The short but fruitful life of Hilde Mangold produced one of the few doctoral dissertation that has ever been directly linked to a Nobel prize.
Hilde performed transplantations of cells from one darker newt embryo (type of amphibian) into a receiver lighter embryo in order to see if the transplanted cells will trigger the formation of parallel body axis that can be distinguished between them by colour. After hundreds of such delicate and complex transplantations, she managed to obtain such animals, proving the fact that thise specific cells were behind the rearrangement and fate specification of the rest of the cells in the embryo. These cells were coined as the "Spemann-Mangold organizer" after Hilde and her supervisor. These were remarkable findings that changed the trajectory of the modern developmental biology. Eleven years later this discovery was awarded the Nobel prize. Unfortunately, Hilde did not get to see this day coming.
If you want to listen to the whole story of this gifted and determined woman, take a peak!
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4. Hilde Mangold (1898-1924) and Spemann's organizer: achievement and tragedy
Peter E. Fiissler*, Klaus Sander
Institut ftir Biologie I (Zoologie) der Albert-Ludwigs-Universit~it, Albertstrasse 21 a,
D-79104 Freiburg, Germany
5. Hilde Mangold, Co-Discoverer of the Organizer
The story for today will be short and intense, but not because there isn’t a myriad of things about our subject worth mentioning, but because she unfortunately had an early and tragic passing. She has written one of the few PhD dissertations directly linked to a Nobel prize and has laid groundwork for modern embryology and developmental biology together with another influential biologist of the 20th century. Her name was Hilde Proescholdt, later called Mangold.
She was born in a wealthy family in Thuringia, Germany, on the 20th October 1898, from Gertrude and Ernest Proescholdt. She was a middle child and her father came from a family of artisans and chinaware painters. He started working at a soap factory during his young years and after gradually going through the ranks he got to marry the owner’s daughter, Gertrude, a woman that was gifted and educated, and who was active in promoting women’s rights. It sounds to me like the proper environment which young Hilde needed to develop her own independence and self-worth.
Of course that a nurturing environment is not enough without a spark a brilliance, which Hilde showed and later being allowed into a prestigious school, Gymnasium Ernestinum, l at 16 yo. There extremely few girls were accepted in those times. After she finished with flying colours, there was an attempt to put her on the path of what was considered appropriate preoccupations for a lady by sending her to a private institute for young women that was specialised in teaching them etiquette and housekeeping. That was however short lived, as after 6 months she got into a chemistry bachelor’s at the Jena University and after a semester she moved to study zoology at Frankfurter Main University. And this is where her whole life trajectory took a turn for the better. Sort of. You’ll see.
Here she met Hans Spemann, trailblazer of modern developmental biology who came as a guest speaker from Freiburg University. He was studying the early development of the salamander embryo and was conducting complex and delicate experiments to figure out how these processes occur. After that she decided to follow the science again, or Spemann for that matter, and moved to Freiburg. Reading this I kind of wished I was in those golden days when science had this chaos about it, moving around with so much ease and having more control over the subjects you could study. If it wasn’t for the sexism, of course. Here Hilde seems to have found her place as she remained a whooping 2 semesters where she took a wide array of lectures and also met the people that would later be her PhD co-sufferers, sorry, colleagues. After a year Spemann realised her potential and accepted her as a PhD student together with Viktor Hamburger with whom she developed a tight friendship.
Her first assignment was to turn the Hydra inside out, which is a small freshwater organism. I will put some pics on the podcast Instagram or you can google this little fellow, but if you think that ain’t nobody got time for that, then imagine a slim tube that is closed at one end and at the other it has around 8 long and thin tentacles. My very sharp deduction is that this is why it got its name. The point of the experiment was to see if the inside layer of cells will acquire characteristics of the inside layer and vice versa upon inversion. This layers resemble an embryo’s organisation, being made of 3 layers, ectoderm (outside), mesoderm (middle) and endoderm (inside). Different organ systems and body components will derive from one of these three, so the point was to see how to they “know” what type of cells they are and what should they later on form. Spemann hoped that they will change identity, especially because Abraham Trembley conducted this experiment nearly 2 centuries before and claimed that this was the case.
The initial small trials were successful, but when attempting the full blown experiments, Hilde could
Not repeat the results. Shockingly, animals tend to not like when they are turned inside out and will revert to their natural state. Because it seems that a prerequisite of being a boss is thinking you could do everything better than your underlings, Spemann tried to do it too, but he was also unsuccessful. Which turned out to be a major win for Hilde, not only because her next project was groundbreaking, but because Spemann wasn’t a stranger to giving his female students grunt work that went largely unrecognised and this temporary fail forced his hand to give her a more meaningful project. Another female student, Salome Waelsch, who was part of his lab around that time was also given boring tasks that were designed to feed into a potential project for a young man later on. Fortunately, Salome went on to become one of the funders of modern developmental biology. Love to see a fellow stubborn woman.
But now, a small break for your daily portion of science and an introduction to Hilde’s new wxciting project. Remember the three layers I mentioned before? Well, the rearrangement of the cells in these three layers occurs just after the egg fertilisation and this phenomenon is called gastrulation. One of the titans developmental biology, Lewis Wolpert, famously said (famously for nerds like me) that ‘It is not birth, marriage or death, but gastrulation which is truly the most important time in your life’. So next time your partner asks you what’s wrong tell them that they missed the most important thing in your life and they never pay attention. Let me know how that went.
Anyway, after the cells are specified in each of the layers, they cannot turn back. Experiments done prior to this crucial point showed that what was later coined as embryonic stem cells could go on and become any of these 3 layers. But nobody knew why. Spemann noticed in the salamander embryo that when it was in the two cell stage (so very early embryo), there is this cleavage forming in the middle of the embryo called the grey crescent. The name is self-explanatory, as it looks exactly like a grey crescent moon. This region will later give rise to the dorsal cells that are initiating gastrulation. At that point in time these cells were thought to be of importance, but their actual function was unknown and this inspired Spemann to go further. Now, back to our normal program.
After the failed attempt with the Hydra, Hilde was given the task to perform transplantations on the newt embryo this time, with the latin name triturus cristatus. It is a small amphibian similar to the salamander. He already did some preliminary work with it and wanted to pursue this project himself, but being a group leader comes with a lot of bureaucratic and organisational bullshit and lack of time made him pass it on to Hilde. If you remember episode one of the podcast, the following experiments will sound familiar. In order to determine if these dorsal cells were doing what they hypothesised them to do, Hilde skilfully transplanted them from a darker colouerd newt embryo to another lighter pigmented one. The catch with these experiments was that they needed to be done in one mating season of the newt, as they didn’t have the techniques to create the embryos in vitro at that time. After reading this, I promised to never complain about time constraints in my research again.
The fertilised eggs needed to be closely supervised and promptly used when they reached the wanted stage. With a very thin glass needle designed by Spemann himself, she had to gently remove the outer membrane of the embryo, dissect the dorsal cells with said needle which were transferred into the host embryo. To be able to manipulate such a delicate sample, Spemann had come up with an ingenious tool called the hairloop, which is exactly what it sounds like. He took a thin strand of baby hair (first time from his own) and made a loop with both ends into a tiny glass pipette which was afterwards sealed with wax. What can I say, this is the only type of child labour I condone.
She performed hundreds of transplantations (around 250) and in the end only 6 embryos were considered fit enough to be presented in the report. Meaning that there many others that displayed a degree of secondary axis formation. According to her notes, the yield was around 10% and this was due to the embryos fragility as well as the high incidence of infection that couldn’t be prevented upon release in the pond. Despite this low number, later experiments will confirm and consolidate the findings.
This is what Viktor Hamburger, her good friemd, had to say about their time doing the experiments in his biographical essay on Hilde: “After some practice, doing the experiments was fun. But we had to cope with a very high mortality; the embryos, once removed from their protective jelly membranes, were extremely delicate, and at that time we had no weapon against bacterial infection. It took most of us two years to complete an experiment. Proescholdt had a particularly dif-ficult job, because her experiment involved transplantation from embryos of one species to those of another species, thereby increasing the risk. Her plight, and also her stamina and perseverance, are attested by the fact that of her many experiments over two breeding seasons, only six embryos were eventually found worthy of being presented to the general public in the famous organizer paper.”
In early May of her second year she managed to obtain an embryo with two separate neural tubes of different colours. This proved that the dorsal cells where the ones that instructing the neighbouring cells to take specific fate and migrate. Everybody, including Spemann, were deeply impressed and a bit later these findings were reported as a postscript in another of the Spemann’s publication. This is when the term “organiser” was coined to describe this region made of dorsal cells that was orchestrating this process. After another breeding season, Hilde was able to finish her project, publish together with Spemann in Roux's Archiv in June 1923 and it appeared in print in 1924. Although the magnitude of the findings were not immediately evident, her research was so important that Spemann insisted to put his name on the publication, while all her male colleagues published alone, as well as putting his name first. But regardless, while he designed the hypothesis, she was able to fulfil a task unlike any that required passion, determination and perseverance.
The saddest part however, is the fact that she will never live to see this discovery being awarded the Nobel Prize and her flourishing career was cut very short in a domestic accident. During her PhD she got married to Otto Mangold, Speman’s right hand, and after successfully defending her dissertation she moved to Berlin with Otto and their young son. In 1924, a gasoline heater exploded and she died the next day due to her severe burns at only 26 years old. In 1935, the discovery of the organiser was awarded in only Spemann’s name, as this prize is not awarded posthumously, so if you intend to win one maybe do all the boring things your doctor told you to. During the Nobel speech he mentioned Hilde only two times and conveniently leaves out the fact that it was her dissertation on this topic that brought the discovery to light. This is one of the reasons why I wanted to make an episode on this, as she is not mentioned in textbooks and sadly her work was greatly minimised especially in the light of the fact that she was active in the field for only 2 years. As someone who knows what a pain biological experiments can be, I would come back from the dead to haunt my supervisor if they would do that. What I also encourage you to do is for all of us to keep talking and keeping her and others memory like hers alive to make up for the lack of recognition they experienced while alive.
So for the silly conclusion of this episode I guess living long enough increases your chances of receiving a Nobel prize? Seriously tho, what I took from this story pursuing what you are passionate about regardless of the barriers put in front of you will eventually yield success and recognition, even if you don’t live the day when it materialises. Success has lot of definitions and can be a very long game, and that doesn’t take one bit off of our accomplishments. Persistence can go a long way and I think it is very important to remember that each of our lives have completely different timelines and going in our pace can be so liberating. And most of all, don’t forget to be humble and thank the people that helped you be where you are now. I hope she will be forever remembered as a woman who broke expectations, took life head first and inspired other people to choose science.
As usual, in the end I will say a few words and read a couple paragraphs from Hamburg’s essay to commemorate Hilde as the person beyond her scientific persona.
“Soon after our arrival, a friendship developed between Hilde and me that was based on common interests in science, art, and literature. By nature she was open, frank, and cheerful. She had a penetrating and reflective intellect and a lively sense of beauty in nature and in the arts. Like myself she had grown up in a small town, loved the outdoors, and was familiar with plant and animal life. But she was perhaps at her best in the endless discussions and debates with kindred minds that ex-tended through long evenings in the open-air taverns at the square around the cathedral or in our small rooms. When we were in danger of taking ourselves too seriously, it was her sense of humor that saved the situation. We were fortunate in that we had more time for such exercises than students today, because we did not have to prepare for examinations: there were neither midterms nor finals. We ourselves were responsible for what we learned or missed in a course. But then, we were at the level of seniors or graduate students and had received most of our college-level education at the gymnasium.
Hilde Proescholdt and I were less adventurous. We were more at-tracted to the intellectual and artistic movements flourishing in the young Weimar Republic. We were attuned to the poetry of Rainer Maria Rilke and Stefan George and to German expressionist art, which challenged the traditional aesthetic values and tried to abrogate the laws of nature. The walls of our rooms were decorated with the "Blue Horses" of Franz Marc, as well as with the graphic art of the German masters Durer and Cranach. We sensed the affinity of expressionism and the medieval art that surrounded us in Freiburg.
Hilde Proescholdt and I shared a vivid interest in the rich flora of the environs of Freiburg. The high mountains of the Black Forest harbored alpine plants and glacial relics, gentians, alpine primroses, and saxifrages. Toward the west, an unusual Mediterranean plant community had settled in the warm and sunny Rhine Valley. In early spring the slopes were covered with white and blue anemones. Our most precious finds were rare orchids in the woods and hillsides of the Kaiserstuhl. a volcanic intrusion that rises like an island out of the Rhine Valley. The vineyards there produce the best local wines. One of their connoisseurs, our botany professor, F. Oltmanns (an elderly bachelor and bon vivant), familiarized us not only with the Latin names of many rare plant species and their long journeys from remote regions of Europe to this idyllic spot, but also with his favorite inns in the small towns and villages and their special homegrown vintages.”