Pourquoi ça a pas marché tout de suite quand ils ont fait le premier essai avec l'insuline ?
Extraction and purification

In October 1920, Canadian Frederick Banting concluded that the digestive secretions that Minkowski had originally studied were breaking down the islet secretion, thereby making it impossible to extract successfully. A surgeon by training, Banting knew that blockages of the pancreatic duct would lead most of the pancreas to atrophy, while leaving the islets of Langerhans intact. He reasoned that a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone. He jotted a note to himself: "Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these + relieve glycosurea."

In the spring of 1921, Banting traveled to Toronto to explain his idea to John Macleod, Professor of Physiology at the University of Toronto. Macleod was initially skeptical, since Banting had no background in research and was not familiar with the latest literature, but he agreed to provide lab space for Banting to test out his ideas. Macleod also arranged for two undergraduates to be Banting's lab assistants that summer, but Banting required only one lab assistant. Charles Best and Clark Noble flipped a coin; Best won the coin toss and took the first shift. This proved unfortunate for Noble, as Banting kept Best for the entire summer and eventually shared half his Nobel Prize money and credit for the discovery with Best. On 30 July 1921, Banting and Best successfully isolated an extract ("isletin") from the islets of a duct-tied dog and injected it into a diabetic dog, finding that the extract reduced its blood sugar by 40% in 1 hour.

Banting and Best presented their results to Macleod on his return to Toronto in the fall of 1921, but Macleod pointed out flaws with the experimental design, and suggested the experiments be repeated with more dogs and better equipment. He moved Banting and Best into a better laboratory and began paying Banting a salary from his research grants. Several weeks later, the second round of experiments was also a success, and Macleod helped publish their results privately in Toronto that November. Bottlenecked by the time-consuming task of duct-tying dogs and waiting several weeks to extract insulin, Banting hit upon the idea of extracting insulin from the fetal calf pancreas, which had not yet developed digestive glands. By December, they had also succeeded in extracting insulin from the adult cow pancreas. Macleod discontinued all other research in his laboratory to concentrate on the purification of insulin. He invited biochemist James Collip to help with this task, and the team felt ready for a clinical test within a month.

On 11 January 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin. However, the extract was so impure that Thompson had a severe allergic reaction, and further injections were cancelled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract. A second dose was injected on 23 January, eliminating the glycosuria that was typical of diabetes without causing any obvious side-effects. The first American patient was Elizabeth Hughes, the daughter of U.S. Secretary of State Charles Evans Hughes. The first patient treated in the U.S. was future woodcut artist James D. Havens; John Ralston Williams imported insulin from Toronto to Rochester, New York, to treat Havens.

Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collip left the project soon after. Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the preparation remained impure. The drug firm Eli Lilly and Company had offered assistance not long after the first publications in 1921, and they took Lilly up on the offer in April. In November, Lilly's head chemist, George B. Walden discovered isoelectric precipitation and was able to produce large quantities of highly refined insulin. Shortly thereafter, insulin was offered for sale to the general public.
La structure de l'insuline

L'insuline fut l'un des projets de recherche les plus extraordinaires de Hodgkin. Il débuta en 1934 lorsqu'elle se vit offrir un petit échantillon d'insuline cristallisée par Robert Robinson. L'hormone captiva son imagination en raison de l'effet complexe et étendu qu'elle exerce sur le corps. Cependant, à cette époque, la cristallographie aux rayons X n'était pas suffisamment développée pour faire face à la complexité de la molécule d'insuline. Elle et d'autres passèrent de nombreuses années à améliorer la technique.

Il fallut 35 ans après avoir pris sa première photographie d'un cristal d'insuline pour que la cristallographie aux rayons X et les techniques informatiques soient en mesure d'aborder des molécules plus grandes et plus complexes comme l'insuline. Le rêve de Hodgkin de percer le secret de la structure de l'insuline fut mis en suspens jusqu'en 1969, lorsque, enfin, elle put travailler avec son équipe de jeunes scientifiques internationaux pour révéler sa structure pour la première fois. Le travail de Hodgkin sur l'insuline fut essentiel pour ouvrir la voie à la production de masse de l'insuline et à son utilisation à grande échelle pour le traitement du diabète de type un et du diabète de type deux. Elle continua à coopérer avec d'autres laboratoires actifs dans la recherche sur l'insuline, en donnant des conseils et en voyageant à travers le monde pour donner des conférences sur l'insuline et son importance pour l'avenir du diabète. La résolution de la structure de l'insuline eut deux implications importantes pour le traitement du diabète, à savoir la rendre possible la production de masse de l'insuline et permettre aux scientifiques de modifier sa structure afin de créer des options thérapeutiques encore meilleures pour les patients à l'avenir.
### Query ###
Pourquoi ça a pas marché tout de suite quand ils ont fait le premier essai avec l'insuline ?

### Main Text ###
Extraction and purification

In October 1920, Canadian Frederick Banting concluded that the digestive secretions that Minkowski had originally studied were breaking down the islet secretion, thereby making it impossible to extract successfully. A surgeon by training, Banting knew that blockages of the pancreatic duct would lead most of the pancreas to atrophy, while leaving the islets of Langerhans intact. He reasoned that a relatively pure extract could be made from the islets once most of the rest of the pancreas was gone. He jotted a note to himself: "Ligate pancreatic ducts of dog. Keep dogs alive till acini degenerate leaving Islets. Try to isolate the internal secretion of these + relieve glycosurea."

In the spring of 1921, Banting traveled to Toronto to explain his idea to John Macleod, Professor of Physiology at the University of Toronto. Macleod was initially skeptical, since Banting had no background in research and was not familiar with the latest literature, but he agreed to provide lab space for Banting to test out his ideas. Macleod also arranged for two undergraduates to be Banting's lab assistants that summer, but Banting required only one lab assistant. Charles Best and Clark Noble flipped a coin; Best won the coin toss and took the first shift. This proved unfortunate for Noble, as Banting kept Best for the entire summer and eventually shared half his Nobel Prize money and credit for the discovery with Best. On 30 July 1921, Banting and Best successfully isolated an extract ("isletin") from the islets of a duct-tied dog and injected it into a diabetic dog, finding that the extract reduced its blood sugar by 40% in 1 hour.

Banting and Best presented their results to Macleod on his return to Toronto in the fall of 1921, but Macleod pointed out flaws with the experimental design, and suggested the experiments be repeated with more dogs and better equipment. He moved Banting and Best into a better laboratory and began paying Banting a salary from his research grants. Several weeks later, the second round of experiments was also a success, and Macleod helped publish their results privately in Toronto that November. Bottlenecked by the time-consuming task of duct-tying dogs and waiting several weeks to extract insulin, Banting hit upon the idea of extracting insulin from the fetal calf pancreas, which had not yet developed digestive glands. By December, they had also succeeded in extracting insulin from the adult cow pancreas. Macleod discontinued all other research in his laboratory to concentrate on the purification of insulin. He invited biochemist James Collip to help with this task, and the team felt ready for a clinical test within a month.

On 11 January 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin. However, the extract was so impure that Thompson had a severe allergic reaction, and further injections were cancelled. Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract. A second dose was injected on 23 January, eliminating the glycosuria that was typical of diabetes without causing any obvious side-effects. The first American patient was Elizabeth Hughes, the daughter of U.S. Secretary of State Charles Evans Hughes. The first patient treated in the U.S. was future woodcut artist James D. Havens; John Ralston Williams imported insulin from Toronto to Rochester, New York, to treat Havens.

Banting and Best never worked well with Collip, regarding him as something of an interloper, and Collip left the project soon after. Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand, but the preparation remained impure. The drug firm Eli Lilly and Company had offered assistance not long after the first publications in 1921, and they took Lilly up on the offer in April. In November, Lilly's head chemist, George B. Walden discovered isoelectric precipitation and was able to produce large quantities of highly refined insulin. Shortly thereafter, insulin was offered for sale to the general public.

### Supplementary Text ###
La structure de l'insuline

L'insuline fut l'un des projets de recherche les plus extraordinaires de Hodgkin. Il débuta en 1934 lorsqu'elle se vit offrir un petit échantillon d'insuline cristallisée par Robert Robinson. L'hormone captiva son imagination en raison de l'effet complexe et étendu qu'elle exerce sur le corps. Cependant, à cette époque, la cristallographie aux rayons X n'était pas suffisamment développée pour faire face à la complexité de la molécule d'insuline. Elle et d'autres passèrent de nombreuses années à améliorer la technique.

Il fallut 35 ans après avoir pris sa première photographie d'un cristal d'insuline pour que la cristallographie aux rayons X et les techniques informatiques soient en mesure d'aborder des molécules plus grandes et plus complexes comme l'insuline. Le rêve de Hodgkin de percer le secret de la structure de l'insuline fut mis en suspens jusqu'en 1969, lorsque, enfin, elle put travailler avec son équipe de jeunes scientifiques internationaux pour révéler sa structure pour la première fois. Le travail de Hodgkin sur l'insuline fut essentiel pour ouvrir la voie à la production de masse de l'insuline et à son utilisation à grande échelle pour le traitement du diabète de type un et du diabète de type deux. Elle continua à coopérer avec d'autres laboratoires actifs dans la recherche sur l'insuline, en donnant des conseils et en voyageant à travers le monde pour donner des conférences sur l'insuline et son importance pour l'avenir du diabète. La résolution de la structure de l'insuline eut deux implications importantes pour le traitement du diabète, à savoir la rendre possible la production de masse de l'insuline et permettre aux scientifiques de modifier sa structure afin de créer des options thérapeutiques encore meilleures pour les patients à l'avenir.

### Draft ###

### 1. Query Parsing

"Pourquoi ça a pas marché tout de suite quand ils ont fait le premier essai avec l'insuline ?"

Key assumption to unpack: "tout de suite" suggests immediate failure expectation. Reality check needed.

? Translation nuance: "marché" = worked/succeeded. "Première essai" = first clinical trial.

### 2. Historical Context Retrieval

⟨H≈0.2⟩ Insulin discovery timeline: 1921-1922. Banting/Best/Macleod, Toronto. First human trial January 1922. Leonard Thompson, 14-year-old diabetic.

● High confidence: January 11, 1922 first injection
◐ Partial: exact failure reasons (need clinical details)

### 3. Information Triangulation 

Multiple sources likely on first trial outcome:

├─ Clinical reports: immediate reactions
├─ Purification issues: contaminant effects  
└─ Timeline: what happened between Jan 11-23

### 4. Memory Retrieval: Clinical Details

⟨H≈0.8⟩ Thompson injected January 11... immediate severe allergic reaction... had to stop... wait several days... then improved preparation... second injection January 23... complete success...

! Key insight: Not "didn't work" but "worked badly initially"

### 5. Technical Analysis

Why first insulin preparation failed:
→ Crude extraction methods
→ Contaminant proteins causing reactions  
→ Impure compounds triggering allergies
→ Pancreatic tissue remnants

∴ Failure mode: clinical intolerance, not therapeutic ineffectiveness

### 6. Timeline Verification

January 11: First injection → allergic reaction
Wait period: several days (reasons?)
January 23: Second injection → therapeutic success

**Critical gap**: What happened during wait period?

⟨H≈1.2⟩ Collip working nights... purification... removing contaminants... isoelectric precipitation... Walden at Lilly discovering better methods... racing against time while patient worsens...

### 7. Synthesis

Initial failure ≠ fundamental problem
Rather: technical limitation in purification
Solution: improved extraction/refinement
Result: dramatic therapeutic success

### 8. Response Construction

Core answer: Insulin *did* work initially, but severely impure preparation caused allergic reactions. First trial January 11, 1922, failed due to crude extraction methods. Improved purification over 12 days, second trial January 23 successful.

Key phrases to emphasize:
- "Didn't work immediately" → caused severe reactions
- "Technical purification problem" → not therapeutic failure  
- "Impure extract" → contaminant allergies
- "12-day improvement cycle" → rapid refinement success

NB: Critical distinction between immediate failure vs. failure due to technical limitations.

### Answer###
L'insuline n'a pas "marché tout de suite" lors du premier essai clinique pour une raison technique majeure : l'extrait utilisé était trop impur.

Le 11 janvier 1922, Leonard Thompson, un garçon de 14 ans diabétique qui était en train de mourir à l'hôpital général de Toronto, a reçu l'injection du premier échantillon d'insuline. Cependant, cet extrait était si peu pur que Thompson a eu une réaction allergique sévère. Cette impureté était telle que les injections suivantes ont dû être annulées.

Le problème résidait dans le fait que les chercheurs n'avaient pas encore maîtrisé la purification de l'insuline. L'extrait était contaminé par des impuretés qui provoquaient ces réactions allergiques chez les patients.

Heureusement, l'amélioration de la purification a permis des résultats spectaculaires : après 12 jours de travail intensif pour purifier l'extrait, une deuxième dose a été injectée le 23 janvier. Cette fois, l'insuline éliminait complètement la glycosurie caractéristique du diabète sans causer aucun effet secondaire visible.

Le processus de purification s'est considérablement amélioré grâce au travail du chimiste James Collip et, plus tard, grâce à la découverte de la précipitation isoélectrique par George B. Walden chez Eli Lilly en novembre 1922. Cette amélioration technique a rendu l'insuline utilisable et disponible pour le traitement général du diabète.