饒毅：世界科學史的百年冤案（中英對照）

　　【本文發表于2019年英文《內分泌與代謝趨勢》雜志，評論迄今廣為流傳的有關腎上腺素的科學史錯誤】

　　本文指出生物醫學史上有三個錯誤與腎上腺素有關：一是誤認為第一個激素是胰泌素，二是誤認為化學分離純化腎上腺素的為美國藥理學家John Abel，三是美國堅稱腎上腺素為epinephrine。

　　實際上：第一個激素是腎上腺素，因為發現活性的時間和分子得到純化的時間都是腎上腺素先于胰泌素；分離到真正腎上腺素的是旅美日本科學家高峰讓吉 (Jōkichi Takamine，1854-1922)，時間為1901年；腎上腺素的英文正確名稱為adrenaline，而epinephrine是無生物學活性的化學衍生物。

　　如果科學界真正公平，日本的第一項諾貝爾生理或醫學獎可能就不是2012年，而推前一百年。日本本土和旅居西方的科學家在科學上有較多重大發現。不過，日本人還長期受美國無意忽視和有意打壓。在生物學方面，早在1901年，日本科學家不止一次達到了相當高的程度。

高峰讓吉

　　高峰讓吉于1901年發現了世界上第一個激素：腎上腺素，命名為adrenalin。但教科書一般誤認為1902年英國生理學家發現了第一個激素（胰泌素），而美國人堅持稱腎上腺素為epinephrine，后兩個錯誤遺留至今。

　　高峰讓吉父母本希望他學醫，但他喜歡上了化學，畢業于東京帝國大學應用化學系，后赴英國格拉斯哥念研究生。回日本后，他建了日本第一個化肥廠（日本人造肥料公司）（Yamashita，2003）。高峰讓吉訪問美國期間，與美國人Caroline Field Hitch戀愛，回日本工作后再度赴美完婚，其后妻子與他回日本。他在日本發現了一種淀粉酶（diastase，amylase），可以降解淀粉，大大降低發酵時間（和成本）。他的岳母建議他到芝加哥將這種酶用于威士忌制造過程。高峰讓吉和妻子從此定居美國。他在芝加哥不遠的Peoria建立了“高峰發酵公司”（Takamine Ferment Company），但遭反對，廠房被縱火焚毀，公司被解散。房漏偏逢下雨天，他自己又得了肝病，妻子以為他病得要死了，緊急住院，一住就幾個月。住院期間，他意識到醫院的飲食以淀粉為主，而三分之二的病人有消化不良(dyspepsia)，他把自己發現的酶命名為Taka-Diastase（高峰淀粉酶），治療消化不良很有效，他獲得ZL后將使用權授予Parke-Davis藥廠，銷售逾三千萬美元，這是他對生物技術產業的貢獻（Yamashita，2003）。

　　高峰讓吉個人收入也可觀，因此于1897年在紐約建自己的實驗室。1900年，他請上中啟三（Keizo Uenaka，1876-1960） 為助手，后者的老師為東京帝大的長井長義（Nagayoshi Nagai，1844-1929），長井長義的一項重要科學工作是從中藥麻黃提取麻黃素（ephedrine）（Nagai，1892）。

　　腎上腺髓質活性成分的分離純化

　　位于美國密西根州底特律的Parke-Davis藥廠建議高峰讓吉分離提取腎上腺所含的化學分子。顧名思義，腎上腺是位于腎臟上面的一個腺體。1855年，倫敦Guy’s醫院的Thomas Addison醫生（1793-1860）發現腎上腺損害后的疾病，后稱為Addison病，人們從而感興趣腎上腺的內涵。很快就有科學家用動物做實驗，試圖看切除動物的腎上腺對動物的影響，常常發現動物死亡（Sch?fer，1908）。

　　George Oliver（1841-1915）是一位對研究感興趣的英國醫生，在家做研究，設計實驗儀器（如他自行了血壓計，當時醫生對血壓還普遍不重視），甚至用兒子做實驗動物。他曾給自己兒子吃腎上腺的提取物（Barcroft and Talbot, 1968）。倫敦大學學院生理系教授Edward Albert Sch?fer（1850-1935）是著名生理學家，除了科學優秀，包括提出“內分泌”概念，還有個人特色，例如：為紀念自己的導師William Sharpey（1802-1880），Sch?fer把長子命名為John Sharpey Sch?fer。他兒子去世后，為了紀念老師和兒子，他把自己改名Edward Albert Sharpey-Sch?fer，而且自己家的姓從此改成Sharpey-Sch?fer。1893年，Oliver慕名找到 Sch?fer，提出合作研究腎上腺提取物的作用（Davenport, 1991）。Oliver和 Sch?fer于1894年發表兩篇會議摘要、1895年發表文章，發現腎上腺提取物的作用，包括收縮血管、升高血壓、加快心跳。

　　1895年，Sch?fer讓自己的兩位同事研究了腎上腺提取物的化學特性（Moore，1895；Nabarro，1895）。1897年，德國科學家Sigmund Fr?nkel（1868-1939）提取了腎上腺的物質，他取名為spygmogenin（Fr?nkel，1897）。1897年，美國霍普金斯大學藥理學系John J Abel（1857-1938）從腎上腺提取到一個分子（Abel and Crawford, 1897； Abel, 1898,1899），他命名為epinephrin，分子式為C17H15NO4（Abel, 1898）。1900年，在德國斯特拉斯堡大學工作的奧地利猶太科學家Otto von Fürth（1867-1938）認為epinephrin沒有生物學活性，Fürth把自己從腎上腺提取的分子命名為suprarenin，分子式為C5H9NO2（von Fürth，1900）。1901年，Abel發表專文回復Fürth的質疑，辯解自己分離的分子還是有活性的，但它不是天然分子（native principle）而是衍生物，可能多了一個苯甲酰（benzoyl）（Abel，1901）。

　　1900年，高峰讓吉和上中啟三獲得了生物活性很強、結晶純的分子，分子式為C10H15NO3。高峰的朋友Wilson醫生建議他命名為adrenaline。高峰讓吉于1901年1月在紐約舉行的化工學會作報告，并于1901年在《美國藥學雜志》發表其結果（Takamine，1901）。1901年12月高峰讓吉在英國生理學會作報告，并于1902年發表于英國《生理學雜志》（Takamine，1902）。

　　Parke-Davis藥廠科學實驗室生物部的Thomas Aldrich于1900年夏也分離了腎上腺素，1901年發表了論文。他認同高峰讓吉當年年初在化工學會的報告， Aldrich通過實驗比較了自己的樣本和高峰讓吉的樣本，推出兩種樣本的正確分子式都是：C9H13NO3（Aldrich，1901）。這一正確的分子式也最接近高峰此前推出的分子式，而與Abel和Fürth的分子式相差甚遠。

同研究領域的科學家通常稱Adrenaline而非Epinephrine

　　1903年，德國伯恩大學的化學家Hermann Pauly（1870-1950）確定了腎上腺素的結構式（Pauly，1903，1904），他也認為高峰讓吉分離純化了有活性的分子，而Abel的epinephrine不可能有活性。

　　1904年，第一位合成腎上腺素的德國化學家Friedrich Stolz（1860-1936）也用adrenalin名稱（Stolz，1904）。1905年，英國科學家Henry Dakin（1880-1952）合成adrenaline時引用高峰讓吉和Aldrich作為發現adrenaline，而不是引用Abel的文章作為發現（Dakin，1905）。

　　1906年，英國著名藥理學家、1936年諾獎得主Henry Dale（1875-1968）堅持認為adrenaline是正確的命名，而不能以Abel沒有活性的epinephrine命名（Tansey，1995；Aronson，2000）。1908年，曾于1895年發現腎上腺活性的Sch?fer建議名稱為adrenin（Sch?fer，1908）。

　　爭議

　　高峰讓吉和Parke-Davis藥廠申請的ZL是Adrenalin，而且Abel提出訴訟后，高峰讓吉在法庭勝訴。英國藥典一直用adrenaline的名稱，而美國藥典用epinephrine是錯誤的，原因是Abel長期不認錯。不僅如此，在高峰讓吉去世5年后、高峰譲吉獲得ZL25年后，Abel在《科學》發表文章還說高峰讓吉是來他實驗室聽他說如何分離腎上腺素的（Abel，1927）。日本人后來找到上中啟三的個人比較，日文、英文夾雜，證明上中啟三認為Abel和Fürth的都不對，而且高峰讓吉和上中啟三找到腎上腺素的時間早于Abel號稱的高峰讓吉訪問Abel的時間（Yamashita，2002）。

　　Abel是美國藥理學的開創性人物，是美國第一位專職的藥理學教授、美國第一位藥理學系主任，共同創辦了《生物化學雜志》、創辦了《美國藥理與實驗治療學雜志》，他對美國學界的影響遠大于高峰讓吉，對Abel的各種介紹（包括Wiki）中，至今仍廣泛流傳有關epinephrine的按Abel版本的錯誤記載。高峰讓吉不僅未獲美國任何學術榮譽，而且無美國國籍。即使當時美國、德國和英國同行都認同高峰讓吉（Aldrich，1901；Pauly，1903，1904；Stolz，1904；Dakin，1905），即使高峰讓吉贏得ZL（Yamashita，2002），即使美國科學家有文章確定高峰讓吉的發明權（Bett，1953；Tansey, 1995； Aronson, 2000），即使德國科學界不用德國科學家取的suprarenin名稱，但很長時間美國科學家還信Abel，例如直到1982年，美國生理學家Davenport仍認為是Abel發現了腎上腺素（Davenport，1982），到1991年才認為是高峰讓吉發現了腎上腺素（Davenport，1991）。而直到今天，錯誤的名稱epinephrine繼續被美國科學界使用。大部分人不知道為什么有美國的名稱和歐洲/日本的名稱，以為是美國和歐洲/日本競爭。其實兩個名稱都是在美國工作的科學家發現的。

　　這一爭議還有藥廠參與。因為Parke-Davis藥廠將“Adrenalin”注冊了ZL，英國Wellcome藥廠的美國創辦人Henry Wellcome（1853-1936）不愿用這一命名，試圖阻止在藥廠研究部工作的Dale用adrenaline名稱、而要求他用epinephrine。Dale指出英國科學界認為adrenaline是腎上腺有活性的物質，而Abel的epinephrine是沒有活性的物質，堅持在自己論文中用adrenaline的名稱（Tansey，1995）。因Parke-DavisZL的名稱為Adrenalin，此后通用adrenaline（A小寫，最后有e）。Abel去世后，Dale為皇家學會的紀念文章雖然贊揚Abel為主、但仍文雅地指出Abel發現的是活性分子的苯甲醛衍生物，如果有時間也可能分離到活性成分（Dale，1939）。

　　這一爭議中，個人的爭名奪利、學界的霸權行為和社會的種族歧視，孰輕孰重不容易說清楚，可能都逃不脫干系。

　　第一個激素

　　基本所有教科書都認為第一個激素是secretin（腸促胰泌素），發現者為英國的一對表兄弟、生理學家William Bayliss（1860-1924）和Ernest Starling（1866-1927），時間是1902，地點是倫敦的大學學院。

　　Bayliss和Starling在研究小腸的運動（Bayliss and Starling，1899）。俄國生理學家巴甫洛夫于1898年發現不同食物經過胃處理為食糜而進入十二指腸或回腸后，刺激胰腺分泌，而且不同食物的食糜導致胰腺分泌的成分不同。巴甫洛夫和其后其他研究者在實驗后提出這都是由于神經所介導的，可以是迷走神經、內臟神經、或腸道局部的神經。

　　Bayliss和Starling發現這不是由于神經，而是由小腸分泌一種化學物質（胰泌素），通過血液到胰腺刺激胰腺細胞分泌。他們于1902年1月16日進行“關鍵實驗”，1902年3月完成所有實驗，先在皇家學會會刊發表初步結果（Bayliss and Starling，1902a），再在英國《生理學雜志》發表全文（Bayliss and Starling，1902b）。

　　1905年，Starling提出激素的命名（Starling，1905a），但承認第一個激素活性為1895年Oliver and Sch?fer注射腎上腺提取物觀察到升高血壓的作用（Starling，1905b）。1902年Bayliss和Starling達到的程度與1895年Oliverand Sch?fer達到的程度相似，發現了胰泌素的活性，知道其不同于神經，但并未清楚其化學本質。而1901年高峰讓吉已經知道腎上腺素的活性和化學本質。胰泌素要等將近60年才被純化（Jorpes and Mutt, 1961），其一級結構還要近十年才被完全確定（Mutt, Jorpes and Magnusson, 1970）。所以無論從生物學活性還是化學本質來說，腎上腺素都是第一個激素。

　　早該還高峰讓吉的功勞

　　腎上腺素在基礎和應用兩方面都有很重要的意義：基礎方面，它不僅是第一個激素，它還對神經生物學很重要；應用方面，最簡單的是立即提高血壓，這是很多急救的一個措施，迄今還在被使用。

　　日本第一位生理或醫學諾獎得主山中伸彌的工作是他在2006年發現4個因子可以將分化的細胞重編程成為干細胞。這一工作的重要性并不高于高峰讓吉的工作：1）重編程是已知的，山中伸彌沒有發現重編程，而是發現可以重編程的四個因子，高峰讓吉也沒有提出內分泌、或神經遞質，只是發現第一個激素（以及與第一個神經遞質相關）；2）山中伸彌發現的因子，不是內源的重編程因子，高峰讓吉發現的激素是內源激素；3）山中伸彌發現的因子，迄今只能用于研究，尚無實際應用，而且因為其中一個分子的可能致癌性而不能排除它們不能直接應用的可能性。相比而言，高峰讓吉的發現不僅很快得到應用，而且迄今仍然應用。

　　日本一直非常重視高峰讓吉，給他很多榮譽，但他在世界科學界恐怕是冤屈百年。迄今，沒有任何跡象顯示這一逾百年的冤案會得到澄清。澄清的標志之一應該是epinephrine一詞從此不再為科學界所使用，而只用adrenaline一詞。

　　不過，高峰讓吉并非第一位在生物醫學方面做出重要貢獻的日本人。例如，1897年，志賀潔（Shiga Kiyoshi，1871-1957）發現痢疾的致病菌。該細菌被稱為“志賀氏桿菌”（Shigella）。痢疾流行在很長年代是人類的大敵，志賀潔發現如此重要的致病菌，善莫大焉。百年后的今天，還沒有一個如此重要致病菌是以中國人命名的。

　　（以下為英文全文，TEM雜志編輯限制本文參考文獻只能16篇，發表版刪除了另外19篇引用文章及其相應文字。本文要點為《生物學概念與途徑》一書第十章的注釋6）

　　The First Hormone: Adrenaline

　　Yi Rao

　　PKU-IDG/McGovern Institute for Brain Research； Peking-Tsinghua Center for Life Sciences； Chinese Institute for Brain Research, Beijing, Beijing, China

　　Abstract

　　It is not often that three mistakes are associated with one molecule for more than a century. This is the case with adrenaline. The record is set here that adrenaline is the first hormone with the discovery of its activity and chemical purification prior to secretin. Adrenaline is the correct name given by JōkichiTakamine, epinephrine being its inactive benzoyl derivative.

　　While adrenaline is a well-known molecule, there have long been three misconceptions. Adrenaline has not been recognized as the first hormone, its discover remains obscure, and it has two names. This article sets the history straight and clarifies these confusions.

　　Secretin vs Adrenaline

　　Most textbooks state that secretin is the first hormone, discovered in 1902 by the British cousins William Bayliss (1860-1924) and Ernest Starling (1866-1927), at the University College London (UCL).

　　In 1899, Bayliss and Starling followed up on one of Ivan Pavlov’s observations published in 1898 that different kinds of substances in the food, after digestion into chyme and movement into the duodenum, induced the pancreatic to secrete different kinds of juices. Pavlov and others have performed experiments and concluded that the effects of chyme on pancreatic secretion were due to nerves (either the vagus, splanchnic or local). Bayliss and Starling made the novel discovery that this resulted from the chemical substance they called secretin, which was made by the mucous membrane of the upper parts of the small intestine, carried by the blood to the pancreatic gland cells.“The crucial experiment” was performed on January 16th, 1902, with all experiments finished by March, 1902, published in a preliminary form as Bayliss and Starling (1902a) and in the full form as Bayliss and Starling (1902b). Starling coined the term hormone in 1905 (Starling, 1905a), and acknowledged (Starling, 1905b) that the first hormonal activity was the increase of blood pressure by the injection of supra-renal extracts observed by Oliver and Sch?fer (Oliver and Sch?fer, 1895).

　　The adrenal gland (or supra-renal capsule) is a small gland above the kidney. In 1855, Dr. Thomas Addison (1793-1860) of Guy’s Hospital in London discovered what was later called Addison’s disease, caused by damages to the adrenal glands. Soon researchers were interested in finding substances in the glands. Removal of adrenal capsules from animals often resulted in death (Sch?fer, 1908).

　　George Oliver（1841-1915）was an English doctor with a home laboratory who might have experimented with his son, feeding adrenal extracts to his son (Barcroft and Talbot, 1968). Edward Albert Sch?fer (1850-1935) was then a professor of physiology at UCL, whose contributions included the proposal of the term “endocrine” for ductless glands. In 1893, Oliver went to Sch?fer, suggesting a collaboration on the physiological effects of adrenal extracts (Davenport, 1991). Oliver and Sch?fer published two abstracts in 1894 and a full paper in 1895, showing the effects of adrenal extracts, including those of increasing the blood pressure and increasing the heart beat (Oliver and Sch?fer, 1895). They determined that the active principle was from the medulla, not the cortex of the adrenal glands.

　　Secretin was not purified until almost six decades later (Jorpes and Mutt, 1961) and determination of its primary structure would take another decade (Mutt, Jorpes and Magnusson, 1970).

　　Thus, the first hormone was clearly adrenaline, because both the discovery of its activity in 1895 and its chemical purification in 1901 predated those of secretin in 1902 and 1961.

　　Purification of the Active Principle from the Adrenal Gland

　　In 1895, Sch?fer asked two of his colleagues at UCL to study adrenal extracts chemically (Moore, 1895； Nabarro, 1895). In 1897, SigmundFr?nkel (1868-1939) of Germany extracted from the adrenal capsules what he called spygmogenin (Fr?nkel, 1897). From 1897 to 1901, John Abel of Johns Hopkins University published a series of papers on what he called epinephrin from 1898 onwards (Abel and Crawford, 1897； Abel 1898, 1899, 1901). The molecular formula of epinephrine was C17H15NO4 (Abel, 1898). In 1900, the Austrian scientist Otto von Fürth (1867-1938), then working at Strasbourg University, after pointing out that epinephrine was inactive, purified what he called suprarenin, with the molecular formula of C5H9NO2 (von Fürth, 1900). In 1901, Abel offered a rebuttal to Fürth, claiming that his principle was active, although it was not the native principle, but might contain an extra benzoyl (Abel, 1901).

　　The pharmaceutical company Parke-Davis in Detroit, Michigan asked Takamine to purify the active principle from the adrenal gland. In 1900, Takamine and his assistant Keizo Uenaka (1876-1960) succeeded in purifying the highly active principle, with the molecular formula of C10H15NO3. In January 1901, Takamine reported his findings to the Society of Chemical Engineering in New York and published in theAmerican Journal of Pharmacy (Takamine, 1901). In December 1901, Takamine reported adrenaline to the British Physiological Society and published the Journal of Physiology in 1902 (Takamine, 1902).

　　By the summer of 1900, Thomas Aldrich of the Department of Biology of the Scientific Laboratory of Parke-Davis had also purified adrenaline, which he published in 1901. He recognized the priority of Takamine’s report to the Society of Chemical Engineering. He compared the physical and chemical properties and concluded that he and Takamine had isolated the same molecule, with the same molecular formula: C9H13NO3(Aldrich, 1901). The correct formula was closer to that deduced by Takamine than those by Abel and Fürth.

　　Adrenaline vs Epinephrine

　　Adrenalin was the name in the patent of Takamine and Parke-Davis. After a lawsuit filed by Abel, Takamine won(Yamashima, 2003). Both the British and the European Pharmacopoeia used adrenaline but the US Pharmacopoeia used epinephrine.

　　Five years after Takamine died (and 25 years after losing the patent fight), Abel claimed that Takamine visited him and modified his method to purify adrenaline (Abel, 1927). A research note by Uenaka, was later found and its mixed Japanese and English text showed that Takamine and Uenaka had purified adrenaline before the date of Takamine’s presumable visit claimed by Abel (Yamashima, 2002).

　　Abel was the first chairman of the first department of pharmacology in the US, one of the two co-founders of theJournal of Biological Chemistry in 1905, and the founder of the American Journal of Pharmacology and Experimental Therapeutics in 1908. His influence was far greater than that of Takamine.

　　Thus, even though historians had argued for Takamine (Bett, 1953； Tansey, 1995； Aronson, 2000), it remains for a long time that American scientists believe more in Abel than in Takamine. For example, the American physiologist Horace Davenport in 1982 believed that Abel discovered the principle, although he changed his mind by 1991 to recognize the discovery of Takamine (Davenport, 1982, 1991). Even though there have been repeated arguments for the usage of adrenaline (e.g., Aronson, 2000), epinephrine is still used in American textbooks and by American scientists. Most assume that there had been priority disputes between American and European scientists, whereas the truth was that both names were proposed by scientists working in the US, though one of Japanese origin and the other of European origin.

　　Experts’ Agreement: Adrenaline

　　In 1903, Hermann Pauly (1870-1950), then at the University of Bonn, determined the structure of adrenaline. He also believed the principle purified by Takamine to be active, whereas that by Abel inactive (Pauly, 1903, 1904). In 1904, the German chemist Friedrich Stolz (1860-1936) became the first scientist to synthesize what he also called adrenalin (Stolz, 1904). The British chemist Henry Dakin (1880-1952) also credited Takamine and Aldrich for discovering adrenaline (Dakin, 1905). In 1906, Henry Dale, the British pharmacologist who would win a Nobel prize in 1936, insisted that adrenaline was the correct name, with epinephrine as the name of the inactive principle (Tansey, 1995； Aronson, 2000). In 1908, Sch?fer suggested the name of adrenin (Sch?fer, 1908), though it was never used by him or others later.

　　Because Takamine and Parke-Davis patented Adrenalin, Henry Wellcome (1853-1936), the American founder of the British pharmaceutical company Burroughs-Wellcome was reluctant to use the name, even trying to block Dale who was working in the research laboratories of Wellcome from using adrenaline. Dale pointed out that British scientists believed that adrenaline was the active principle while epinephrine of Abel was inactive, insisting the usage of adrenaline in his papers (Tansey, 1995). Because Parke-Davis patented Adrenalin, scientists use adrenaline. After Abel passed away, Dale wrote an obituary for Abel, still politely noting that Abel’s epinephrine was “a monobenzoyl-derivative of the active principle” (Dale, 1939).

　　Credit Long Overdue

　　Adrenaline is important for both basic research and medical applications. In basic research, it is not only the first hormone, it also helped the discovery of the neurotransmitter noradrenaline which is the precursor in the biological synthesis of adrenaline. In medicine, adrenaline was used almost immediately and is still in use today, a record not matched by many molecules. One wonders whether racial and other biases resulted in the award of the first Nobel prize to a Japanese biologist in 2012 rather than a hundred years earlier.

　　Takamine has won respects and awards from Japan, including the gift of cherry trees by the Japanese emperor, but is not well recognized by the rest of the world. Using the term adrenaline, instead of epinephrine, is a right step forward for credit long overdue.

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　　（The version published in Trends in Endocrinology and Metabolism has limited the number of references to 16, thus resulting in the deletion of 19 references and associated text）