迈克·萨顿(Mike Sutton)庆祝一位曾经被误认为茶夫人的女性晶体学家的非凡职业

1941年11月,即第二次世界大战最艰难的月份之一,英国牛津大学的化学家们正努力从特立独行的模具中提取有用的药物。尽管亚历山大·弗莱明(Alexander Fleming)在1928年就注意到了这种细菌的抗菌能力,但其有效成分仍然神秘。由于标准分析技术似乎无法提供青霉素分子的图谱,因此邀请牛津大学最有能力的X射线晶体学专家来尝试。

多萝西·霍奇金(Dorothy Hodgkin)急切地接受了挑战。但是,由于她的大部分时间都已经占用了学术职责以及一个两个月大的婴儿,她需要在实验室中提供更多帮助。没有人可用,直到她的一名学生上前。这项任命最初遭到官员的反对,他们认为这些研究在战时是多余的,并且不知道青霉素的潜在重要性。幸运的是,霍奇金(Hodgkin)说服了公务员联系以扭转这一决定,从而开始了非凡的职业生涯。

芭芭拉·沃顿·洛(Barbara Wharton Low)于1920年出生在兰开斯特,她的父母在那里经营杂货店。 1939年,她开始在萨默维尔(Somerville)学习化学,这是牛津少数几所女子大学中科学最活跃的。她于1942年完成学位课程的第一部分,她预计再花一年准备第二部分的实验室论文。但是那个夏天,霍奇金聘请她为青霉素项目的助理。

霍奇金相信将人们带入深渊

Low对这项工作表现出了很高的才能,因此成为她的论文以及后来的博士学位的基础。与常规的学生研究任务相比,这是一个更严峻的挑战,但她还是挺身而出。将青霉素从实验室的好奇心转变为可靠的药物的过程涉及多个机构的许多工人,但是Low的贡献至关重要。

通过对晶体上的X射线束照射产生的图形进行分析已经产生了重要的结果。在1920年代,威廉(William)和劳伦斯·布拉格(Lawrence Bragg)展示了原子如何以二元盐(如氯化钠)的形式堆叠。在1930年代攻读博士学位期间,霍奇金和她的主管戴斯蒙德·伯纳尔(Desmond Bernal)使用X射线衍射揭示了诸如甾醇的有机分子的更复杂结构。到1940年代初,实验室技术和数学工具得到了进一步的改善,但青霉素分子比以前的任何靶标都更大,更复杂。

显示Barbara Low入学照片的图像

Source: ? Principal and Fellows of Somerville College/Oxford

芭芭拉·洛(Barbara Low)于1939年进入牛津萨默维尔学院,并于1942年开始与多萝西·霍奇金(Dorothy Hodgkin)合作研究青霉素

At first, it was a struggle just to obtain useable crystals. Penicillin was resisting all efforts to crystallise it, while its derivatives and breakdown products seemed almost equally uncooperative. Hodgkin described one sample as ‘quite decent crystals to look at but simply awful to handle’; they were ‘extremely hygroscopic’ and ‘practically impossible to leave out in the air for more than a few minutes or so’. She spent hours fruitlessly trying ‘to get them into little tubes to be photographed’. Low was soon tackling similar problems. Low recalled in Hodgkin’s biography that ‘[Hodgkin] believed in throwing people in at the deep end. She expected you to work with crystals that you could only just see under the highest power of the microscope, and she expected you to manipulate and mount them. I remember being told to mount on a little piece of glass fibre a sort of nasty resinous mess with a little crystal in the middle.’

随着实验结果的积累,Low在解释它们方面的作用变得越来越重要。晶体原子散射的X射线束在照相板上留下点。每个点的强度表示衍射光束的强度,而其位置则显示出被衍射的角度。需要将晶体放置在与光束不同的角度下拍摄照片,并且每次都要重复进行分析。将这些测量结果输入复杂的数学公式中,可能会揭示出分子的结构,也可能不会。

为了加快工作速度,牛津小组开始使用原始的机械计算机处理结果,该计算机使用打孔卡输入数据。它的白天功能是优化海上车队的货物分配。晚上,Low在其上运行程序以尝试定位青霉素分子中原子的位置。早期结果看起来很有希望,但需要更多的实验数据。

用周期表中相同基团的重原子取代目标分子中的一个原子会影响生成的X射线照片,为该化合物的分子结构提供更多线索。通过比较从青霉素的钠盐,钾盐和rub盐获得的结果,霍奇金和洛特在其他研究人员的帮助下于1945年初确立了其分子结构。但是,战时保密(以及战后商业考虑)延迟了他们的研究工作的全面发表。几年,这可能削弱了它的广泛影响。

Penicillin helped win the war, and launched a post-war revolution in healthcare. But for years, industrial-scale fermentation remained the only way to meet massive demand for this ‘wonder drug’. Although Hodgkin and Low’s investigation of its molecular structure opened pathways towards new antibiotics with wider capabilities, their work did not deliver a short-cut to a penicillin synthesis. Consequently, it may have seemed of lesser significance to non-specialists.

1945年诺贝尔医学奖由弗莱明(Emst Chain)和霍华德·弗洛里(Howard Florey)分享,他们首先发现了青霉素的潜力,他们协调了跨国合作使之成为可使用的链诺贝尔奖得到了霍奇金和洛特的贡献。

The 1945 Nobel prize for medicine was shared by Fleming – who first spotted penicillin’s potential – with Ernst Chain and Howard Florey, who coordinated the multinational effort to make it useable Chain’s Nobel lecture acknowledged the contribution made by Hodgkin and Low. But somewhat confusingly, he stated that ‘the predominant role’ in determining penicillin’s structure was played by ‘Mrs D Crowfoot and her colleague Mrs B Rogers-Low’.

混乱的出现是因为霍奇金使用上的学术刊物娘家的姓只有她当选为英国皇家学会在1947年后也开始了她自己的造型多萝西·克劳福特霍奇金结婚托马斯·霍奇金在1937年后继续进行。在1944年与伦纳德·罗杰斯(Leonard Rogers)结婚后,劳特(Low)出版为B·W·罗杰斯·洛(B W Rogers-Low)–与许多战时工会一样,这是短暂的。 1950年,她与哈佛大学教授Mieczyslaw Budka结婚后,她的出版物仅归功于Barbara(或B W)Low。

Before gaining her Oxford doctorate in 1948, Barbara had spent a year in the US as a research fellow at Caltech under the direction of Linus Pauling. With his endorsement she became an assistant professor at Harvard in 1950, and thereafter they remained friends, despite occasional episodes of rivalry. In 1951, Pauling’s group identified the alpha-helix as the commonest spatial arrangement (‘tertiary structure’) of a linear protein molecule. When Low’s x-ray investigations a year later revealed another form of protein folding – the pi-helix – his response was equivocal.

After congratulating her on the discovery, Pauling suggested that the pi-helix might have been observed by his own team ‘a while back’, and then subsequently ‘overlooked’. Today, Pauling’s alpha-helix discovery is considered a landmark in the history of molecular biology. However, Low’s pi-helix – despite recent estimates that it may occur in around 10% of protein molecules – is rarely mentioned in student textbooks.

Low希望哥伦比亚不辜负拥有多元化教职员工的理想,这非常有力

Low在1956年成为美国公民。同年,她从哈佛大学搬到纽约的哥伦比亚大学,于1966年成为该大学的正式教授。她向许多年轻的研究人员介绍了先进的X射线晶体学技术,同时继续从事生物学重要分子的结构研究。她对致命的海蛇毒(erabutoxin)的研究不仅揭示了其分子结构,还揭示了其操作方式: its molecular ‘three-finger’ structure binds to – and deactivates – acetylcholine receptors at the neuromuscular interface, thereby inhibiting both breathing and heartbeat.

Throughout her career, Low fought to open doors in academia for women and ethnic minorities. ‘On the university’s affirmative action committee, she was very forceful in wanting Columbia to live up to its ideals of having a diverse faculty and workforce,’ Arthur Palmer, a biochemist at Columbia, recalled in her 大学ob告. One of her former postdocs, Philip Bourne, added that she was ‘leading a charge that really improved the situation for women in science, and she suffered a lot of bruises for it’.

在1990年退休后不久,芭芭拉(Barbara)与哥伦比亚保持了联系,为来宾做讲座并为研究学生提供指导和支持。自2019年去世后,前同事曾向他致敬,但最生动的轶事来自他的终身朋友海伦·伯曼(Helen Berman),他曾在Low的实验室里当本科生,后来成为罗格斯大学的生物化学教授。新泽西州。她在英国广播公司(BBC)的一次电台采访中回顾了多年前发生的一起事件,当时在教职员工会议前正在为茶点服务。当Low进入会议室时,一位男同事让她离开-出于对她是茶馆的误解。希望那些日子已经过去。

迈克·萨顿(Mike Sutton)是英国纽卡斯尔的科学历史学家