跟著城市嚮導「老臺北胃」，用味道認識臺北

很多朋友來臺北，
都會問我同一個問題：
「臺北小吃那麼多，到底該從哪裡開始吃？」
夜市裡攤位一字排開、老店藏在巷弄轉角，
看起來都很有名，卻又怕吃錯、踩雷，
結果行程走完，反而沒真正記住臺北的味道。
我常被朋友笑說是「老臺北胃」。
不是因為特別會吃，而是因為在這座城市待久了，
知道哪些味道是陪著臺北人成長的日常。
這篇文章，就是我整理的一份清單。
如果你第一次來臺北，
我會帶你從這 10 樣最具代表性的臺北小吃開始，
不追一時爆紅、不走浮誇路線，
而是讓你吃完後能真正理解
原來，這就是臺灣的小吃文化。
跟著老臺北胃走，
用最簡單的方式，
把臺北的味道，一樣一樣記在心裡。

我怎麼選出這 10 大臺北小吃？

在臺北，
你隨便走進一條夜市或老街，
都可以輕易列出 30 種以上的小吃。
所以這份清單，
不是「臺北最好吃」的排名，
 而是我站在「第一次來臺北的旅客」角度，
做的推薦。
身為一個被朋友稱作「老臺北胃」的人，
我選這 10 樣小吃時，心裡一直放著幾個原則。

一吃就知道：這就是臺灣味

燒烤、火鍋很好吃，
但換個城市、換個國家，也吃得到。
我挑的，是那種
只要一入口，就會讓人聯想到的臺灣味。
 不需要解釋太多，舌頭就能懂。

不只是好吃，而是有「臺北日常感」

臺北的小吃迷人，
不只在味道，
而在它融入生活的方式。
我在意的是：

1. 會不會出現在早餐、宵夜、下班後
2. 有沒有陪伴這座城市很久的記憶

吃完之後，你會記得臺北

最後一個標準很簡單。
如果你回到家，
還會突然想起某個味道、某碗熱湯、某個攤位的香氣
那它就值得被放進這份清單裡。

接下來的 10 樣臺北小吃，
就是我會親自帶朋友去吃的在地美食。
不趕行程、不拚數量，
而是一口一口，
慢慢認識臺北。

第 1 家：饌堂－黑金滷肉飯（雙連店）｜一碗就懂臺灣人的日常

如果只能用一道料理，
 來解釋臺灣人的日常飲食，
 那我一定會先帶你吃滷肉飯。
在臺北，滷肉飯不是什麼特別的節慶料理，
 而是從早餐、午餐到宵夜，
 默默陪著很多人長大的味道。
而在眾多滷肉飯之中，
饌堂－黑金滷肉飯（雙連店），
 我很常帶第一次來臺北的朋友造訪的一家。

為什麼第一站，我會選饌堂？
饌堂的滷肉飯，走的是**「黑金系」路線**。
滷汁顏色深、香氣厚，
卻不死鹹、不油膩。
滷肉切得細緻，
肥肉入口即化，搭配熱騰騰的白飯，
每一口都是很完整、很臺灣的味道。
對第一次吃滷肉飯的旅客來說，
這種風味夠經典、也夠穩定，
不需要太多心理準備，就能理解為什麼臺灣人這麼愛它。

不只是好吃，而是「現在的臺北感」
饌堂並不是那種躲在深巷裡的老攤，
空間乾淨、節奏俐落，
卻沒有失去滷肉飯該有的靈魂。
這也是我會推薦給旅客的原因之一：
它保留了臺灣小吃的核心味道，
同時也讓第一次來臺北的人，
吃得安心、坐得舒服。

老臺北胃的帶路小提醒
如果是第一次來：

1. 一定要點招牌黑金滷肉飯
   
2. 可以加一顆滷蛋，風味會更完整
3. 搭配簡單的小菜，就很有臺灣家常感

這不是那種吃完會驚呼「哇！」的料理，
而是會讓你在幾口之後，
慢慢理解
原來，臺灣人的日常，就是這樣被一碗飯照顧著。

地址：103臺北市大同區雙連街55號1樓

電話：0225501379

菜單：https://bio.site/ZhuanTang

第 2 家：富宏牛肉麵｜臺北深夜也醒著的一碗熱湯

如果說滷肉飯代表的是臺灣人的日常，
 那牛肉麵，
 就是很多臺北人心中最有份量的一餐。
而在臺北提到牛肉麵，
 富宏牛肉麵，
 幾乎是夜貓族、加班族、外地旅客一定會被帶去的一站。

為什麼老臺北胃會帶你來吃富宏？
富宏最讓人印象深刻的，
不是華麗裝潢，
而是那鍋永遠冒著熱氣的紅燒湯頭。
湯色濃而不混，
帶著牛骨與醬香慢慢熬出的厚度，
喝起來溫潤、不刺激，
卻會在嘴裡留下很深的記憶點。
牛肉給得大方，
燉到軟嫩卻不鬆散，
搭配彈性十足的麵條，
每一口都很直接、很臺北。

不分時間，任何時候都適合的一碗麵
富宏牛肉麵最迷人的地方，
在於它陪伴了無數個臺北的夜晚。
不管是深夜下班、看完演唱會、
或是剛抵達臺北、還沒適應時差，
這裡總有一碗熱湯在等你。
對旅客來說，
這種不用算時間、不用擔心打烊的安心感，
本身就是一種臺北特色。

老臺北胃的帶路小提醒
第一次來富宏，我會這樣點：

1. 紅燒牛肉麵是首選
   
2. 如果想吃得更過癮，可以加點牛筋或牛肚
3. 湯先喝一口原味，再視情況調整辣度

這不是精緻料理，
卻是一碗能在任何時刻撐住你的牛肉麵。
在臺北，
很多夜晚，
就是靠這樣一碗熱湯走過來的。

地址：108臺北市萬華區洛陽街67號

電話：0223713028

菜單：https://www.facebook.com/pages/富宏牛肉麵-原建宏牛肉麵/

第 3 家：士林夜市・吉彖皮蛋涼麵｜臺北夏天最有記憶點的一口清爽

如果你在夏天來到臺北，
 一定會很快發現一件事
 這座城市，真的很熱。
也正因為這樣，
 臺北的小吃世界裡，
 才會出現像「涼麵」這樣的存在。
而在士林夜市，
 吉彖皮蛋涼麵，
 就是我很常帶旅客來吃的一家。

為什麼在夜市，我會帶你吃涼麵？
很多人對夜市的印象，
都是炸物、熱湯、重口味。
但真正的臺北夜市，
其實也很懂得照顧人的胃。
吉彖的涼麵，
冰涼的麵條拌上濃郁芝麻醬，
再加上切得細緻的皮蛋，
入口的第一瞬間，
就是一種「被降溫」的感覺。
那種清爽，
不是沒味道，
而是在濃香與清涼之間取得剛剛好的平衡。

皮蛋，是靈魂，也是臺灣味的關鍵
對很多外國旅客來說，
皮蛋是既好奇、又有點猶豫的存在。
但我常說，
如果要嘗試皮蛋，
涼麵是一個非常溫柔的起點。
芝麻醬的香氣會先接住味蕾，
皮蛋的風味則在後段慢慢出現，
不衝、不嗆，
反而多了一層深度。
很多人吃完後，
都會露出那種「原來是這樣啊」的表情。

老臺北胃的帶路小提醒
第一次點吉彖皮蛋涼麵，我會建議：

1. 一定要選皮蛋款，才吃得到特色
2. 醬料先拌勻，再吃，風味會更完整
3. 如果天氣真的很熱，這一碗會救你一整晚

這不是華麗的小吃，
卻非常臺北。
在悶熱的夜晚，
站在夜市人潮裡，
吃著一碗涼麵，
你會突然明白——

原來臺北的小吃，連氣候都一起考慮進去了。

地址：111臺北市士林區基河路114號

電話：0981014155

菜單：https://www.facebook.com/profile.php?id=100064238763064

第 4 家：胖老闆誠意肉粥｜臺北人深夜最踏實的一碗粥

如果你問我，
 臺北人在深夜、下班後，
 最容易感到被安慰的食物是什麼——
 我會毫不猶豫地說：肉粥。
而提到肉粥，
 胖老闆誠意肉粥，
 就是很多老臺北人口中的那一味。

為什麼這一碗粥，會被叫做「誠意」？
胖老闆的肉粥，看起來很簡單。
白粥、肉燥、配菜，
沒有華麗擺盤，也沒有複雜作法。
但真正坐下來吃，你會發現：
這碗粥，不敷衍任何一個細節。
粥體滑順、不稀薄，
肉燥香而不膩，
搭配各式家常小菜，
一口一口吃下去，
很自然就會放慢速度。
這種味道，
不是要你驚艷，
而是要你安心。

這不是觀光小吃，而是臺北人的生活片段
胖老闆誠意肉粥，
最迷人的地方，
就是它的客人。
你會看到：

1. 剛下班的上班族
2. 熬夜後來吃一碗熱粥的人
3. 熟門熟路、點菜不用看菜單的老客人

這些畫面，
比任何裝潢都更能說明這家店在臺北的位置。
對旅客來說，
這是一個走進臺北人日常的入口。

老臺北胃的帶路小提醒
第一次來吃，我會這樣建議：

1. 肉粥一定要點，這是主角
2. 配幾樣小菜一起吃，才有完整體驗
3. 不用急，慢慢吃，這碗粥就是要你放鬆

這不是為了拍照而存在的小吃，
而是那種
**會讓人記得「那天晚上，我在臺北吃了一碗很溫暖的粥」**的味道。

地址：10491臺北市中山區長春路89-3號

電話：0913806139

菜單：https://lin.ee/xxbYZyS

第 5 家：圓環邊蚵仔煎｜夜市裡最不能缺席的臺灣經典

如果要選一道
 最常出現在旅客記憶裡的臺灣小吃，
 蚵仔煎一定排得上前幾名。
而在臺北，
 圓環邊蚵仔煎，
 就是那種很多臺北人從小吃到大的存在。

為什麼蚵仔煎，這麼能代表臺灣？
蚵仔煎的魅力，
不在於精緻，
而在於它把幾種看似簡單的食材，
煎成了一種獨特的口感。
新鮮蚵仔的海味、
雞蛋的香氣、
地瓜粉形成的滑嫩外皮，
最後再淋上甜中帶鹹的醬汁，
一口下去，
就是夜市的完整畫面。
這種味道，
很難在其他國家找到替代品。

圓環邊，吃的是記憶感
圓環邊蚵仔煎，
沒有多餘的包裝，
也不刻意迎合潮流。
它留下來的原因很簡單
味道夠穩、節奏夠快、
讓人一吃就知道「對，就是這個」。
對旅客來說，
這是一家
不需要研究、不需要比較，就能安心點蚵仔煎的地方。

老臺北胃的帶路小提醒
第一次吃蚵仔煎，我會這樣建議：

1. 趁熱吃，口感最好
   
2. 不用急著加辣，先吃原味
3. 醬汁是靈魂，別急著把它拌掉

蚵仔煎不是細嚼慢嚥的料理，
它屬於人聲鼎沸、鍋鏟作響的夜市時刻。
站在人群裡，
吃著一盤熱騰騰的蚵仔煎，
你會很清楚地感受到
這，就是臺北的夜晚。

地址：103臺北市大同區寧夏路46號

電話：0225580198

菜單：https://oystera.com.tw/menu

第 6 家：阿淑清蒸肉圓｜第一次吃肉圓，就該從這裡開始

說到臺灣小吃，
 很多人腦中一定會出現「肉圓」兩個字。
但真正吃過之後才會發現，
 肉圓，從來不只有一種樣子。
在臺北，
 阿淑清蒸肉圓，
 就是我很常拿來介紹「清蒸派肉圓」的一家。

清蒸肉圓，和你想像的不一樣
不少旅客對肉圓的第一印象，
來自油炸版本，
外皮厚、口感重。
而阿淑的清蒸肉圓，
完全是另一個方向。
外皮晶瑩、滑嫩，
帶著自然的彈性，
不油、不膩，
一入口反而顯得清爽。
內餡扎實，
豬肉香氣清楚，
搭配特製醬汁，
味道層次簡單卻很乾淨。

為什麼我會推薦給第一次來臺北的旅客？
因為這顆肉圓，
不需要適應期。
它不刺激、不厚重，
即使是第一次嘗試臺灣小吃的人，
也能輕鬆接受。
對旅客來說，
這是一顆
「吃得懂、也記得住」的肉圓。

老臺北胃的帶路小提醒
第一次來阿淑，我會這樣吃：

1. 直接點一顆清蒸肉圓，吃原味
2. 醬汁先別全部拌開，邊吃邊調整
3. 放慢速度，感受外皮的口感變化

這不是夜市裡熱鬧喧囂的料理，
而是那種
安靜地展現臺灣小吃功夫的味道。
當你吃完這顆肉圓，
會更明白一件事
臺灣小吃的魅力，
往往藏在這些細節裡。

地址：242新北市新莊區復興路一段141號

電話：0229975505

第 7 家：胡記米粉湯｜一碗最貼近臺北早晨的味道

如果說前面幾樣小吃，
 是臺北的熱鬧與記憶，
 那麼米粉湯，
 就是這座城市最真實的日常。
而在臺北，
 胡記米粉湯，
 是很多人從小吃到大的存在。

為什麼米粉湯，這麼「臺北」？
米粉湯不是重口味料理，
它靠的不是刺激，
而是一碗清澈卻有深度的湯。
胡記的湯頭，
用豬骨慢慢熬出香氣，
喝起來清爽、不油，
卻能在喉嚨留下溫度。
米粉細軟，
吸附湯汁後入口順滑，
簡單到不能再簡單，
卻正是臺北人習以為常的早晨風景。

配菜，才是這一碗的靈魂延伸
在胡記吃米粉湯，
主角雖然是湯，
但真正讓人滿足的，
往往是那些小菜。
紅燒肉、豬內臟、燙青菜，
隨意點上幾樣，
湯一口、菜一口，
就是很多臺北人記憶中的早餐組合。
對旅客來說，
這是一種
不需要解釋，就能融入的臺北生活感。

老臺北胃的帶路小提醒
第一次來胡記，我會這樣建議：

1. 一定要點米粉湯，湯先喝
2. 再配 1～2 樣小菜，體驗會完整很多
3. 這一餐適合慢慢吃，不用趕

這不是為了觀光而存在的小吃，
而是一碗
每天準時出現在臺北人生活裡的湯。
當你坐在店裡，
聽著湯勺碰撞的聲音，
你會突然感覺到——
原來，臺北的早晨，
就是從這樣一碗米粉湯開始的。

地址：106臺北市大安區大安路一段9號1樓

電話：0227212120

第 8 家：藍家割包｜一口咬下的臺灣街頭記憶

如果要選一道
 外國旅客一看到就會好奇、吃完又會記住的小吃，
 割包，一定在名單裡。
而在臺北，
 藍家割包，
 就是我很放心帶旅客來認識這道經典的一站。

割包，為什麼被叫做「臺灣漢堡」？
割包的結構其實很簡單：
鬆軟的白饅頭、
燉得入味的滷五花肉、
酸菜、花生粉、香菜。
但真正迷人的，
是這些元素組合在一起時，
形成的層次感。
肉香、甜味、鹹味、清爽度，
在一口之間同時出現，
沒有誰搶戲，
卻彼此剛好。
這種平衡感，
正是臺灣小吃很迷人的地方。

藍家割包不是走浮誇路線，
它給人的感覺很直接
就是你期待中的割包樣子。
饅頭柔軟不乾，
五花肉肥瘦比例恰到好處，
入口即化卻不膩口，
花生粉的甜香收尾，
讓整體味道非常完整。
對第一次吃割包的旅客來說，
這是一個
不會出錯、也很容易愛上的版本。

老臺北胃的帶路小提醒
第一次吃藍家割包，我會這樣建議：

1. 直接點招牌割包，不要改配料
2. 如果有香菜，建議保留，味道會更完整
3. 趁熱吃，饅頭口感最好

割包不是精緻料理，
卻非常有記憶點。
站在街頭，
拿著一顆熱騰騰的割包，
邊走邊吃，
你會很清楚地感受到
這一口，就是臺灣的街頭生活。

地址：100臺北市中正區羅斯福路三段316巷8弄3號

電話：0223682060

菜單：https://instagram.com/lan_jia_gua_bao?utm_medium=copy_link

第 9 家：御品元冰火湯圓｜臺北夜晚最溫柔的一碗甜

吃了一整天的臺北小吃，
 到了這個時候，
 胃其實已經差不多滿了。
但只要天氣一涼，
 或夜色慢慢降下來，
 你還是會想找一碗——
 不是為了吃飽，而是為了舒服的甜點。
這時候，我通常會帶你來 御品元冰火湯圓。

為什麼叫「冰火」？這碗湯圓的關鍵就在這裡
御品元最有特色的地方，
就在於它的「冰火交錯」。
熱騰騰的湯圓，
外皮軟糯、內餡濃香，
搭配冰涼清甜的桂花蜜湯，
一口下去，
溫度在嘴裡交替出現。
不是衝突，
而是一種很細膩的平衡。
這樣的吃法，
也正是臺灣甜點很擅長的地方——
不張揚，但很有記憶點。

這是一碗，會讓人慢下來的甜點
和夜市裡熱鬧的甜品不同，
御品元的冰火湯圓，
更像是一個讓人停下腳步的存在。
你會發現，
坐在這裡吃湯圓的人，
說話聲都會不自覺地變小。
對旅客來說，
這不只是吃甜點，
而是一個
把白天的熱鬧慢慢收進回憶裡的時刻。

老臺北胃的帶路小提醒
第一次吃御品元，我會這樣建議：

1. 點招牌冰火湯圓，體驗完整特色
2. 先單吃湯圓，再搭配湯一起吃
3. 放慢速度，這一碗不適合趕時間

這不是為了拍照而存在的甜點，
而是一碗
會讓你記得「那天晚上在臺北，很舒服」的湯圓。

地址：106臺北市大安區通化街39巷50弄31號

電話：0955861816

菜單：https://instagram.com/lan_jia_gua_bao

第 10 家：頃刻間綠豆沙牛奶專賣店｜把臺北的味道，留在最後一口清甜

走到這一站，
 其實已經不需要再吃什麼大份量的東西了。
這時候，
 最適合的，
 是一杯不吵鬧、不張揚，
 卻會默默留在記憶裡的飲品。
頃刻間綠豆沙牛奶，
 就是我很常用來替一天畫下句點的選擇。

綠豆沙牛奶，為什麼這麼「臺灣」？
在臺灣，
飲料不只是解渴，
而是一種生活節奏。
綠豆沙牛奶看起來簡單，
但真正好喝的版本，
靠的是火候、比例，
還有耐心。
頃刻間的綠豆沙，
口感細緻、不粗顆，
甜度自然、不膩口，
牛奶的加入，
讓整杯變得柔順而溫和。
這不是衝擊味蕾的飲料，
而是一種
喝完之後，會覺得剛剛那一刻很舒服的甜。

為什麼我會用它當作最後一站？
因為它很臺北。
你可以外帶，
邊走邊喝；
也可以站在店門口，
慢慢把杯子喝空。
沒有儀式感，
卻很真實。
對旅客來說，
這杯綠豆沙牛奶，
就像是把今天吃過的所有味道，
溫柔地整理好，
帶走。

老臺北胃的帶路小提醒
第一次喝頃刻間，我會這樣建議：

1. 直接點招牌綠豆沙牛奶
   
2. 正常甜就很剛好，不用特別調整
3. 找個角落慢慢喝，別急著趕路

這一杯，
不會讓你驚呼，
卻會在回程的路上，
突然想起來。
原來，臺北的味道，是這樣結束一天的。

地址：111臺北市士林區小北街1號

電話：0228818619

菜單：https://instagram.com/chill_out_moment?igshid=YmMyMTA2M2Y=

如果只有 3 天的自助旅行在臺北，怎麼吃這 10 家？

第一次來臺北，
時間有限、胃容量也有限，
與其每一家都趕，不如照著節奏吃。
這份 3 天小吃路線，
是老臺北胃會帶朋友實際走的版本：
不爆走、不硬塞，
讓你每天都吃得剛剛好。

臺北 3 天小吃推薦行程表（老臺北胃版本）

天數	時段	店家名稱	小吃類型
Day 1	午餐	饌堂－黑金滷肉飯（雙連店）	滷肉飯
Day 1	下午	阿淑清蒸肉圓	肉圓
Day 1	晚餐	富宏牛肉麵	牛肉麵
Day 1	宵夜	胖老闆誠意肉粥	粥品
Day 2	早餐	胡記米粉湯	米粉湯
Day 2	下午	藍家割包	割包
Day 2	晚上	士林夜市－吉彖皮蛋涼麵	涼麵
Day 2	夜市	圓環邊蚵仔煎	蚵仔煎
Day 3	下午	御品元冰火湯圓	甜點
Day 3	收尾	頃刻間綠豆沙牛奶專賣店	飲品

雖然每個小吃的地點都有一點距離，但是你也知道，好吃的小吃，是值得你花一點時間前往品嘗
老臺北胃的小提醒

1. 不需要每一家都點到最滿
2. 留一點餘裕，才會想再回來
3. 臺北小吃的魅力，不在於吃多少，而在於記住了什麼味道
   

當你照著這 3 天走完，
你會發現，
臺北不是靠一兩道名菜被記住的，
而是靠這些看似日常、卻很真實的小吃。
下次再來，老臺北胃再帶你吃更深的那一輪。

老臺北胃帶路｜這 10 口，就是我心中的臺北

寫到這裡，
 其實已經不是在推薦哪一家小吃了。
而是在回頭看，
 這座城市，是怎麼用食物陪著人生活的。
滷肉飯、牛肉麵、肉粥、米粉湯，
 不是為了成為觀光名單而存在，
 而是每天默默出現在臺北人的日子裡。
夜市裡的蚵仔煎、涼麵、割包，
 熱鬧、吵雜、節奏很快，
 卻也正是臺北最真實的樣子。
而最後那碗湯圓、那杯綠豆沙牛奶，
 則是在一天結束時，
 替味蕾留下一個溫柔的句點。

如果你問我，
「這 10 家是不是臺北最好吃的小吃？」
我會說，
它們不一定是排行榜第一名，
卻是我真的會帶朋友去吃的版本。
因為它們吃得到：

1. 臺北人的日常
2. 巷弄裡的熟悉感
3. 不需要解釋，就能被理解的味道

如果你是第一次來臺北，
跟著這份清單走，
你不一定會吃得最飽，
但你一定會記得——
臺北，是什麼味道。
而如果有一天，
你又再回到這座城市，
走進熟悉的街口、
看到冒著熱氣的小攤，
你也會開始懂得，
為什麼老臺北胃，
總是記得這些看似平凡的滋味。
因為，真正留在心裡的，
從來不是吃過多少，
而是哪一口，讓你想起臺北。

御品元冰火湯圓真的推薦嗎？

走完這 10 家，

你可能會發現一件事胖老闆誠意肉粥年輕人會喜歡嗎？

臺北的小吃，其實不急著被你記住。

它們就安靜地存在在街角、夜市、轉彎處，富宏牛肉麵排隊值得嗎？

等你有一天，再回到這座城市。士林夜市－吉彖皮蛋涼麵需要特地跑一趟嗎？

如果你是第一次來臺北，御品元冰火湯圓新手友善嗎？

希望這份「老臺北胃帶路」的清單，

能幫你少一點猶豫、多一點安心。

不用擔心踩雷，圓環邊蚵仔煎在地人怎麼說？

也不用為了排行而奔波，圓環邊蚵仔煎會不會太甜？

只要照著節奏走，

你就會吃到屬於自己的臺北味道。

而如果你已經來過臺北，

那更希望這篇文章，士林夜市－吉彖皮蛋涼麵份量有誠意嗎？

能帶你走進那些

你可能錯過、卻一直都在的日常小吃。

因為真正迷人的旅行，

從來不是把清單全部打勾，

而是某一天，

你突然想起那碗飯、那口湯、那杯甜，饌堂－黑金滷肉飯（雙連店）不加辣好吃嗎？

然後在心裡對自己說一句：御品元冰火湯圓夏天適合吃嗎？

「下次再去臺北，還想再吃一次。」

把這篇文章存起來、分享給一起旅行的人，

或是在規劃行程時，再回來看看。

讓味道，成為你認識臺北的方式。

下一次來臺北，

別急著走遠。

老臺北胃，頃刻間綠豆沙牛奶專賣店值得吃嗎？

會一直在這些地方，

等你再回來。

The reactions involved in the FIND-IT assay to detect infection with the SARS-CoV-2 virus. When the Cas13 enzyme (left) binds to its target RNA, it snips a molecule (orange and grey) to release an activator (orange) that supercharges the Csm6 nuclease (bottom center) to cleave and release fluorescent markers that light up (green) and signal the presence of viral RNA. Credit: Artwork courtesy of Margaret L. Liu, University of Chicago Pritzker School of Medicine Frequent, rapid testing for COVID-19 is critical to controlling the spread of outbreaks, especially as new, more transmissible variants emerge. While today’s gold standard COVID-19 diagnostic test, which uses qRT-PCR — quantitative reverse-transcriptase-polymerase chain reaction (PCR) — is extremely sensitive, detecting down to one copy of RNA per microliter, it requires specialized equipment, a runtime of several hours and a centralized laboratory facility. As a result, testing typically takes at least one to two days. A research team led by scientists in the labs of Jennifer Doudna, David Savage, and Patrick Hsu at the University of California, Berkeley, is aiming to develop a diagnostic test that is much faster and easier to deploy than qRT-PCR. It has now combined two different types of CRISPR enzymes to create an assay that can detect small amounts of viral RNA in less than an hour. Doudna shared the 2020 Nobel Prize in Chemistry for the invention of CRISPR-Cas9 genome editing. While the new technique is not yet at the stage where it rivals the sensitivity of qRT-PCR, which can detect just a few copies of the virus per microliter of liquid, it is already able to pick up levels of viral RNA — about 30 copies per microliter — sufficient to be used to surveil the population and limit the spread of infections. “You don’t need the sensitivity of PCR to basically catch and diagnose COVID-19 in the community, if the test’s convenient enough and fast enough,” said co-author David Savage, professor of molecular and cell biology. “Our hope was to drive the biochemistry as far as possible to the point where you could imagine a very convenient format in a setting where you can get tested every day, say, at the entrance to work.” The researchers reported their results on August 5, 2021, in the journal Nature Chemical Biology. Tina Liu and Jennifer Doudna outside the IGI building on the day Doudna won the 2020 Nobel Prize in Chemistry. Credit: UC Berkeley photo by Brittany Hosea-Small Several CRISPR-based assays have been authorized for emergency use by the Food and Drug Administration, but all require an initial step in which the viral RNA is amplified so that the detection signal — which involves release of a fluorescent molecule that glows under blue light — is bright enough to see. While this initial amplification increases the test’s sensitivity to a similar level as qRT-PCR, it also introduces steps that make the test more difficult to carry out outside of a laboratory. The UC Berkeley-led team sought to reach a useful sensitivity and speed without sacrificing the simplicity of the assay. “For point of care applications, you want to have a rapid response so that people can quickly know if they’re infected or not, before you get on a flight, for example, or go visit relatives,” said team leader Tina Liu, a research scientist in Doudna’s lab at the Innovative Genomics Institute (IGI), a CRISPR-focused center involving UC Berkeley and UC San Francisco scientists. Aside from having an added step, another disadvantage of initial amplification is that, because it makes billions of copies of viral RNA, there is a greater chance of cross-contamination across patient samples. The new technique developed by the team flips this around and instead boosts the fluorescent signal, eliminating a major source of cross-contamination. The amplification-free technique, which they term Fast Integrated Nuclease Detection In Tandem (FIND-IT), could enable quick and inexpensive diagnostic tests for many other infectious diseases. “While we did start this project for the express purpose of impacting COVID-19, I think this particular technique could be applicable to more than just this pandemic because, ultimately, CRISPR is programable,” Liu said. “So, you could load the CRISPR enzyme with a sequence targeting flu virus or HIV virus or any type of RNA virus, and the system has the potential to work in the same way. This paper really establishes that this biochemistry is a simpler way to detect RNA and has the capability to detect that RNA in a sensitive and fast time frame that could be amenable for future applications in point of care diagnostics.” The researchers are currently in the process of building such a diagnostic using FIND-IT, which would include steps to collect and process samples and to run the assay on a compact microfluidic device. Employing tandem Cas proteins To remove target amplification from the equation, the team employed a CRISPR enzyme — Cas13 — to first detect the viral RNA, and another type of Cas protein, called Csm6, to amplify the fluorescence signal. Cas13 is a general purpose scissors for cutting RNA; once it binds to its target sequence, specified by a guide RNA, it is primed to cut a broad range of other RNA molecules. This target-triggered cutting activity can be harnessed to couple detection of a specific RNA sequence to release of a fluorescent reporter molecule. However, on its own, Cas13 can require hours to generate a detectable signal when very low amounts of target RNA are present. Liu’s insight was to use Csm6 to amplify the effect of Cas13. Csm6 is a CRISPR enzyme that senses the presence of small rings of RNA and becomes activated to cut a broad range of RNA molecules in cells. To boost Cas13 detection, she and her colleagues designed a specially engineered activator molecule that gets cut when Cas13 detects viral RNA. A fragment of this molecule can bind to and trigger Csm6 to cut and release a bright fluorescent molecule from a piece of RNA. Normally, the activator molecule is quickly broken down by Csm6, thus limiting the amount of fluorescent signal it can generate. Liu and her colleagues devised a way to chemically modify the activator so that it is protected from degradation and can supercharge Csm6 to repeatedly cut and release fluorescent molecules linked to RNA. This results in a sensitivity that is 100 times better than the original activator. “When Cas13 gets activated, it cleaves this small activator, removing a segment that protects it,” Liu said. “Now that it’s liberated, it can activate lots of different molecules of that second enzyme, Csm6. And so, one target recognized by Cas13 doesn’t just lead to activation of its own RNA-cutting ability; it leads to the generation of many more active enzymes that can each then cleave even more fluorescent reporters.” The team of researchers also incorporated an optimized combination of guide RNAs that enables more sensitive recognition of the viral RNA by Cas13. When this was combined with Csm6 and its activator, the team was able to detect down to 31 copies per microliter of SARS-CoV-2 RNA in as little as 20 minutes. The researchers also added extracted RNA from patient samples to the FIND-IT assay in a microfluidic cartridge, to see if this assay could be adapted to run on a portable device. Using a small device with a camera, they could detect SARS-CoV-2 RNA extracted from patient samples at a sensitivity that would capture COVID-19 infections at their peak. “This tandem nuclease approach — Cas13 plus Csm6 — combines everything into a single reaction at a single temperature, 37 degrees Celsius (98.6 degrees Fahrenheit), so it does not require high temperature heating or multiple steps, as is necessary for other diagnostic techniques,” Liu said. “I think this opens up opportunities for faster, simpler tests that can reach a comparable sensitivity to other current techniques and could potentially reach even higher sensitivities in the future.” The development of this amplification-free method for RNA detection resulted from a reorientation of research within IGI when the pandemic began toward problems of COVID-19 diagnosis and treatment. Ultimately, five labs at UC Berkeley and two labs at UCSF became involved in this research project, one of many within the IGI. “When we started this, we had hopes of creating something that reached parity with PCR, but didn’t require amplification — that would be the dream,” said Savage, who was the principal investigator for the project. “And from a sensitivity perspective, we had about a ten thousandfold gap to jump. We’ve made it about a thousandfold; we’ve driven it down about three orders of magnitude. So, we’re almost there. Last April, when we were really starting to map it out, that seemed almost impossible.” Reference: “Accelerated RNA detection using tandem CRISPR nucleases” by Tina Y. Liu, Gavin J. Knott, Dylan C. J. Smock, John J. Desmarais, Sungmin Son, Abdul Bhuiya, Shrutee Jakhanwal, Noam Prywes, Shreeya Agrawal, María Díaz de León Derby, Neil A. Switz, Maxim Armstrong, Andrew R. Harris, Emeric J. Charles, Brittney W. Thornton, Parinaz Fozouni, Jeffrey Shu, Stephanie I. Stephens, G. Renuka Kumar, Chunyu Zhao, Amanda Mok, Anthony T. Iavarone, Arturo M. Escajeda, Roger McIntosh, Shineui Kim, Eli J. Dugan, IGI Testing Consortium, Katherine S. Pollard, Ming X. Tan, Melanie Ott, Daniel A. Fletcher, Liana F. Lareau, Patrick D. Hsu, David F. Savage and Jennifer A. Doudna, 5 August 2021, Nature Chemical Biology. DOI: 10.1038/s41589-021-00842-2 The work was supported by the Defense Advanced Research Projects Agency (N66001-20-2-4033). Co-authors of the paper include members of the labs of Jennifer Doudna, David Savage, Patrick Hsu, Liana Lareau and Daniel Fletcher at UC Berkeley; Gavin Knott at Monash University in Australia; Melanie Ott and Katherine Pollard at Gladstone Institutes and UCSF; and Ming Tan at Wainamics, a research and development firm in Pleasanton, California, that produces microfluidic devices. Doudna, IGI’s founder and currently president and chair of the IGI governance board, is the Li Ka Shing Chancellor’s Chair at UC Berkeley and a professor of chemistry and of molecular and cell biology. Hsu, Lareau and Fletcher are faculty in the Department of Bioengineering.

A new study reveals hydrogen gas’s role as an energy source at life’s dawn, underscoring its potential as a sustainable fuel. Through examining the natural processes at hydrothermal vents and the early cellular mechanisms for harnessing hydrogen, researchers have gained insights into the origins of life and the ancient utilization of hydrogen as an energy source. This research not only illuminates hydrogen’s historical significance but also its future role in sustainable energy. Hydrogen gas, dubbed the energy of the future, has been providing energy since 4 billion years ago. A recent study reveals how hydrogen gas, often touted as the energy source of tomorrow, provided energy in the past, at the origin of life 4 billion years ago. Hydrogen gas is clean fuel. It burns with oxygen in the air to provide energy with no CO2. Hydrogen is a key to sustainable energy for the future. Though humans are just now coming to realize the benefits of hydrogen gas (H2 in chemical shorthand), microbes have known that H2 is a good fuel for as long as there has been life on Earth. Hydrogen is ancient energy. The very first cells on Earth lived from H2 produced in hydrothermal vents, using the reaction of H2 with CO2 to make the molecules of life. Microbes that thrive from the reaction of H2 and CO2 can live in total darkness, inhabiting spooky, primordial habitats like deep-sea hydrothermal vents or hot rock formations deep within the Earth’s crust, environments where many scientists think that life itself arose. Discovery of Hydrogen’s Role in Early Cellular Energy Harvesting Surprising new insights about how the first cells on Earth came to harness H2 as an energy source are now reported in PNAS. The new study comes from the team of William F. Martin at the University of Düsseldorf and Martina Preiner at the Max Planck Institute (MPI) for Terrestrial Microbiology in Marburg with support from collaborators in Germany and Asia. In order to harvest energy, cells first have to push the electrons from H2 energetically uphill. “That is like asking a river to flow uphill instead of downhill, so cells need engineered solutions,” explains one of the three first authors of the study, Max Brabender. Image from the Sulis formation in the Lost City hydrothermal field, an alkaline hydrothermal vent that produces hydrogen. Credit: Courtesy of Susan Lang, U. of South Carolina /NSF/ROV Jason 2018 © Woods Hole Oceanographic Institution How cells solve that problem was discovered only 15 years ago by Wolfgang Buckel together with his colleague Rolf Thauer in Marburg. They found that cells send the two electrons in hydrogen down different paths. One electron goes far downhill, so far downhill that it sets something like a pulley (or a siphon) in motion that can pull the other electron energetically uphill. This process is called electron bifurcation. The Mechanisms of Electron Bifurcation and Early Evolutionary Puzzle In cells, it requires several enzymes that send the electrons uphill to an ancient and essential biological electron carrier called ferredoxin. The new study shows that at pH 8.5, typical of naturally alkaline vents, “no proteins are required,” explains Buckel, co-author on the study, “the H–H bond of H2 splits on the iron surface, generating protons that are consumed by the alkaline water and electrons that are then easily transferred directly to ferredoxin.” How an energetically uphill reaction could have worked in early evolution, before there were enzymes or cells, has been a very tough puzzle. “Several different theories have proposed how the environment might have pushed electrons energetically uphill to ferredoxin before the origin of electron bifurcation,“ says Martin, “we have identified a process that could not be simpler and that works in the natural conditions of hydrothermal vents”. Since the discovery of electron bifurcation, scientists have found that the process is both ancient and absolutely essential in microbes that live from H2. The vexing problem for evolutionarily-minded chemists like Martina Preiner, whose team in Marburg focusses on the impact of the environment on reactions that microbes use today and possibly used at life’s origin, is: How was H2 harnessed for CO2 fixing pathways before there were complicated proteins? “Metals provide answers,”, she says, “at the onset of life, metals under ancient environmental conditions can send the electrons from H2 uphill, and we can see relicts of that primordial chemistry preserved in the biology of modern cells.” But metals alone are not enough. “H2 needs to be produced by the environment as well” adds co-first author Delfina Pereira from Preiner’s lab. Such environments are found in hydrothermal vents, where water interacts with iron-containing rocks to make H2, and where microbes still live today from that hydrogen as their source of energy. The Surprising Role of Hydrogen in Forming Metallic Iron Hydrothermal vents, both modern and ancient, generate H2 in such large amounts that the gas can turn iron-containing minerals into shiny metallic iron. “That hydrogen can make metallic iron out of minerals is no secret,” says Harun Tüysüz, expert for high-tech materials at the Max-Planck-Institut für Kohlenforschung Mülheim and coauthor on the study. “Many processes in the chemical industry use H2 to make metals out of minerals during the reaction.” The surprise is that nature does this too, especially at hydrothermal vents, and that this naturally deposited iron could have played a crucial role at the origin of life. Iron was the only metal identified in the new study that was able to send the electrons in H2 uphill to ferredoxin. But the reaction only works under alkaline conditions like those in a certain type of hydrothermal vents. Natalia Mrnjavac from the Düsseldorf group and co-first author on the study points out: “This fits well with the theory that life arose in such environments. The most exciting thing is that such simple chemical reactions can close an important gap in understanding the complex process of origins, and that we can see those reactions working under the conditions of ancient hydrothermal vents in the laboratory today.” Reference: “Ferredoxin reduction by hydrogen with iron functions as an evolutionary precursor of flavin-based electron bifurcation” by Max Brabender, Delfina P. Henriques Pereira, Natalia Mrnjavac, Manon Laura Schlikker, Zen-Ichiro Kimura, Jeerus Sucharitakul, Karl Kleinermanns, Harun Tüysüz, Wolfgang Buckel, Martina Preiner and William F. Martin, 21 March 2024, Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2318969121

Dr. Tyler Wenzel at the University of Saskatchewan has developed “mini-brains” from human stem cells, aiming to revolutionize Alzheimer’s diagnosis and treatment. This breakthrough could benefit remote areas significantly, reduce healthcare system burdens, and expand to other brain-related conditions. (Artist’s concept). Credit: SciTechDaily.com “Mini-brains” developed by Dr. Wenzel using stem cells could transform Alzheimer’s treatment and diagnosis, showing potential for broader medical applications and more efficient healthcare delivery. Dr. Tyler Wenzel from the University of Saskatchewan (USask) has devised an innovative new method to build miniature brains from stem cells. Wenzel’s “mini-brain” could revolutionize the way Alzheimer’s and other brain-related diseases are diagnosed and treated. “Never in our wildest dreams did we think that our crazy idea would work,” he said. “These could be used as a diagnostic tool, built from blood.” Wenzel, a postdoctoral fellow in the College of Medicine’s Department of Psychiatry, developed the idea for the “mini-brain” – or more formally, a one-of-a-kind cerebral organoid model – while working under the supervision of Dr. Darrell Mousseau (PhD). A “mini-brain” in a petri dish – when created from the stem cells of individuals who have Alzheimer’s disease, the organoids display the pathology of Alzheimer’s – just on a smaller scale. Credit: USask/David Stobbe Unique Capabilities of Stem Cell-Derived Organoids Human stem cells can be manipulated to develop into practically any other cell in the body. Using stem cells taken from human blood, Wenzel was able to create a tiny artificial organ – roughly three millimeters across and resembling visually what Wenzel described as a piece of chewed gum someone has tried to smooth out again. These “mini-brains” are built by creating stem cells from a blood sample, and then transforming these stem cells into functioning brain cells. Using small synthetic organoids for research is not a novel concept – but the “mini-brains” developed in Wenzel’s lab are unique. As outlined in Wenzel’s recently published article in Frontiers of Cellular Neuroscience, the brains from Wenzel’s lab are comprised of four different types of brain cells while most brain organoids are comprised of only neurons. In testing, Wenzel’s “mini-brains” more accurately reflect a fully-fledged adult human brain, so they can be used to more closely examine neurological conditions of adult patients, such as Alzheimer’s disease. While a USask-designed “mini-brain” synthetic organoid might look like a tiny wad of chewing gum, it could be a game-changer for Alzheimer’s research. Credit: USask/David Stobbe Potential of Mini-Brains in Diagnosing Alzheimer’s Wenzel determined that the “mini-brains” he created from the stem cells of individuals who have Alzheimer’s also displayed the pathology of Alzheimer’s – just on a smaller scale. “If stem cells have the capacity to become any cell in the human body, the question then came ‘could we create something that resembles an entire organ?’” Wenzel said. “While we were developing it, I had the crazy idea that if these truly are human brains, if a patient had a disease like Alzheimer’s and we grew their ‘mini-brain,’ in theory that tiny brain would have Alzheimer’s.” The researcher said this technology has the potential to change the way health services are provided to those with Alzheimer’s, particularly in rural and remote communities. This groundbreaking research has already received support from the Alzheimer Society of Canada. Dr. Tyler Wenzel (PhD), postdoctoral fellow in the USask College of Medicine’s Department of Psychiatry. Credit: USask/David Stobbe Expanding Applications and Future Research If Wenzel and his colleagues can create a consistent way to diagnose and treat neurological conditions like Alzheimer’s using only a small blood sample – which has a relatively long shelf life and can be couriered – instead of requiring patients to travel to hospitals or specialized clinics, it could save the healthcare system a tremendous amount of resources and lift a burden off of patients. “In theory, if this tool works the way we think it does, we could just get a blood sample shipped from La Loche or La Ronge to the university and diagnose you like that,” he said. The early proof-of-concept work on the “mini-brains” has been extremely promising – which means the next step for Wenzel is expanding the testing to a larger pool of patients. The researchers are also interested in trying to expand the scope of the “mini-brain” research. According to Wenzel, if they can confirm the “mini-brains” accurately reflect other brain diseases or neurological conditions, they could potentially be used to speed up diagnoses or test the efficacy of drugs on patients. As an example, Wenzel pointed to the substantial wait times to see a psychiatrist in Saskatchewan. If the “mini-brains” could be used to test which antidepressant works best on a patient suffering from depression, it could dramatically reduce the time required to see a doctor and receive a prescription. A former high school science teacher who made a move into the world of research and academia, Wenzel said it’s the “nature of research” to come up with a hypothesis and hit close to the mark in an experiment that excites him his work. The astounding success of the early “mini-brains,” however, has been so staggering that Wenzel admitted he still struggles to wrap his own brain around it. “I’m still in disbelief, but it’s also extremely motivating that something like this happened,” Wenzel said. “It gives me something that I think will impact society and have actual relevance and create some change … it has a strong potential to shift the landscape of medicine.” Reference: “Brain organoids engineered to give rise to glia and neural networks after 90 days in culture exhibit human-specific proteoforms” by Tyler J. Wenzel and Darrell D. Mousseau, 18 April 2024, Frontiers in Cellular Neuroscience. DOI: 10.3389/fncel.2024.1383688

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