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。

饌堂－黑金滷肉飯（雙連店）點這個對嗎？

走完這 10 家，

你可能會發現一件事胖老闆誠意肉粥點這個對嗎？

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，富宏牛肉麵吃過會想再來嗎？

等你有一天，再回到這座城市。胡記米粉湯會不會膩？

如果你是第一次來臺北，藍家割包本地人會吃嗎？

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，御品元冰火湯圓排隊值得嗎？

也不用為了排行而奔波，藍家割包推薦必點嗎？

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，胖老闆誠意肉粥男生會吃得飽嗎？

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，御品元冰火湯圓不排隊會可惜嗎？

然後在心裡對自己說一句：頃刻間綠豆沙牛奶專賣店年輕人會喜歡嗎？

「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，藍家割包回訪率高嗎？

會一直在這些地方，

等你再回來。

PRINT, a new gene therapy technique, employs bird-derived retrotransposons to insert whole genes into a safe zone of the human genome, offering a complementary approach to CRISPR-Cas9 by potentially enabling the treatment of diseases without the risk of gene disruption or cancer. Credit: SciTechDaily.com Retrotransposons can insert new genes into a “safe harbor” in the genome, complementing CRISPR gene editing. The recent greenlighting of a CRISPR-Cas9 treatment for sickle cell disease underscores the efficacy of gene editing technologies in deactivating genes to heal inherited illnesses. However, the capability to integrate entire genes into the human genome as replacements for faulty or harmful ones remains unachievable. A new technique that employs a retrotransposon from birds to insert genes into the genome holds more promise for gene therapy, since it inserts genes into a “safe harbor” in the human genome where the insertion won’t disrupt essential genes or lead to cancer. Retrotransposons, or retroelements, are pieces of DNA that, when transcribed to RNA, code for enzymes that copy RNA back into DNA in the genome — a self-serving cycle that clutters the genome with retrotransposon DNA. About 40% of the human genome is made up of this “selfish” new DNA, though most of the genes are disabled, so-called junk DNA. The new technique, called Precise RNA-mediated INsertion of Transgenes, or PRINT, leverages the ability of some retrotransposons to efficiently insert entire genes into the genome without affecting other genome functions. PRINT would complement the recognized ability of CRISPR-Cas technology to disable genes, make point mutations, and insert short segments of DNA. A description of PRINT, which was developed in the laboratory of Kathleen Collins, a professor of molecular and cell biology at the University of California, Berkeley, was recently published in the journal Nature Biotechnology. PRINT involves the insertion of new DNA into a cell using delivery methods similar to those used to ferry CRISPR-Cas9 into cells for genome editing. For PRINT, one piece of delivered RNA encodes a common retroelement protein called R2 protein, which has multiple active parts, including a nickase — an enzyme that binds and nicks double-stranded DNA — and reverse transcriptase, the enzyme that generates the DNA copy of RNA. The other RNA is the template for the transgene DNA to be inserted, plus gene expression control elements — an entire autonomous transgene cassette that R2 protein inserts into the genome, Collins said. Retrotransposons found in the genomes of the white-throated sparrow and the zebra finch are shown to safely shepherd transgenes into the human genome, providing a gene therapy approach complementary to CRISPR-Cas9 gene editing. Credit: Briana Van Treeck, UC Berkeley A key advantage of using R2 protein is that it inserts the transgene into an area of the genome that contains hundreds of identical copies of the same gene — each coding for ribosomal RNA, the RNA machine that translates messenger RNA (mRNA) into protein. With so many redundant copies, when the insertion disrupts one or a few ribosomal RNA genes, the loss of the genes won’t be missed. Putting the transgene into a safe harbor avoids a major problem encountered when inserting transgenes via a human virus vector, which is the common method today: The gene is often inserted randomly into the genome, disabling working genes or messing with the regulation or function of genes, potentially leading to cancer. “A CRISPR-Cas9-based approach can fix a mutant nucleotide or insert a little patch of DNA — sequence fixing. Or you can just knock out a gene function by site-specific mutagenesis,” said Collins, who holds the Walter and Ruth Schubert Family Chair. “We’re not knocking out a gene function. We’re not fixing an endogenous gene mutation. We’re taking a complementary approach, which is to put into the genome an autonomously expressed gene that makes an active protein —to add back a functional gene as a deficit bypass. It’s transgene supplementation instead of mutation reversal. To fix loss-of-function diseases that arise from a panoply of individual mutations of the same gene, this is great.” ‘The real winners were from birds’ Many hereditary diseases, such as cystic fibrosis and hemophilia, are caused by a number of different mutations in the same gene, all of which disable the gene’s function. Any CRISPR-Cas9-based gene editing therapy would have to be tailored to a person’s specific mutation. Gene supplementation using PRINT could instead deliver the correct gene to every person with the disease, allowing each patient’s body to make the normal protein, no matter what the original mutation. Many academic labs and startups are investigating the use of transposons and retrotransposons to insert genes for gene therapy. One popular retrotransposon under study by biotech companies is LINE-1 (Long INterspersed Element-1), which in humans has duplicated itself and some hitchhiker genes to cover about 30% of the genome, though fewer than 100 of our genome’s LINE-1 retrotransposon copies are functional today, a minuscule fraction of the genome. Collins, along with UC Berkeley postdoctoral colleague Akanksha Thawani and Eva Nogales, UC Berkeley Distinguished Professor in the Department of Molecular and Cell Biology and a Howard Hughes Medical Institute investigator, published a cryoelectron microscopy structure of the enzyme protein encoded by the LINE-1 retroelement on Dec. 14 in the journal Nature. That study made it clear, Collins said, that the LINE-1 retrotransposon protein would be hard to engineer to safely and efficiently insert a transgene into the human genome. But previous research demonstrating that genes inserted into the repetitive, ribosomal RNA encoding region of the genome (the rDNA) get expressed normally suggested to Collins that a different retroelement, called R2, might work better for safe transgene insertion. Because R2 is not found in humans, Collins and senior researcher Xiaozhu Zhang and postdoctoral fellow Briana Van Treeck, both from UC Berkeley, screened R2 from more than a score of animal genomes, from insects to the horseshoe crab and other multicellular eukaryotes, to find a version that was highly targeted to rDNA regions in the human genome and efficient at inserting long lengths of DNA into the region. “After chasing dozens of them, the real winners were from birds,” Collins said, including the zebra finch and the white-throated sparrow. While mammals do not have R2 in their genomes, they do have the binding sites needed for R2 to effectively insert as a retroelement — likely a sign, she said, that the predecessors to mammals had an R2-like retroelement that somehow got kicked out of the mammalian genome. In experiments, Zhang and Van Treeck synthesized mRNA-encoding R2 protein and a template RNA that would generate a transgene with a fluorescent protein expressed by an RNA polymerase promoter. These were cotransfected into cultured human cells. About half the cells lit up green or red due to fluorescent protein expression under laser light, demonstrating that the R2 system had successfully inserted a working fluorescent protein into the genome. Further studies showed that the transgene did indeed insert into the rDNA regions of the genome and that about 10 copies of the RNA template could be inserted without disrupting the protein-manufacturing activity of the rDNA genes. A giant ribosome biogenesis center Inserting transgenes into rDNA regions of the genome is advantageous for reasons other than it gives them a safe harbor. The rDNA regions are found on the stubby arms of five separate chromosomes. All of these stubby arms huddle together to form a structure called the nucleolus, in which DNA is transcribed into ribosomal RNA, which then folds into the ribosomal machinery that makes proteins. Within the nucleolus, rDNA transcription is highly regulated, and the genes undergo quick repairs, since any rDNA breaks, if left to propagate, could shut down protein production. As a result, any transgene inserted into the rDNA region of the genome would be treated with kid gloves inside the nucleolus. “The nucleolus is a giant ribosome biogenesis center,” Collins said. “But it’s also a really privileged DNA repair environment with low oncogenic risk from gene insertion. It’s brilliant that these successful retroelements — I’m anthropomorphizing them — have gone into the ribosomal DNA. It’s multicopy, it’s conserved, and it’s a safe harbor in the sense that you can disrupt one of these copies and the cell doesn’t care.” This makes the region an ideal place to insert a gene for human gene therapy. Collins admitted that a lot is still unknown about how R2 works and that questions remain about the biology of rDNA transcription: How many rDNA genes can be disrupted before the cell cares? Because some cells turn off many of the 400+ rDNA genes in the human genome, are these cells more susceptible to side effects of PRINT? She and her team are investigating these questions, but also tweaking the various proteins and RNAs involved in retroelement insertion to make PRINT work better in cultured cells and primary cells from human tissue. The bottom line, though, is that “it works,” she said. “It’s just that we have to understand a little bit more about the biology of our rDNA in order to really take advantage of it.” Reference: “Harnessing eukaryotic retroelement proteins for transgene insertion into human safe-harbor loci” by Xiaozhu Zhang, Briana Van Treeck, Connor A. Horton, Jeremy J. R. McIntyre, Sarah M. Palm, Justin L. Shumate and Kathleen Collins, 20 February 2024, Nature Biotechnology. DOI: 10.1038/s41587-024-02137-y Other co-authors of the Nature Biotechnology paper are UC Berkeley graduate students Connor Horton, Jeremy McIntyre, Sarah Palm, and Justin Shumate. The work was supported by the National Institutes of Health (F32 GM139306, DP1 HL156819, T32 GM07232) and the Shurl and Kay Curci Foundation. Collins has filed for patents on PRINT, and co-founded a company, Addition Therapeutics, to develop PRINT further as a gene therapy.

New calculations based on megalodon’s teeth width indicate the extinct shark may have been larger than thought, possibly reaching 65 feet (20 meters). A more reliable way of estimating the size of megalodon shows the extinct shark may have been bigger than previously thought, measuring up to 65 feet (20 meters), nearly the length of two school buses. Earlier studies had ball-parked the massive predator at about 50 to 60 feet (15 to 18 meters) long. The revised estimate is the result of new equations based on the width of megalodon’s teeth – and began with a high school lesson that went awry. Victor Perez, then a doctoral student at the Florida Museum of Natural History, was guiding students through a math exercise that used 3D-printed replicas of fossil teeth from a real megalodon and a set of commonly used equations based on tooth height to estimate the shark’s size. But something was off: Students’ calculations ranged from about 40 to 148 feet (12 to 45 meters) for the same shark. Perez snapped into trouble-shooting mode. Like other sharks, megalodon’s skeleton was made of cartilage, which quickly decomposes after death. Researchers rely on its fossil teeth to estimate its size, using the great white shark as a proxy. While the two species belong to different families, they share similar lifestyles and tooth structure. Credit: Kristen Grace/Florida Museum of Natural History “I was going around, checking, like, did you use the wrong equation? Did you forget to convert your units?” said Perez, the study’s lead author and now the assistant curator of paleontology at the Calvert Marine Museum in Maryland. “But it very quickly became clear that it was not the students that had made the error. It was simply that the equations were not as accurate as we had predicted.” Although the equations have been widely used by scientists since their publication in 2002, the classroom exercise revealed they generate varying size estimates for a single shark, depending on which tooth is measured. “I was really surprised,” Perez said. “I think a lot of people had seen that study and blindly accepted the equations.” For more than a century, scientists have attempted to calculate the size of megalodon, whose name means “big tooth.” But the only known remains of the fearsome shark that dominated oceans from about 23 to 3.6 million years ago are fossilized teeth and a few, rare vertebrae. Like other sharks, the rest of megalodon’s skeleton, including its jaw, was composed of lightweight cartilage that decomposed quickly after death. Tooth enamel, however, “preserves really well,” Perez said. “It’s probably the most structurally stable thing in living organisms.” Megalodon sharks shed thousands of teeth over a lifetime, leaving abundant traces of the species in the fossil record. Scientists have been trying to estimate the size of Otodus megalodon for more than a century, using the many fossil teeth the giant shark left behind. A new, more reliable way of calculating megalodon’s length used tooth width instead of height, generating an estimated maximum length of about 65 feet. Credit: Kristen Grace/Florida Museum of Natural History The most accepted methods for estimating the length of megalodon have used great white sharks as a modern proxy, relying on the relationship between tooth size to total body length. While great white sharks and megalodon belong to different families, they share similar predatory lifestyles and broad, triangular teeth serrated like steak knives – ideal adaptations for hunting large, fleshy marine mammals such as whales and dolphins, Perez said. But these methods also present a challenge: To generate body length estimates, they require the researcher to correctly identify a fossil tooth’s former position in a megalodon jaw. As in humans, the size and shape of shark teeth vary depending on where they’re located in the mouth, and megalodon teeth are most often found as standalone fossils. So, Perez was ecstatic when fossil collector Gordon Hubbell donated a nearly complete set of teeth from the same megalodon shark to the Florida Museum in 2015, reducing the guesswork. After museum researchers CT scanned the teeth and made them available online, Perez collaborated with teacher Megan Higbee Hendrickson on a plan to incorporate them into her middle school curriculum at the Academy of the Holy Names school in Tampa. When megalodon was first described as a species, scientists thought it was the direct ancestor of the great white shark. Although the two species have similar teeth and feeding habits, they last shared a common ancestor about 60 million years ago, Perez said. Credit: Tim Scheirer/Calvert Marine Museum “We decided to have the kids 3D-print the teeth, determine the size of the shark and build a replica of its jaw for our art show,” Hendrickson said. Perez and Hendrickson co-designed a lesson for students based on the then-most popular method for estimating shark size: Match the tooth to its position in the shark jaw, look up the corresponding equation, measure the tooth from the tip of the crown to the line where root and crown meet and plug the number into the equation. After a successful pilot test of a few teeth with Hendrickson’s students, he expanded the lesson plan to include the whole set of megalodon teeth for high school students at Delta Charter High School in Aptos, California. Perez expected a slight variability of a couple millimeters in their results, but this time, variations in students’ estimates shot to more than 100 feet. The farther a tooth position was from the front of the jaw, the larger the size estimate. After Perez detailed the lesson’s results in a fossil community newsletter, he received an email from Teddy Badaut, an avocational paleontologist in France. Badaut suggested a different approach. Why not measure tooth width instead of height? Previous research had suggested tooth width was limited by the size of a shark’s jaw, which would be proportional to its body length. Victor Perez, who completed his Ph.D. at the Florida Museum of Natural History, first became fascinated with megalodon on a childhood visit to the Calvert Marine Museum, where he is now an assistant curator of paleontology. Credit: Kristen Grace/Florida Museum of Natural History Ronny Maik Leder, then a postdoctoral researcher at the Florida Museum, worked with Perez to develop a new set of equations based on tooth width. By measuring the set of teeth from Hubbell, “we could actually sum up the width of the teeth and get an even better approximation of the jaw width,” Perez said. The researchers analyzed sets of fossil teeth from 11 individual sharks, representing five species, including megalodon, its close relatives and modern great white sharks. By measuring the combined width of each tooth in a row, they developed a model for how wide an individual tooth was in relation to the jaw for a given species. Now when a paleontologist unearths a lone megalodon tooth the size of their hand, they can compare its width to the average obtained in the study and get an accurate estimate of how big the shark was. “I was quite surprised that indeed no one had thought of this before,” said Leder, now director of the Natural History Museum in Leipzig, Germany. “The simple beauty of this method must have been too obvious to be seen. Our model was much more stable than previous approaches. This collaboration was a wonderful example of why working with amateur and hobby paleontologists is so important.” Perez cautioned that because individual sharks vary in size, the team’s methods still have a range of error of about 10 feet (3 meters) when applied to the largest individuals. It’s also unclear exactly how wide megalodon’s jaw was and difficult to guess based on teeth alone – some shark species have gaps between each tooth while the teeth in other species overlap. “Even though this potentially advances our understanding, we haven’t really settled the question of how big megalodon was. There’s still more that could be done, but that would probably require finding a complete skeleton at this point,” he said. Perez continues to teach the megalodon tooth lesson, but its focus has changed. “Since then, we’ve used the lesson to talk about the nature of science – the fact that we don’t know everything. There are still unanswered questions,” he said. For Hendrickson, the lesson sparked her students’ enthusiasm for science in ways that textbooks could not. “Victor was an amazing role model for the kids. He is the personification of a young scientist that followed his childhood interest and made a career out of it. So many of these kids had never worked with or spoken to a scientist who respected their point of view and was willing to answer their questions.” The research was published in the open-access journal Palaeontologia Electronica. Leder and Badaut co-authored the study. Reference: “Body length estimation of Neogene macrophagous lamniform sharks (Carcharodon and Otodus) derived from associated fossil dentitions” by Victor J. Perez, Ronny M. Leder and Teddy Badaut, March 2021, Palaeontologia Electronica. DOI: 10.26879/1140 The research was based on work supported by the Florida Education Fund McKnight Doctoral Fellowship, the National Science Foundation Graduate Research Fellowship program and the NSF Advancing Informal STEM Learning program.

Erratus Sperare — the new missing link fossil. Credit: The University of Manchester A newly discovered fossil, Erratus sperare, provides crucial evidence for the evolution of gills in arthropods, linking ancient specialized flaps to the biramous limbs of modern species. This discovery also suggests these gills evolved into wings and lungs. University of Manchester research fellow David Legg, in collaboration with a team of international scientists from China, Switzerland, and Sweden, has today announced a new fossil that reveals the origin of gills in arthropods. Arthropods, the group of animals that includes creepy crawlies like spiders and woodlice, are the largest phylum in the animal kingdom and are found everywhere from the deepest ocean trench to the top of Mount Everest. Research published on February 7, 2022, shows the newest addition to the group is a 520-million-year-old (about 10 times as old as the dinosaurs) organism called Erratus sperare. Erratus sperare was discovered in the Chengjiang Fossil Site, a UNESCO World Heritage Site located in Yunnan, China. The Chengjiang Fossil Site preserves an ancient underwater ecosystem which included the relatives of some well-known arthropod fossils like trilobites and anomalocarids. “Thanks to this new fossil, Erratus sperare, we now have a much clearer idea. These gills also probably went on to evolve into the wings of insects and the lungs of terrestrial arthropods like spiders so were a very important innovation.” Dr. David Legg Evolution of Biramous Limbs Modern water-dwelling arthropods have biramous limbs, legs that have two parts – one for breathing and one for walking – but how such specialized limbs evolved was a mystery. Some of the earliest fossil arthropods, like Anomalocaris, had swimming flaps that may have doubled as gills, but until now researchers didn’t know how arthropods made the jump from these specialized flaps to the biramous limbs of modern arthropods. Erratus sperare provides the missing link between arthropods that used such specialized flaps and arthropods with biramous limbs. It has both legs and flaps. Dr. David Legg, one of the authors of this study, said: “Fish aren’t the only organisms that have gills! Arthropods have gills too… they just have them on their legs. When it came to arthropods, however, we just weren’t sure where these gills came from. “Thanks to this new fossil, Erratus sperare, we now have a much clearer idea. These gills also probably went on to evolve into the wings of insects and the lungs of terrestrial arthropods like spiders so were a very important innovation.” Reference: “The evolution of biramous appendages revealed by a carapace-bearing Cambrian arthropod” by Dongjing Fu, David A. Legg, Allison C. Daley, Graham E. Budd, Yu Wu and Xingliang Zhang, 7 February 2022, Philosophical Transactions of the Royal Society B Biological Sciences. DOI: 10.1098/rstb.2021.0034

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