Sep 10

Sep 10 The organiser: Hilde Mangold

100 Ideas, Developmental genetics, History of genetics, Women in genetics

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Our story starts in 1898 in Germany, with the birth of a baby girl: Hilde Proescholdt. Hilde’s father was a merchant who owned a soap factory, and her mother was an activist who defended women’s rights.

The family was comfortably well off and liberal, so Hilde received a good education - an exception for girls at the time. After graduating from high school, she was sent to a finishing school, although that didn’t last last long. After half a year, she enrolled at the local university, before quickly moving on again to the larger University of Frankfurt, where she studied zoology.

Hilde’s friends described her as a gifted, vivacious and charming young woman who was open, frank and cheerful.

‘She had a penetrating and reflective intellect and a lively sense of beauty in nature and the arts,’ said her friend, Viktor Hamburger, in a 1984 memoir.

Hilde soon identified an outlet for her talents and enthusiasm: scientific research. And, more specifically, embryology, the study of the earliest stages of life. Her interest in the topic was sparked after she saw a guest lecture by the rising star of this new field: Hans Spemann.

Spemann was well known for his work in experimental embryology. This was a new field that involved changing the course of development of embryos, often by dividing the growing organism or transplanting cells from place to another, then observing the changes as the embryo continued to develop.

He was a master of the microsurgical techniques that were needed for delicate experiments on embryos and invented several tools for the job, including a tiny lasso made from a strand of his own infant daughter’s hair, used for separating microscopic embryonic cells.

At the time, embryologists were conducting the majority of their experiments on amphibians, because their large cells and rapid development proved easiest to work on. Spemann's early research focused on the effects of dividing salamander embryos in different planes - top from bottom, front from back, left from right - at various stages of development.

He found that two complete new salamanders formed when he divided an embryo into two during the earliest stages of development. But when he split the embryo later, the results depended on exactly where the division took place.

He found that if the dorsal or back side, including a small dimple called the dorsal lip, was separated from the ventral (front) side, only the dorsal side developed. But if the dorsal lip was divided between the two halves, both grew. Spemann theorised that the lip contained an "organisation centre” that influenced what the other cells would become and the growth of the whole embryo.

Spemann’s lecture obviously inspired Hilde, who immediately asked if she could move to his lab at the Zoological Institute in Freiburg to do a PhD under his supervision - an audacious move for a woman at the time.

Hilde arrived in Freiburg in 1920 and, by all accounts, she found the atmosphere in Spemann’s laboratory stimulating and exciting.

‘She was perhaps at her best in the endless discussions and debates with kindred minds that extended through long evenings in open-air taverns at the square, around the cathedral, or in our small rooms,’ said Hamburger in his memoir, remarking ‘We cared more about food for thought than the nourishment of our bodies.’

That was probably a good thing, because in inter-war Germany, food wasn't the easiest thing to come by, with some students having to survive on turnips through the harsh winter.

Hilde found the intellectual stimulation she was looking for in Freiburg, but she also found love, falling for Spemann’s favourite assistant, Otto Mangold, who she married in 1921.

Despite this promising start, things were less good on the scientific side. Hilde was undoubtedly disappointed when Spemann assigned her thesis project: repeating a series of obscure experiments performed decades earlier by French naturalist Abraham Trembley, who had been experimenting with a tiny organisms called Hydra - little more than a tube of cells with tentacles - apparently showing that turning the poor creatures inside out resulted in their outsides transforming into insides, and vice versa.

Hilde tried her best but her Hydra failed to perform as Trembley had claimed. Spemann eventually attempted the experiments himself, but he failed too. So Hilde needed a new project.

Perhaps feeling guilty at wasting her time and effort, Spemann assigned her an exciting new project transplanting cells from the dorsal lip of one embryo to another, hoping to prove his theory about the lip acting as an ‘organisation centre’ directing the growth of the early stages of life.

In 1921, Hilde began a series of very delicate transplantation experiments with pairs of embryos from two differently coloured salamanders, one white and one brown. Using the tools developed by Spemann, she painstakingly extracted cells from one embryo's dorsal lip and transplanted them onto the other embryo, opposite its own lip. Then she waited and hoped.

The embryos were extremely fragile, and the experiments frequently failed. Sometimes the grafts failed to take, or the embryos died of infection. But, perhaps by beginners’ luck, Hilde’s first successful attempt came quickly. One day, in May 1921, she found exactly what she had been hoping for when she returned to her microscope: an embryo that looked for all the world like twins conjoined at the gut.

Her results showed that the organiser effect was real. Cells from the dorsal lip were directing the development of the cells around them, telling them which part of the embryo to become.

So, two organisation centres on opposite sides of an embryo means two attempts at building an embryo - hence the double embryo effect. What’s more, Hilde observed that the transplanted cells had recruited tissue from the host embryo to form the second body, controlling them in an effect known as induction.

But this one-off success was not enough to prove the theory of the organiser. And unfortunately, studying amphibian development before the invention of modern lab techniques involved waiting around until spring to collect your eggs, and then doing all of your experiments as fast as possible before the breeding season ended.

It took Hilde 259 attempts over two breeding seasons to obtain just six successful experiments, which formed the body of her PhD dissertation. Spemann must have been happy with her work because he insisted on putting his name on her thesis as first author, effectively claiming it as his own.

Hilde’s friend Viktor Hamburger noted:

“Mrs Mangold was not happy that Spemann had added his name to her thesis publication, while Holtfreter and I and all the rest of us saw ourselves proudly in print as sole authors. Moreover, Spemann had insisted on having his name precede hers!"

As a result, the special cells of the dorsal lip therefore became known as the Spemann-Mangold organiser (Or, more insultingly for Hilde, often simply shortened to the Spemann organiser).

There has been speculation that Spemann added his name to Mangold’s thesis simply because she was a woman. Others, including Hamburger, suggested that he added his name because of the importance of the results, and wanted to stake a claim for his contribution to the work and the development of the techniques behind it. Either way, Spemann's treatment of Hilde does seem unfair, but unfortunately, not unusual for young women working in the laboratories of older men at the time.

After completing her PhD, Hilde and her husband Otto moved to Berlin, where Otto had been appointed the director of the Division of Experimental Embryology at the Kaiser Wilhelm Institute, thanks to a recommendation from Spemann. Hilde, meanwhile, had been working on her own personal developmental biology project - a baby boy - and was kept busy caring for their newborn son while Otto went off to work in the lab.

Tragically, Hilde Mangold never got to resume her scientific career. By the time her work on the embryonic organiser was published in 1924, she was dead.

The circumstances around Hilde’s death are mysterious. Hamburger wrote in his memoir that she died when a faulty gasoline heater exploded in her kitchen at her home in Berlin. However, a letter from Otto assigns her death to a spill when Hilde was refilling an alcohol stove at his mother's house and that, curiously, she refused help from her mother-in-law to douse the flames. Otto finally put out the fire, but it was too late, and Hilde died the next day of her injuries aged just 25. But was it really an accident? Others who knew her weren’t so sure.

“The truth of the matter is that she killed herself,” UCL Professor Claudio Stern told Nautilus magazine in 2015, after hearing the story directly from Mangold’s friend and contemporary, Salome Gluecksohn-Waelsch.

Unfortunately, we may never know what really happened to Hilde on that day, and what her husband really knew of it. But what is true is that a child lost his mother, a husband lost his wife, and the world of developmental biology lost a brilliant and talented researcher.

After Hilde's death, Otto Mangold resumed his scientific career. He continued to be Spemann's favourite protege, taking over from his leadership role at the institute in Freiburg in 1937. Otto also became actively involved in the Nazi party.

He was appointed to the highly political role of rector of the university, helping to implement Nazi policies and writing a book called 'The tasks of biology in the Third Reich'. After the war, he was removed from Freiburg University because of his Nazi affiliations and spent the rest of his career at a privately financed research institute.

As for Spemann, he continued studying his beloved embryonic organiser. He later showed that different parts of the dorsal lip produced different parts of the embryo. Further work demonstrated that the organiser cells were capable of influencing the surrounding cells even after they had been killed, suggesting that an inert, signalling molecule released from the organiser cells must be responsible for this induction effect.

Spemann went on to win a Nobel prize in 1935 for his embryology work, much of which was underpinned by Hilde’s PhD project. Although he did mention her briefly in his acceptance speech, many feel she is not given enough credit for her work. So - now you know her story, let’s make sure her name is not forgotten. It’s the Spemann-Mangold organiser, not just the Spemann organiser, OK?

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