機器就知道,功能要來了,後面跟著的是一串資訊,直到終止碼出現。

終止訊號有三個,在表上用黑方塊標出來。也就是說,開始只有一種方式,停下來有三種方式。

那 20 種氨基酸是從哪兒挑出來的?自然界已知的氨基酸有 500 種左右,生命只用了 20 種。為什麼是這 20 種,沒人能給出確定答案。卡查爾說,別指望四億年,四十億年也沒給出解釋,可能還得再等四十億年。也可能早期根本不是這 20 種,只是我們無從驗證。

密碼錶的冗餘不是浪費,是給錯誤留的緩衝

64 個狀態只用掉 20 個編碼加 4 個起止,三分之二的位置看起來是空轉。卡查爾說,從資訊學角度看,這恰恰是這套系統的精髓。

一個氨基酸往往對應兩到四個不同的密碼子。賴氨酸(K)可以由 AAA 編碼,也可以由 AAG 編碼,第三個位置的字母錯了,產物還是賴氨酸。

這就是密碼子的簡併性。它意味著訊息可以帶錯字,但意思還能傳達出去。

把這件事放到整個系統的層面看,你會發現容錯是層層巢狀的。資訊層有冗餘,計算層有冗餘,化學層有容錯區間,生物層更是直接把錯誤變成了演化的原料。一個系統在五個層面同時留了後路,這才是它跑了四十億年沒停機的真正原因。

至於自然選擇是怎麼把這套冗餘挑出來的,哪種錯誤能保住功能、哪種會導致失能,人類的理解還非常有限。卡查爾說得很坦白,這是生物學裡最難的問題之一,是生物學的暗面。它如此基礎,我們對它的演化機制卻幾乎一無所知。

做古基因重建,和解碼一門死語言是同一套方法

卡查爾在這裡給了一個跨度很大的類比,也是整場對話裡最漂亮的一段連線。

研究已經消失的語言和文明,起點是今天的語言。拿印歐語系各支做對比,一個詞一個詞地推,建一棵語言樹,最後反推出那個共同祖先怎麼說“雪”。

如果很多支文化裡都有專門指雪的詞,你就能推斷,他們生活的地方會下雪,否則不需要這個詞。

生物學乾的是同一件事。搞清楚某個古老酶的功能,就能推斷它主人當年活在什麼環境裡。基因序列是詞,蛋白質功能是詞的意思,環境是說話的人所處的世界。

生命之樹和那張密碼錶,在這個框架下其實是同一件事的兩種檢視。密碼錶是字母表,64 個狀態,20 個成品字。生命之樹是這四十億年裡寫下的全部文字。你今天看到的每一個物種,都是這套字母表在環境壓力下寫出來的一篇文章。

卡查爾的落點很剋制:理論上,用這套語言可以描述地球上存在過的所有生命。實際上,我們的水平離這個目標還差得遠。

如果別處也有生命,它會不會也發明同樣的東西

作為天體生物學家,卡查爾真正在追問的是一個更硬的問題:生命的哪些部分是被地球環境逼出來的偶然,哪些是任何地方的生命都繞不開的必然。

固氮這件事給了她一個線索。整個生物圈只發明瞭一次,之後再也沒有第二種寫法。這種“唯一解”的現象,暗示某些生化路徑可能是被化學和熱力學嚴格限定的,換一個星球,未必有別的選擇。

翻譯機器更是這樣。一個把資訊與功能直接耦合、在五個層面同時容錯的系統,很難想象有更省事的替代方案。

但她沒往下斷言。她反覆說的一句話是,我們只有一個樣本。這既是對科學邊界的誠實,也是這門學科真正的吸引力所在:想搞明白哪些是偶然,唯一的辦法是找到第二個樣本。

可以馬上做的幾件事

  • 把標準遺傳密碼錶列印出來貼在桌上。看幾天之後,你會開始理解為什麼起始碼只有一種、終止碼有三種,這種不對稱本身就是資訊。
  • 去 NCBI 用 BLAST 跑一段你自己的基因,或者直接從網上找一段人類細胞色素 c 的序列,跟酵母、水稻的同源序列比對。你會親眼看到四十億年的分歧在序列上留下什麼痕跡,比讀十篇綜述都直觀。
  • 找一本講早期地球化學的書來讀。卡查爾反覆強調的一件事是,不懂化學就沒法碰生命起源,這門課繞不過去。
  • 關注卡查爾實驗室的公開論文和訪談。她做的是把古蛋白真的合成出來、裝回活細胞裡觀察,這種“復原再造”的路子,比純計算推斷更有說服力。
  • 下次看到“某個古代特徵被重建”的說法,先問一句:它是從今天的資料往回推的,還是有獨立證據?霧很濃,方法論是唯一的手電筒。
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Lex Fridman Podcast #350 – Betül Kaçar: Origin of Life, Ancient DNA, Panspermia, and Aliens Machine transcription by Qwen3-ASR 0.6B (MLX, local, Apache-2.0). May contain recognition errors. The following is a conversation with Batul Kachar, an astrobiologist at University of Wisconsin studying the essential biological attributes of life. And now a quick few second mention of each sponsor. Check them out in the description. It's the best way to support this podcast. We got House of Macadamias for a satiating and delicious snack, Mizanameen for style, A Sleep for naps, ExpressVPN for privacy and security, Give Directly for philanthropy and Blinkist for nonfiction. Choose wisely, my friends. And now onto the full ad raids. As always, no ads in the middle. I try to make this interesting, but if you skip them, please still check out our sponsors. I enjoy their stuff, maybe you will too. This show is brought to you by House of Macadamias, a company that ships delicious, high quality and healthy macadamia nuts directly to your door, which they did just today. Another shipment. I got in my hand an unopened box dipped macadamias chocolate flavor. This is the one I went through first last time, and it was delicious. It is an incredible source of happiness for me. I knew for a long time that macadamia nuts were really healthy because I remember when I was first exploring. Okay, so on keto, what is the way to get fats into the diet? Because that's to be a high fat diet. And I was looking at nuts and I was thinking of it. Okay, which which nuts are the healthiest? And I remember macadamias always coming up to the top of the list. I'm going to try not to eat all of them so that I have some for guests when they come over. Because it's like a perfect guest snack, it's healthy, is delicious, is just pure perfection. 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Blinkist takes key ideas from thousands of nonfiction books and condenses them down into 15 minutes that you can read or listen to. I set the goal of reading one book a week. I set a classic book, but really what I mean is a book that really challenges you and really makes you think. So I look forward to seeing sort of using Blinkist to help me review the books, actually also choose the books and maybe help others that are interested in following along to with my reading to get deeper and deeper insights into these different books. I think my perspectives on many books I read are non-standard. I get lost on a single quote here and there, and it just kind of takes me down this whole tangent of thought. These ideas that get inspired and get sparked, and then I I just construct this whole world from a single quote sometimes. But that's what makes it interesting. It's a very subjective experience like appreciating art, appreciating books and so on. Anyway, you can claim a special offer for savings and blinkist dot com slash lex. This is the lex Friedman podcast to support it. Please check out our sponsors in the description. And now dear friends, here's Batul Kachar. What is the phylogenetic tree or the evolutionary tree of life and what can we learn by running it back and studying ancient gene sequences as you have? I think phylogenetic trees could be one of the most romantic and beautiful notions that can come out of biology. It shows us a way to depict the connectedness of life and all living beings with one another. It itself is an ever evolving notion. Biologists like visualizations. They like these graphics, these diagrams, and tree of life is one of them. So the tree starts at common ancestor. It's actually the other way around. It starts from at the end. It starts from the from the branches. It starts from the tip of the branch actually, and then the further depending on how what you collect it. To build the tree, so depending on the branches, depending on what's on the tip of the branch, and I will explain what I mean. The root will be determined by what is really sitting on the tip of the branch of the tree. So we could study the leaves of the tree by looking at what we have today and then start to reverse engineer, start to move back in time to try to understand what the rest of the tree, what the roots of the tree look like. Exactly. So the tree itself by just taking a few steps back and looking at the entire tree itself can give you an idea about the connectedness, the relatedness of the organisms or whatever again you use to create your tree. There are different ways, but in this case I'm imagining entire diversity of life today is sitting on the tips of the branches of this tree. And we look at biologists, look at the the tree itself. We like to think of it as the topology of the tree to understand when certain organisms or their ancestry may have merged over time. Depending on the tools you use, you might use this tree to then reconstruct the ancestors as well. And so what are the different ways to do the reconstruction? So you can do that at the gene level, or you could do it at the higher complex biology level, right? So what what in which way have you approached this this fascinating problem? We approached it in every way we can. So it's the gene could be protein, the product of the gene or species, or could be even groups of species. It will depend. It totally depends on what you want to do with your tree. If you want to understand certain past events, whether an organism exchanged a certain DNA with another one along the course of evolution, you can build your tree accordingly. If you rather use the tree to reconstruct or resurrect ancient DNA, which is what we do. Then in our case, for instance, we do both gene protein and species because we want to compare the tree that we create using these different information. Okay, well let me ask you the ridiculous question then. So how realistic is Jurassic Park? Can we study the genes of ancient organisms and can we bring the those ancient organisms back? So the reason I ask that kind of ridiculous sounding question is maybe gives us context of what we can and can't do. Yeah, by looking back in time. Yeah, so dinosaurs or all these mammals in in at least for us is the exciting thing already happened by the time we hit to the larger organisms or to eukaryotes. Oh, to you the fun stuff is before we got to the mammals. The fun stuff is what people think is boring. I think the the phase that well these two different times in the geologic history one is the first life past origin of life how did first life look like. And the second is why do we think that over certain periods of geologic time, no significant innovation happened to the degree of leaving no record behind. So what do we not have a record of? Which which part? So you say the fun stuff to you is after the origin of life, which we'll talk about after the origin of life. There are single cell organisms. The the whole thing with the photosynthesis, the whole thing with eukaryotes and multicellular organisms and what what else is the fun stuff? The whole oxygen thing, which mixes in with the origin of life. There's a bunch of different inventions all they have to do with this primitive kind of looking organisms that we don't have a good record of. So I will tell you the more interesting things for us. One is the origin of life or what happened right following the emergence of life. How did the first cells look like? And then pretty much anything that we think shaped the environments and was shaped by the environments in a way that impacted the entire planet that enabled you and I to have this conversation. We have very little understanding of the biological innovations that took place in the past of this planet. We work with a very limited set of I don't want to even say data because they are fossil records. So let's say imprints either that comes from the rock and the rock record itself, or what I just described these trees that we create and whatever we can infer about the past. So we have two distinct ways that comes from geology and biology and they each have their limitations. Okay, so right so there's an interplay. The geology gives you that little bit of data, and then the biology gives you that little bit of kind of constraints and the materials you get to work with to infer how does this result in the kind of data that we're seeing. And now we can have this through the fog. We can see we can look back hundreds of millions of years, a couple of billion years and try to infer. Even further and and I like that you said fog it is pretty foggy, but we're and it gets fogier and fogier the the more you the further you try to see into the past. Biology is you you basically study with study the survivors broadly speaking and you're trying to pitch the sort of put together their history based on whatever you can recover today. What makes biology fascinating also let it it erase its own history in a way right. So you work with this four billion year product that's genome that's the DNA. It's great. It's a very dynamic, ever evolving chemical thing, and so you will get some information, but you're not going to get much unless you know where to look. Because it is responding to the environment. Yeah, so what we have is fascinating. What we have is the survivors, the successful, successful organisms, even the primitive ones, even the bacteria we have today. So bacteria is not primitive and we. Sorry, sorry to offend the bacteria. It's we should be very grateful to bacteria. First of all, they are our great great ancestors. I like this quote by Douglas Adams: Humans don't like their ancestors. They rarely invite them over for dinner, right? But bacteria is in your dinner. Bacteria is in your gut. Bacteria is helping you along way. We might well they get themselves invited in a way. Yes, and so we and they're definitely older and and definitely very sophisticated, very resilient than anything else as someone working at. As a as a bacteriologist, I feel like I need to defend them in this case because they don't get much shout out when we think about life. So you do study bacteria. So which organisms gives you hints that are alive today that give you hints about what ancient organisms were like? Is it bacteria or viruses? What do you study in the lab? We study variety of different bacteria depending on the questions that we ask. We engineer bacteria. So ideally, we want to work with bacteria that we can engineer. Seldom we developed the tools to engineer them, and it depends on the question that we are interested in. If we are interested in connecting the biology and geology to understand the early life and and fundamental innovations across billions of years, there are really good candidates like cyanobacteria. So we we use cyanobacteria very frequently in the lab. We can engineer its genome. We can pervert its function by poking its own DNA with the foreign DNA that we engineer in the lab. We work with E. coli. It's the most simple in in terms of model systems go goes organism that one can study well established sort of a pet lab pet that we use it a lot for cloning and for understanding basic functions of the cell given that it's really well studied. So and what you do with that E. coli? You said that you injected with foreign DNA. We inject pretty much all the bacteria that we work with with foreign DNA. We also work with diazotrophs. These are azotobacteria. They're one of the prime nitrogen fixers nitrogen fixing bacteria. Can you explain what that is nitrogen fixing? Is that is the source of its energy? So nitrogen is a triple bond gas that's pretty abundant in the atmosphere, but nitrogen itself cannot be directly utilized by cells given it is triple bond. It needs to be converted to ammonia that is then used for the downstream cellular functions. And that's what counts as nitrogen fixing. Yes, so nitrogen needs to be fixed before our cells can make use of it, and and it's no offense to nitrogen either. Well, it's actually a very important element. It's one of the most abundant elements on on our planet that is used by biology. It's in ATP. It's in chlorophyll that uses that relies on nitrogen. So it's a very important enzyme for a lot of cell functions. And there's just one mechanism that evolution invented to convert it is. So far we know there's there's only one nitrogen fixation pathway as opposed to say carbon you can find up to seven or eight different carbon based microbes invented to fix carbon. That's not the case for nitrogen. It's a it's a singularity across geologic time. We think it evolved around 2.7 maybe roughly three probably less than three billion year old billion years ago, and that's the only way that nature invented to fix the nitrogen in the atmosphere for the subsequent use. Would we still have life as we know today if we didn't invent that nitrogen fixing step? I cannot think of it. No, it's it's it's essential to life as we know you you and I are having this conversation because life found a way to fix nitrogen. Is that one of the tougher ones if you put it sort of oxygen. Nitrogen, carbon. What are in terms of being able to work with these elements? What is the hardest thing? What is the most essential for life? Just to give context. Well, we think of this as the cocktail. You may hear. What's in the cocktail? It's the schnapps, right? Carbon, hydrogen, oxygen, nitrogen, sulfur. So there are five elements that life relies on. We don't quite know whether that's the only out of many options that life necessarily needs to operate on, but that's just how it happened on our own planet. And there are many abiotic ways to fix nitrogen, and like lightning, right? Lightning can accumulate ammonia. Humans found a way about 100 years ago, I think around World War One, the Haber Bosch process that we can abiotically convert nitrogen into ammonia. Actually, 50% of the nitrogen in our bodies comes from the human conversion of nitrogen to ammonia. It's helped. It's the fertilizer that we use urea comes from that process. It's it's in our food, so we helped we found a way to fix our own nitrogen for ourselves. Yeah, but that you know that's way after the original invention of. Oh, absolutely, absolutely, and without that, we wouldn't have. We wouldn't have all the steps of evolution along the way. Oh, absolutely, it's we tried to replicate in the most simplest way what nature has come up with. Right, we do this by taking nitrogen using a lot of pressure and then generating ammonia. Life does this in a more sophisticated way, relying on one single enzyme called nitrogenase. It's the nitrogen that is used together with eight electron donor and ATP together with a lot of hydrogen. Life pushes this metabolism down to create fixed nitrogen. It's quite remarkable. So the lab pet E. coli inject them with DNA. Those are so E. coli does nitrogen fixing in part, or is that was that a different one? So some biological engineers engineered E. coli to fix nitrogen. I believe not not us. We use the nature's nitrogen nitrogen fixing bug and engineer it with the nitrogen fixing metabolism that we resurrected using our computational and phylogenetic tools. How complicated are these little organisms? What are we talking about? Depends on how you define complication. Okay, so I could tell that you appreciate and respect the full complexity of even the most seemingly primitive organisms because none of them are primitive. Okay, that said, what what kind of what what are we talking about? How how. What kind of machinery do they have that you are working with when you are injecting them with DNA? So I will start with one of the most fascinating machinery that we target, which is the translation machinery. It is a very unique subsystem of cellular life in comparison to I would say metabolism. And we used to you know when we are thinking about cellular life, we think of cell as the basic units or the building block. But from a key perspective, that's not the case. That one may argue that everything that happens inside the cell serves the translation and the translation machinery. There is a nice paper that called this that entire cell is hopelessly addicted to this main informatic. Computing biological chemical system that it is operating at the heart of the cell, which is the translation. It is the translation translating from what to what. So RNA to enzymes. It converts a linear sequence of mRNA into a folded later folded protein. That's that's when the that's the core processing center for information for life. It's has multiple steps. It initiates, it elongates, it terminates, and it recycles. It operates discrete bits of information. Its itself is like a chemical decoding device, and that is incredibly unique for translation that I don't think you will find anywhere else in the cell that does this. So even though it's called translation, it's really like a factory that reads the schematic and builds a three dimensional object. It's like a printer. I would divide it into actually even four more additional steps or disciplines than what would it take to study it by the way you described it. It's a chemical system. It's the compounds that make it up are chemicals. It's physical. It tracks the energy to make its job to do its job. It's informatic. What is processed are the bits. It's computational. The discrete states that the system is placed when the information is being processed that's itself is computational and it's biological. It said there is variability and inheritance that come from imperfect replication even an imperfect computation. So you're and that's so good. So from the biology comes the like when you mess up the bugs of the features that's the biology. Informatics is obvious in RNA that's a set of information there. The different steps along the way is actually kind of what the computer does with with bits. It's own computation, physical. There's a. I guess like almost like a mechanical process to the whole thing. It requires energy and actually you know it's manipulating actual physical objects. And chemical is because you're. Have to ultimately it's all chemistry. Yeah, and it tracks this information, so it is almost a mini computer device inside our cells. Yeah, and that's the oldest computational device of life. It's it's likely the key operation system that had to evolve for life to emerge. It's more interesting or it's more complicated in interesting ways than the computers we have today. I mean everything you said which is really really nice. I mean I guess our computers have the informatic and they have the computational but they don't have the chemical the physical or the biological. Exactly and and the computers don't have don't link information to function. Right, they are not tightly coupled. No, are close to what translation and or the way translation does it. So that's the number one I think difference between the two. And yes, it's it's informatic and we can discuss this further too. One hundred percent. Let's please discuss this further. Which part are we discussing? For each one of those are fascinating worlds. Each each of the five. Yeah, so well we can start with the more I guess the the ones that are more established which is the the chemical aspect of the translation machinery. It's the specific compounds make up the assembly of RNA. Chemists showed this in many different ways. We can rip apart the entire machinery. We know that at the core of it there's an RNA that that operates not only as an information information system itself or information itself but also as an enzyme. And and origin of life chemists make these molecules easily now we know we can manipulate RNA we can make even single pot chemistry is we can create compounds. What's a single pot chemistry? That's I would say when you add all the recipes that you know that will lead you to the final product. This is what original lab chemists do is they they come up with this pot they throw a bunch of chemicals in and they try to try to they're basically chefs of a certain kind. I'm not sure if that's what they call it, but that's how I think of it because it is all combined in a test tube and you know the outcome and and it's it's very mathematical. Once you know the right environment and the right chemistry that needs to get into this container or this pot, you know what the outcome is. There is no luck there anymore. It's a pretty rigid, established input output system and it's all chemistry. So you actually wear a lot of hats as one of them, origin of life chemists. My PhD is in chemistry, but I don't do origin of life chemistry. But you're interested in origin of life. Yes, absolutely. So some of your some of your best friends origin of life chemists. Just make sure that you have good chemist friends if you're interested in origin of life. Yeah, that's a hundred percent required. It should be mandatory. Okay, so chemistry. So what else about this machinery that we need to know chemically? Well, chemically I think that's it. You have enzymes, you have proteins. Enzymes are doing their thing. They know how to chew energy using ATP or GTP. They they they know what to do on their in their own way. They do their enzymatic thing. So it's not just the the ribosome that is at the heart of the translation, but there are a lot of different proteins. You're looking about 100 different components that compose this machinery. Well, let me ask kind of maybe it's a ridiculous question, but did the chemistry make this machine or did the machine use chemistry to achieve a purpose? So like, um, I guess there's a lot of different chemical possibilities on Earth. Is is this translation machinery just like choosing picking and choosing different chemical reactions that it can use to achieve a purpose? Or did the chemistry basically like there's like a momentum like a constraint to the thing that can only build a certain kind of machinery? That's basically is is is chemistry fundamental or is is just emergent? Like how important is chemistry to this whole process? You cannot have life without chemistry. You cannot have any cellular process without chemistry. What makes life interesting is that even if the chemistry is imperfect, even if there are accidents along the way, if something binds to another chemical in in a way it shouldn't, there is resilience within the system that it can maybe not necessarily repair itself but it moves on however imperfect mistakes can be handled. That's where the biology. That's where the biology comes in, but in terms of chemistry, you absolutely cannot have a translation machinery without chemistry. And so you you as I said there are four main steps. These are the core steps that are conserved in all translation machinery. And I should say all life has this machine, right? Every cell, everything on Earth, on Earth. Yeah, yes. When you think of this machine, do you think very specifically about the kind of machinery that we're talking about, or do you think more philosophically a machine that converts information into function? It's I cannot separate the two. I think what makes this machinery fascinating is that those five components that I listed are they coexist. So for instance, if we let's just talking about the chemistry part, we we know the certain rate constant all these proteins that operate in this machinery needs to harbor in order to get the mechanism going. Right, if you are bringing the the information to the translation machinery and you are the initiator of this computation system, you need to have you can only afford a certain range of mistakes. If you're too fast, then the next message cannot be delivered fast. If you're too slow, you may stall the process. So there is definitely a chemistry constant going on within the machinery. Again, it's it's not perfect far from it, but they all have their own margin of error that they can tolerate versus they cannot otherwise they collapse the system collapses. So it's like a jazz ensemble, the notes of the chemistry, but you can be. I like that you said jazz. It's definitely true. It's a party and it's like everybody is invited and and and they need to operate together, right and and they what's really cool about it I think there are many things that are very interesting about this thing but if you take if you remove it from the cell and put it in a cell free environment it works just fine right so you can get cell free translation systems put this translation in a test tube and it is doing its thing it doesn't need the rest of the cell to translate information of course you need to feed the information at least so far but because we are far from evolving a translation maybe not so far evolving a translation in the lab or a machine that can process information as it generates it we have not done that yet. It's a pretty complicated machinery. It's hard for for those origin of life chemists to find a pot that generates because it's far more than chemistry. You need you need biology obviously you need biochemistry you need to think as I think a network systems folk you need to think about computation you need to think about information and and that is not happening yet except we are trying to bring this perspective but the more you understand how information systems work you cannot once you see it you cannot unsee it it's one of those things. So but you can still rip it out and the chemistry happens. Yes, and chemistry can happen even if even if you strip some of the parts out. It can you can get very minimal level of information processing that does not look anything like the translation that cells rely on but that but chemists showed from linear you can generate information that arrives to a processing center in the form of a linear polymer. The informatic part of this system that I think sets the part from computation and from metabolism comes in if you think about the information itself right so we have four nucleotide letters that compose DNA and they are processed in the translation in triplets. So you have in in triplet codon fragments. So you have four times four times four. So you have 64 possible states that can be encoded by four letters in three positions. All right, so it's so amazing. Yeah, it's so amazing. There is only one code that says start. That's that there is only one, and there is two if not three that says stop. So that's that's that's what you work with, but you can have 64 possible states, but life only uses 20 amino acids. So we use life uses 64 possible states minus four of the starts and stops to code for 20 amino acids in different combinations. That is really amazing. If you think about there, there are 500 different amino acids life can choose. Right, it's narrowed it down to 20. We don't know why a lot of people think about this genetic code is quite fascinating. It's all right. I mean it didn't do it for 4 billion years. I don't know. We may wait for another 4 billion years, but but you didn't have those amino acids in the very beginning, right? Like we don't know. So we we would be fooling ourselves if we said we know exactly how how many amino acids existed early on, but there is no reason to think that it it wasn't the same or similar. Yeah, we don't we don't have a good reason, but but because roughly 20 out of 60 states are used, you're using one third of your possible states in the in your information system. So this may seem like a waste, but informatically it's important because it is abundant and it is redundant, right? So so this code degeneracy you see this in that's implemented by this translation machinery inside the cell. So it means we can make errors, right? You can make errors, but the message will still get through. You you can speak missing some letters to the information can miss some parts, but the message will still get through. So that two thirds of the not you states gives you that robustness and resilience within this system. So at the informatic level, there's room for error. There's probably room for error, probably in all five categories we're talking about. There's probably room for error in the computation. There's probably room for error. Yes, exactly. Everywhere there's room for error because because the this informatic capacity is made possible together with the other components and not only that but also the the product yields. Function no, in this case enzyme or protein, right? So so that's really amazing for me. It is. I mean, I mean, in my head, just so you know, because I'm a computer science AI person, the the parallels between even like language models that encode language. Or now they're able to encode basically any kind of thing, including images and actions, all in this kind of way. The the parallel in in terms of informatic and computation is just incredible. Actually, I have a image. Maybe I can send you. Can we pull it up now? If you just do genetic codon charts, we can pull that up. Yeah, it's a very standard table. So I can I can explain what why this is so amazing. So you're looking at like this is life's alphabet, right? And so I also want to make a very quick link now to your first question: the tree of life. When when we link when we try to understand ancient languages, right or the cultures of the or the cultures that use these extinct languages, we start with the modern languages, right? So we look at Indo European languages and and try to understand certain words and make trees to understand you know this is what a Slavic word is for snow something like snake. Now we jump to languages that humans spoke. Human history exactly. So we make trees to understand what is the original ancestor. What did they use? To say snow, and if you have a lot of cultures who use the word snow, you can imagine that it was snowy. That's why they needed that word. It's the same thing for biology, right? If if they have some, if we understand some function about that enzyme, we can understand the environment that they lived in. It's it's the similar, it's similar in that sense. So now you are looking at the alphabet for of life. In this case, it's not twenty or twenty five letters. It's you have four letters. So what is really interesting that stands out to me when I look at this. On the outer shell, you are looking at the twenty amino acids that compose life, right? The one, the methionine that you see, that's the start. So the start is always the same. To me, that is fascinating. That all life starts with the same start. There is no other start code. So you send the AG, you know AUG to the cell. That when that information arrives, the translation knows, all right, I gotta start. Function is coming. The following this is a chain of information until the stop. Code arrives, which are highlighted in black squares. So for people just listening, we're looking at a standard RNA colored table organized in a wheel. There is an outer shell and there is an inner shell, all using the four letters that we're talking about. And with that, we can compose all of the amino acids. And there is a start and there is a stop, and presumably you put together. The the with these letters you walk around the wheel to put together with the words the sentences that. The words the sentences and. Um, you again you get one start, you get three. There are three different ways to stop this. One way to start it, and for each letter you have multiple options. So you say you have a code A. The second code can be another A, and even if you mess that up, you still can rescue yourself. So you can get a for instance, I am looking at the lysine K. You get an A and you get an A and then you get an A that gives you the lysine. Right, but if you get an A and if you get an A and I get a G, you still get the lysine. So there are different combinations. So even if there is an error, we don't know if these are selected because they were erroneous and somehow they got locked down. We don't know if there is a mechanism behind this to or we. We certainly don't know this definitively, but this is the informatic part of this. And notice that the the colors in some tables too, the colors will be coded in a way that the the type of the nucleotides can be similar chemically. But the point is that you will still end up with the same amino acids or something similar to it even if you mess up the code. Do we understand the mechanism how natural selection interplays with this resilience to error? So which errors result in the same output like the same function and which don't. Which actually results in a dysfunction or which are. We understand to some degree the how translation and the rest of the cell work together. How an error at the translation level this is the really core level can impact entire cell. But we understand very little about the evolutionary mechanisms behind the selection of the system. It's thought to be one of the hardest problems in biology and it is still the dark side of biology. Even though it is so essential. So this is yeah you are looking at the language of life so to speak and how it can found ways rather to tolerate its own mistakes. So the entire phylogenetic tree. Can be like a deconstructed with this wheel of language. Because all the final letters, those are that's the twenty amino acids that's our alphabet. They are all brought together with these bits of information, right? So you when you look at the genes, you are looking at those four letters. When you look at the proteins, you are looking at the twenty amino acids. Which may be a little easier way to track the information when we create the tree. So using this language, we can describe all life that's lived on Earth. One perspective. It's we are not that good at it yet, right? So in theory, this is one way to look at

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