I[NTRODUCTION]{.smallcaps} {#sec1-1}
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William Osler (1849-1919), considered one of the founders of Modern Medicine, and the most renowned English-speaking physician of his days, was a Canada-born physician, educator, medical historian, and also the highest prankster \[[Figure 1](#F1){ref-type="fig"}\].\[[@ref1][@ref2]\] The American Harvey Williams Cushing (1869-1939), was the world\'s first fruitful brain surgeon, and he was also pathologist, writer and draftsman, besides an addicted to work \[[Figure 2](#F2){ref-type="fig"}\].\[[@ref3][@ref4][@ref5][@ref6][@ref7]\] Their key career link was the development of neurosurgery.

![William Osler (1849-1919) holding open a copy of Vesalius Tabulae Anatomicae, in the Bodleian Library, reprinted from Cushing, 1919.\[[@ref2]\] William Osler (1849-1919) is mainly remembered for the "Oslerian Tradition" of patient-centered medical education, life-long learning, humanism, and personal generosity. Osler was also remembered as a lover of books and journals, and he became a collector of rare medical books, an avocation adopted by Cushing](AIAN-22-384-g001){#F1}

![Harvey Williams Cushing\'s (1869-1939) colossal struggle in the coming of age in the neurosurgery. He improved fundamental surgical techniques through careful neurological examination, and advancing understanding of neuropathology (Reproduced with the permission of the Neurological Museum -- Institute of Neurology/Federal University of Rio de Janeiro, Brazil)](AIAN-22-384-g002){#F2}

Many happenstances tie these two singular beings, and this is a good occasion to consider them: 2019 is the death centennial for Osler and marks 150 years since Cushing\'s birth.

A first outlook: Osler\'s and Cushings\'s life and career stages {#sec2-1}
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Osler was born on Bond Head, Canada, July 12, 1849, but raised on Dundas -- both in the nowadays Ontario Province, Canada. Osler\'s father, Featherstone Osler, officially retired from the British Navy and immigrated to Canada in 1837 with his bride. He became a "saddle-bag minister" in rural Upper Canada where William was born. William Osler was the eighth of the couple\'s nine children. In the beginning, Osler would want to trail his father\'s footsteps into the ministry, but he changed his mind and followed medicine, first at Toronto School of Medicine, but achieving his MD degree from McGill University, in 1872. The subsequent year was spent in Berlin under the instruction of the renowned pathologist Rudolf Virchow.\[[@ref8]\] Osler was appointed to faculty at McGill in 1874. In 1884, he left Montreal for Philadelphia, where he was appointed clinical medicine professor of at the Pennsylvania University. After 4 years, in 1888, he moved to Baltimore and became one of the "Big Four" physician founders of the newly planned Johns Hopkins Hospital, at the side of William Stewart Halsted (surgery), William Henry Welch (pathologist), and Howard Kelly (gynecologist).\[[@ref9]\] In 1904, Osler was offered the regius professorship of medicine at Oxford University, where he stayed until his death. He married, in 1892, Grace Revere (1854-1928), and they had two sons.

Regarding Cushing, he grew in a family already in the third generation of physicians.\[[@ref5][@ref6]\] His hometown was Cleveland, where he born on April 8, 1869, but he earned a Bachelor of Arts degree from Yale University, in 1891, and MD from Harvard Medical School, in 1895. Thereafter, he studied for four years at Johns Hopkins Hospital under the mentorship of the surgeon William Stewart Halsted, one of Osler\'s "Big Four" founding contemporaries at the Baltimorean hospital. In 1900, the growing great neurosurgeon leaves for Europe and expended 14 months overseas with Victor Horsley, a surgeon at University College Hospital/London; Theodor Kocher, Professor of Surgery at the University of Berne; Hugo Kronecker, an experimental physiologist at Berne; and subsequently, with Charles Scott Sherrington, at Liverpool in the chair of Physiology.\[[@ref5][@ref6]\] He then came to Johns Hopkins again as a surgeon, from 1902 to 1912, and then he was surgeon-in-chief at the Peter Bent Brigham Hospital, and professor of surgery at the Harvard Medical School, in Boston.\[[@ref5][@ref6]\] His final nomination came, in 1933, at Yale University. Cushing married Katharine Stone Crowell (1870--1949), in 1902, and they had five children.

Intersection: Associated life and career of the two medicine giants {#sec2-2}
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A common turning point in the career of Osler and Cushing happened at Johns Hopkins Hospital where both worked, the first from 1888 to 1904, and Cushing, 1896-1912. Osler was Cushing\'s senior and became his valued and beloved mentor, which continued until Osler\'s death. However, they apparently had not come to be on close terms until the summer of 1900, in Europe.\[[@ref4]\]

At the time, Osler was already a legend, combining high clinical standards with a friendly personality and a broad interest in history and culture, and good living -- a contrast with Cushing\'s tight focus on his work, surgery, but they came together on the history of medicine, under the Osler\'s influence.\[[@ref3][@ref4]\]

Osler emphasized the need for physicians expressly trained in the anatomical, physiological, clinical and surgical aspects of the neurological disorders,\[[@ref10]\] and Cushing was an emblematic herald of this purpose. In this way, Cushing became the first great American product of the vision held mainly by Osler and Halstead at Johns Hopkins, for USA to become a Mecca for medicine, with Cushing attracting worldwide neurosurgery attention.\[[@ref3]\]

In spite of being a general physician, Osler was often considered Canada\'s first neurologist, because about one-third of his prolific writing was dedicated to neurology.\[[@ref11]\] This could already be inferred from his famous general medical textbook, "The Principles and Practice of Medicine: Designed for the Use of Practitioners and Students of Medicine": more than 20% of the content of the first edition was devoted to neurology.\[[@ref12]\]

During his continuing career in Philadelphia and Baltimore, Osler published widely on problems in clinical neurology, including monographs on cerebral palsies and chorea, as well as chapters on disorders of the nervous system, in the first five editions of his popular textbook.\[[@ref10]\] Ultimately, almost 200 of his approximately 1400 papers, monographs, and notes were concerned with neurological disorders, the details often derived from autopsies he had personally performed, as quoted by Ebers.\[[@ref13]\]

Indeed, as referred to by Ebers,\[[@ref13]\] Osler\'s interests in the neurosciences began early, because already in 1884, he wrote on the comparative anatomy of the brain of the seal, having given a speech on "the brain as a thinking organ" in the preceding year. Besides, he was considered by some to be "Canada\'s foremost pathologist of the 19^th^ century", as quoted by Del Bigio *et al.*\[[@ref8]\] During the 10 years of his stay at McGill University (1874-1884), Osler accomplished almost 1000 autopsies, with increasing concern in localization of brain functions, and also psychopathology.\[[@ref8]\] Osler\'s actions in autopsy persisted after his move to Philadelphia in 1884, but in Johns Hopkins, while he preserved his interest for the importance of the practice, he was only a spectator.\[[@ref14]\]

Regarding psychopathology, he inspected the brains of criminals, on occasion sending assistants to attend executions and accomplish brain removals onsite. His histopathological reports covered the topics of cerebral aneurysm, apoplectic hemorrhage, vascular infarction, subdural hematoma, meningitis, multiple sclerosis, cerebral abscess, and brain tumor. He wrote about cerebral localization and anatomy and the relationships between the morphological characteristics of the brain and intelligence and criminality. Osler also had close association with clinical neurologists such as Jean-Martin Charcot, William Gowers, Silas Weir Mitchell and Pierre Marie, and the famous surgeon, Victor Horsley.\[[@ref13]\]

Many histological methods were used by Osler who became acquainted with them during visits to the laboratories of exceptional European neuropathologists.\[[@ref8]\]

Osler emphasized the necessity for specialist neurological surgeons, as quoted by Feindel.\[[@ref10]\] Osler\'s intellectual contributions to, and inspirational attitudes about, the neurosciences had a weighty effect on the development of the profession of neurosurgery. This was potentiated by his friendship with Victor Horsley (1857-1916), a British pioneer of neurological surgery, and also by Cushing. Likewise, Wilder Penfield, while on a Rhodes scholarship, encountered Osler in Oxford in 1915, and his first autopsy was under Osler\'s guidance. In this way, the great first neurosurgery masters of USA and Canada, came under Osler\'s auspices.\[[@ref8]\]

Besides Osler\'s bias for neurology, he was also a great educator and humanist, as emphasized by Pandya.\[[@ref15]\] Indeed, Osler played a key role in converting the organization and curriculum of medical education, highlighting the position of clinical experience, critical appraisal of the evidence from research in medicine, and the patient as the focus of attention of the care. In this way, he is placed at the roots of what is called today Evidence-Based Medicine.\[[@ref16]\]

Although several disorders, signs or maneuvers were named after him, Osler is not remembered for his great scientific discoveries, in comparison to Cushing who moved from the general surgery to peripheral-nerve surgery, with successful attempts at surgically treating trigeminal neuralgia, then onward toward the center of the brain. It is interesting that Halsted felt that no talented young surgeon should throw his life away on such a discouraging field as neurosurgery, but Cushing found a way.\[[@ref5][@ref17]\]

Indeed, Cushing constructed with great energy many of the operating procedures and techniques that even today are basic to the surgery of the brain, and his work significantly reduced the high mortality rates that had previously been linked with brain surgery. In this way, he became the leading expert in the diagnosis and treatment of intracranial tumors, with particular interest in the meningiomas and pituitary basophilic tumors, and he was able to work from just signs and symptoms to identify and locate as many tumors as he did.\[[@ref4][@ref5][@ref18]\]

Cushing advanced operative techniques, but he did not take advantage of new technology for diagnosis in some critical instances. As a medical resident, he used the newly discovered technology of X-rays. However, he was slow to adopt Walter Dandy\'s ventriculography/pneumoencephalography procedure. Indeed, Cushing was reluctant to adopt it, because he felt that this new diagnostic tool would dissuade neurosurgeons from becoming appropriately skilled as neurologists, and from doing their own neurological evaluation.\[[@ref4]\]

Cushing made several technical contributions, many regarding the improvement of neurosurgery as presented by Bhattacharyya\[[@ref7]\] in his paper. At the [Table 1](#T1){ref-type="table"}, it is presented many of Cushing\'s books.

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Cushing's book in several areas: from medicine to history of medicine

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  In 1912, Cushing published "The Pituitary Body and its Disorders", and this research gained high reputation. He recorded 50 cases (on most of which he had himself operated) and gave remarkably full case histories.\[[@ref5]\] Cushing first defined the symptom complex of obesity, diabetes, hirsutism, and adrenal hyperplasia, but it was only in his publication of 1932 that he properly credited these features to basophilic pituitary adenoma.^\[[@ref4][@ref19]\]^ However, the first typical report of a patient with Cushing's syndrome was perhaps made by William Osler, in 1898, but Osler inappropriately attributed the features to myxedema.\[[@ref20]\]

  In 1936, Cushing published his book "From a surgeon's journal 1915-1918 about his experiences in World War I", and he understood that "the lessons learned had significance both for medicine and for the nation", as mentioned by Fulton.\[[@ref4]\] Cushing went to France twice at this time to oversee a surgical unit, and to operate mainly head wounds. The first stay was in 1915, when Cushing lead a Harvard unit for a 3-month period, and he returned in 1917, staying until the end of the war.

  In 1932, it was launched Cushing's influential book, "Intracranial Tumours. Notes upon a series of two thousand verified cases with surgical-mortality percentages pertaining thereto".\[[@ref4]\]\
  Besides, Cushing wrote plentiful technical works and even he was awarded with the Pulitzer Prize (1926) for his biography, "Life of Sir William Osler", in 1925, but the book about Andreas Vesalius was issued after his death, in 1943.
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Cushing was an outstanding illustrator, leaving a large collection of drawings.\[[@ref4]\] Indeed, he made sketches of the whole thing, counting patients, because he always believed that it would at all times tell more than the written word.\[[@ref5]\]

Cushing was also a great collector of books, and his large and respected collection, mainly on the history of medicine, was to convert the basis for the Historical Library at Yale. This was taken over by John Fulton, a Harvard physiologist, after Cushing\'s death. Fulton fell in love with the Osler\'s charisma and became the last adopted son of a medical father he never actually met, as mentioned by Bliss.\[[@ref3]\]

Cushing\'s attitudes were different from Osler\'s, but he tried to trail Osler\'s joyful way of life, even to accepting a severe Osler\'s criticism. Fulton\[[@ref5]\] reproduced a letter about this (1902), where Osler criticizes the Cushing\'s rude way of dealing with the students and members of the staff. However, to the contrary, his patients discerned another, more humane Cushing, besides, above all, Cushing was self-critical and he would regret for days after a patient died.\[[@ref4]\]

Anyway, these two human beings were attached with so many links, but many are the strongest such as Johns Hopkins Hospital, the first main tie, besides neurosurgery, old books, but mainly affection and mutual respect \[[Figure 3](#F3){ref-type="fig"}\].

![Important ties between Cushing and Osler: Johns Hopkins Hospital, Old historical books-Vesalius/Neurology and friendship](AIAN-22-384-g003){#F3}

Farewell stages: The spectrum end of extraordinary lives {#sec2-3}
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Cushing gives an account of his saddest experience of World War I when he described the death of Osler\'s only child Revere who was mortally wounded in action September 2, 1917, in the Ypres salient. While two surgeons operated on Revere\'s abdominal wound, Cushing stayed at his side, keeping track of his pulse until he died.\[[@ref1][@ref3][@ref4]\] Duffy\[[@ref21]\] remarks that the death of Osler\'s son was only tolerable to the father, because Cushing had given Revere the gift of a peaceful death. This moment was the supreme sample of the link of these two noble men that tied personal, professional, and domestic lives, besides a shared passion for reading and collecting rare books.

Cushing recognized that Osler never fully recovered after his son\'s death, suffering much from insomnia and becoming an easy victim to bronchial infection. Osler died 2 years after his son\'s death, in December 1919, of lung abscess and empyema which were complications of pneumonia, and the initial event may have been influenza of the great pandemic. However, for many years, he had experienced frequent severe chest infections suggesting underlying bronchiectasis. His post-mortem examination, performed in his home by his colleague George Gibson, makes clear that he had localized bronchiectasis with multiple abscesses in the right lower lobe and an overlying empyema. However, Gibson could not find the source of the hemorrhage that had been the immediate cause of Osler\'s death.\[[@ref1]\]

Osler had directed that his brain go to the Wistar Institute in Philadelphia where only the brain gross appearance was reported, but in 1959, Wilder Penfield had Osler\'s brain sent to Montréal, where a complete examination was accomplished by Gordon Mathieson; nothing extraordinary was found.\[[@ref7]\]

For Cushing\'s last 20 years, his life was not healthy. Since the end of the World War I, he had respiratory troubles and developed bad circulation in both lower extremities.\[[@ref5]\] Tobacco consumption was a key factor for his health, and he could not give it up. In 1918, he had a probable bout of Guillain Barré syndrome. In spite of these problems, from 1920 to 1932, he developed a formidable neurosurgical clinic.\[[@ref5]\] At his end, on the evening of October 3, 1939, after shifting a heavy Vesalius folio, he had an attack of substernal pain. Cushing died of myocardial infarction, on October 7, 1939, in New Haven, Connecticut. His autopsy showed a posterior coronary occlusion, complete occlusion of the femoral artery on both sides, and a 1-cm colloid cyst of the third ventricle. His brain showed no sign of atrophy, but the arteries were patchily sclerosed.\[[@ref4]\]

Concluding what has already been said, the intense lives of Cushing and Osler were connected, and at the end, Cushing gave brilliant tribute for his master by accepting the invitation of his widow to produce Osler\'s biography (1925) that merited a Pulitzer Prize (1926).

Financial support and sponsorship {#sec2-4}
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Nil.

Conflicts of interest {#sec2-5}
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There are no conflicts of interest.

I would like to express my deep gratitude to Professor Brian Haynes for his generous, valuable and constructive suggestions during the writing phase of this manuscript.
