Centenary of Insulin Discovery (1921-2021): Nicolae Paulescu’s Original Contributions

Abstract

Nicolae Paulescu (1869-1930) was born in Bucharest in an aristocratic family. His education from childhood to maturity (Paris University of Medicine) was marked by illustrious professors, even pioneers of their field. After completing his medical and scientific education in Paris under his mentor, Etienne Lancereaux, considered the founder of modern physiology, he returned to Romania where he founded the first Department of Physiology at “Carol Davila” University of Medicine and Pharmacy.

His scientific career is marked by the publishing of 88 original research articles in renown international medical journals of the time and two Treatise on Physiology (comprising in total 8 volumes and 5976 pages).

His activity as an endocrinologist reaches the peak with the discovery of insulin with the article Recherche sur le rôle du pancréas dans l’assimilation nutritive published in the Archives Internationales de Physiologie (Liege, Belgium) on August 31^st, 1921.

While he was not internationally or even nationally acclaimed for the discovery of insulin, his contribution to the reformation of the national education and medical system and the recommendation of his students to pioneers of their fields of interest still have reverberations even today.

Introduction

The outlook on diabetes mellitus throughout history

Although insulin was discovered only in 1921, diabetes was known as a disease since antiquity. The Egyptians were the first ones who described polyuria as a common symptom in Ebers papyrus from 1500 BC. This papyrus was found and sold to George Ebers, a German Egyptologist, only in 1872. Susruta of India was the one who described the clinical diagnosis of diabetes around 1000 years later after mentioning polyuria (1).

The symptoms of diabetes were described by the Greeks Aretaeus, Celsus, and Galen. In 164 B.C. Galen formulated the wrong conclusion that diabetes is a disease of the kidney. Arateus of Cappadocia gave the name of the disease, which means “siphon” in Greek (1).

One of the main characteristics of diabetes was the sweet taste of the patient’s urine, but the cause was unknown. The literature shows that outside of Europe, diabetes was diagnosed until the 11th century by tasting the urine of the patient. Also, the Indians observed that the ants were attracted to the patient’s urine. Considering the sweet taste, the disease became “diabetus mellitus”. The term “mellitus” represents the Latin word for honey (2).

The history of modern diabetology can be divided in four distinct periods (3):

1. The first period, “the physiological period” is embodied by the distinguished personality of Claude Bernard (1813-1878) represents the period when the physiological mechanisms that govern the intermediary metabolisms (especially the glucose metabolism) were discovered.

2. The second period is represented by the discovery of the relationship between diabetes and the pancreas. The medical literature marks the first step towards this discovery as the description of the pancreatic islets composed of different acinar tissue cells by Paul Langerhans (1847-1888). Because he did not make any remark on the possible relationship between these cells and diabetes, placing him in this period is mostly artificial.

The most important contribution towards this discovery is represented by introduction of the notion of “pancreatic diabetes” by Étienne Lancereaux (1829-1910) and later, demonstrated by Mering and Minkovski in 1889.

3. The third period is represented by the discovery of insulin. Through a series of significant experiments, published 1 year before Banting and Best in a treatise of physiology and in two international journals, Nicolae Paulescu (1869-1930) discovered the presence of a endocrine pancreatic secretion and isolated it. He considered it “the key to treating diabetes”. Originally, he named it “pancreine”.

4. The fourth period is represented by the clinical application of the pancreatic extract, containing the antidiabetic hormone, insulin, purified by James Collip (1892-1965) in the University of Toronto, and the first clinical use by Frederick Banting (1891-1941) under John Macleod’s (1876-1935) supervision and with the help of Charles Best (1899-1978).

Today, 100 years later, we are still in this period, and it will not be overpassed until the complete cure of the diabetic syndrome.

Nicolae Paulescu: from a prodigious child to a refined doctor, scientist and professor

Motto: “He lived like a martyr and died like a saint” – Nicolae Iorga (1871-1940)

The illustrious Romanian scientist, doctor and professor, Nicolae Paulescu was born on October 30th, 1869, in the Romanian capital, Bucharest. His family was well known in their community and benefited from an aristocratic status. His father, Constantin Paulescu, a respected merchant in Bucharest represented the merchants’ guild in the Romanian Parliament in 1885. He instilled in his children the sense of responsibility, punctuality, and honor. Also, he passed on to his children his love for classical music, opera, and ballet, which he acquired while traveling through Vienna, Lipsca and Paris. His two daughters, Elena and Constanta were alumni of the Music Conservatory of Bucharest and while Nicolae Paulescu is better known for his medical career, his friends and family enjoyed his singing and piano and organ playing. He frequently sang operas composed by Gounod, Verdi, Massenet, Berlioz, or Puccini for the delight of guests or hosts alike (4).

Figure 1.

Nicolae Paulescu`s childhood home and family carriage

His mother, Maria Dancovici, was a well-educated woman who originated from another well-known merchant family – her uncle, Vasile Dancovici, was one of the leaders of the very consequential 1848 Romanian Revolt. She was raised in the patriotic tradition of her family and followed the Christian Orthodox values: kindness, gracefulness, and above all else love for people (5).

During childhood, Nicolae Paulescu was characterized by his teachers and family as “docile and obedient, with a frail constitution, delicate and gentle, with a special inclination for meditation, at the same time proving a very special capacity of memorization, analysis and synthesis.” He graduated from primary school first prize with laurels “for his diligence in music and good conduit” (4,5).

The high school years represented the foundation of his development into sciences for two reasons:

1. During this time, he amassed an impressive general culture by learning French, Greek and Latin. This subsequently allowed him to read the classical philosophy work in original.

2. His biology teacher, Dumitru Ananescu, instilled him the love for medical sciences with his superb mixture of theoretical and practical demonstrations. Throughout the years, Paulescu constantly mentioned his teacher’s contributions to his education.

After graduating from high school in 1888, he is accepted to the renown Paris University of Medicine. This was the place where he truly flourished. Here, he had the tremendous opportunity to study medicine with some of the most well-known medical personalities of the time: anatomy with Louis Farabeuf (1841-1910), histology with Masthias Duval (1844-1907), organic chemistry with Armand Gautier (1825-1894). Still, the one that made the longest lasting impact on Nicolae Paulescu was Etienne Lanceraux (1829-1910), his anatomopathology professor (4,5).

After graduating from the Paris University of Medicine in 1891, he becomes an extern at Hotel Dieu Hospital (through national exam) and continues his collaboration with his mentor, Prof. Etienne Lancereaux. Here, he cultivated a personality-forming relationship with his mentor, who taught him the importance of discipline and a meticulous approach towards the medical and scientific activities. At the end of his two years as extern (1893), he already managed to impress his mentor and formed a great connection with him. Out of appreciation for his entire work, Prof. Lancereaux made the necessary steps to transfer him in his service at Notre Dame de Perpetuel Secours Hospital, where he was chief of medicine, and in 1897, when Paulescu obtained his doctorate degree he names him deputy chief of medicine (4,5).

The following years, until his return to Romania, were marked by three major activities that will refine his personality and his scientific methods:

1. His activity as a doctor at Notre Dame de Perpetuel Secours Hospital was exceptionally fruitful. He managed to impress his fellow colleagues and the hospital administration with his thousands of carefully categorized patient’s charts, numerous precisely prepared biopsy samples and endless hours spent in the hospital’s lab.

2. The perfection of his scientific training was fundamental for all his future medical research.

- Towards this endeavour, he obtained his diploma for superior studies in Biological Chemistry (1897) and General Physiology (1898).

Figure 2.

The medical staff of Hotel Dieu Hospital, 1892 (Nicolae Paulescu marked with the X; bottom center his mentor Etienne Lancereaux. Courtesy of the Nicolae Paulescu Museum.

- Even more so, in 1897 he obtained the title of doctor in medicine and surgery with the thesis “Research on the structure of the spleen” in which he describes the vascularization of the spleen and creates the first classification of epithelial glands.

- In 1899 he obtains the title of doctor in natural sciences from the Paris Faculty of Sciences with the thesis a) “Experimental research on the respiratory and cardiac rhythm under the influence of diverse body positions” and b) “The causes and the mechanism of sudden death consecutive to changing the body position from a horizontal to a vertical attitude”. This thesis represents one of the first researches on the phenomenon of sudden death.

- In 1901 he obtains the title of doctor in medicine from Paris Sorbonne University with the thesis “Comparative study of the action of alkaline chlorides on living matter”, offering valuable information regarding the behavior of living matter.

3. The scientific medical research represented a constant interest. While in Paris, he managed to publish 42 papers in only three years of activity in well-known international journals such as: Journal de Medecine Interne, Archives de Physiologye, Bulletin de L’Académie de Médecine, Bulletins et mémoires de la Société de chirurgie de Paris, Compte Rendus de l’Académie des Sciences.

In 1900, motivated by his patriotic, religious principles and homesickness, he returns to Romania wishing to take an active role as a leader in the national reformation of the education, medical and research systems. He left behind a long-lasting impression on his French peers, so much so, that he granted the rank of Officer of the French Academy and the Order of Academic Palms. Even more impressive is the fact that Notre Dame de Perpetuel Secours Hospital will offer yearly for 40 years two intern positions to Romanian students recommended directly by Nicolae Paulescu. This situation will continue even after his death, and it will become a respectable tradition between France and Romania. Unfortunately, it will end at in 1940 due to the difficult conditions of World War II.

Once returned to his home country, Paulescu focused all his efforts on establishing the first Physiology Department at “Carol Davila” University of Medicine and Pharmacy in Bucharest. This was not only a local, but a national première. He left Romania only for very short periods at a time, in 1901 to defend his third and last doctoral thesis in Paris and 2 weeks per year until 1906 to collaborate with his mentor, Lancereaux. It is worth mentioning that while he worked on this project, he was offered the position of Professor at the Faculty of Medicine in Fribourg (Switzerland) and in Paris after his mentor’s retirement. Each time, he declined the offer and delved deeper into his project of establishing a Physiology Department in its own right.

For 31 more years, until his death, he continued his work with the same energy, enthusiasm and meticulosity as when he was in Paris. His activity can be divided in 3 parts:

As a University Professor, he was renown for his fascinating courses and for his justness. While he was considered harsh by some students, he was definitely considered just by all, for his impartial attitude during examinations.

He co-authored three of the five Treatise on Medicine with his mentor, Lancereaux:

- Vol. I, Nosology, 1903 – 940 pages;

- Vol. II, The Nervous Apparatus and the Cutaneous Apparatus, 1906 – 1052 pages;

- Vol. III, The Respiratory Apparatus and the Digestive Apparatus, 1912 – 1200 pages

He published the fourth volume by himself after the death of Prof. Lancereaux: Assimilating Apparatus and Urinary and Genital Apparatus, 1928 -674 pages. The final volume remained in the manuscript stage, never to reach the printing press: Sanguino-lymphatic system and the locomotor system.

From 1919 until 1921 he published the three volumes of his Treatise on Physiology: Vol. I in 1919 (448 pages); Vol. II in 1920 (732 pages); Vol. III in 1921 (930 pages).

It is worth mentioning that his Treatise on Physiology containing in total 2110 pages was handwritten and afterwards published using the lithography method. Thanks to this, we can still see his handwriting even today (Fig. 3).

Figure 3.

Lithographed page 646 describing the function of the pancreas in the book: Nicolae Paulescu, Physiology Course, Faculty of Medicine, Bucharest, 1919. Courtesy of the “Carol Davila” University of Medicine and Pharmacy Library.

Another field of interest is the reformation and reorganization of the Romanian medical education system. After the Great Union, in 1918 when Romania was officially and entirely reunited a profound reform was necessary. At the time, the country had only 3 university centers: Bucharest, Iasi and Cluj-Napoca. He fights for a better quality of life for the students and prioritizes the practical aspect of medicine over theory (4,5).

As a scientist, he is the author of 46 experimental and clinical studies published in renown international journals of the time: Comptes Rendu de la Societe de Biologie , Archives Internationales de Physiologye-Liege, Bulletin de l’Academie de Medicine, etc.

Three of his experimental studies are consequential even today: the discovery of the role of the hypophysis (proving that its absence leads to death), the transparietal approach for hypophysis ablation (still in use today in neurosurgery) and the discovery of insulin (or as he called it, pancreine).

Research into pancreatic secretions and the discovery of insulin – or as he originally named it, pancreine.

His activity as an endocrinologist reaches the peak with the discovery of insulin. His first incursion into this field is made in 1899 when he began working with Prof. Dartre “to isolate and study the active product of the internal secretion of the pancreas”. This paper was not finished, nor published due to Paulescu’s return to Romania (4,5).

The next step is marked by the isolation of a “watery pancreatic extract“ in 1916. This extract when injected in a diabetic dog (through pancreatectomy) led immediately to the “temporary disappearance of the symptoms of diabetes, the lowering of hyperglycemia and the suppression of glycosuria” (4,5).

Between April 24^th and June 23^rd 1921, Paulescu presents at the Paris Society of Biology Congress his 4 experimental studies:

- The action of the pancreatic extract injected in the blood of a diabetic animal (6)

- The influence of the amount of time passed since the intravenous injection of the pancreatic extract on a diabetic animal (7)

- The influence of the quantity of pancreas used in the preparation of the extract injected in the blood of a diabetic animal (8);

- The action of the pancreatic extract injected in the blood of a normal animal (9).

On June 22^nd, 1921, he sends the article Recherche sur le rôle du pancréas dans l’assimilation nutritive to the Archives Internationales de Physiologie (Liege, Belgium), which will be published in August 31^st, 1921. In this comprehensive 26-page article he presented for the first time the effect of the pancreatic extract on glycemia, glycosuria, acetonemia and acetonuria. In other words, the insulin (pancreine) was discovered (10).

His discovery was not recognized and celebrated by his peers. The news that the Nobel Prize was awarded to the Canadian team further aggravated his underlying pathology (since the First World War he began having episodes of hematuria). Unfortunately, this situation radicalized his sociopolitical views in the context of his time (the advent of national socialism), publishing some extremely radical articles and books. This radicalization would prove to be new opportunities for his rivals to exploit in discrediting his scientific contributions. He died in full academic maturity and creative activity at the age of 62 on July 27^th, 1931 (4,5).

Legacy

Besides his important scientific contributions to multiple medical fields he left behind the first Physiology Department in all Romanian Medical Universities. His way of organizing courses and hands-on laboratory courses are still in practice today.

A less known legacy derives from his studies of the hypophysis. His publishing of the first successful surgical approach of the hypophysis traveled the entire globe and reached Harvey Cushing (1869-1939) in Boston, USA, the “father of neurosurgery”. Because he could not honor Cushing’s invitation to his world-first neurosurgical department at Peter Bent Birgham Hospital, he sent Dumitru Bagdasar (1893-1946), a young doctor who proved his interest in this emerging field to his Professor, Nicolae Paulescu. This fateful event proved to be truly consequential in the sense that upon his return to Romania, Dumitru Bagdasar became the founder of Romanian neurosurgery in Bucharest (5).

The university where he worked for half of his life, “Carol Davila” University of Medicine and Pharmacy, still honors him today. Here, the museum keeps all his original belongings, including his (still functioning) typewriter (Fig. 4). Also, the Physiology Department is named after him.

Figure 4.

Nicolae Paulescu`s original office preserved in the Nicolae Paulescu Museum at “Carol Davila” University of Medicine and Pharmacy.

While he was not internationally or even nationally acclaimed, his contribution to the reformation of the national education and medical system and the recommendation of his students to pioneers of their fields of interest still have reverberations even today.

Conflict of interest

The authors declare that they have no conflict of interest.

Acknowledgements

Special thanks to Ms. Monica Mocanu, director of the “Carol Davila” University of Medicine and Pharmacy Library and custodian of Nicolae Paulescu Museum at “Carol Davila” University of Medicine and Pharmacy for offering the support necessary in writing the article. All images are obtained with permission from the Nicolae Paulescu Museum and the books referenced in the text are available in “Carol Davila” University of Medicine and Pharmacy Library.